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Special challenges related to persecution and imprisonment for Woman in Syria – aspects of neglected problems in the support of survivors

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DOI: 10.31038/AWHC.2020313

Abstract

Women are at present experiencing unique challenges in the war in Syria and in neighbouring countries with autocratic regimes, especially in two areas so far at least partly neglected in research and humanitarian interventions. Prisons especially in Syria and Iran are not only a risk factor for the present spread of the present Covid-19 pandemic, but have exposed women to torture, sexual violence, forced disappearances, and other traumatic events, that are further aggravated by factors such as separation, and impact on the family. Perpetrators usually go unpunished. In our paper, we discuss problems and health implication, the context of international human rights and humanitarian standards, and measures to address redress and rehabilitation based on women survivors initiatives qualitative research we had conducted in several countries.

Keywords

human rights, gender, torture, war, forensic medicine, torture, rehabilitation

Imprisonment

Women who are imprisoned because of actual crimes, false allegations or as in Syria and Iran frequently due to political abuse of the legal or prison system, are in an especially vulnerable situation. This is in spite of the fact, that the international community, specifically the UN, has created a framework of special guidelines to protect women. These guidelines are safeguarding women’s humanitarian and human rights during this critical times [1, 2], independent from the reason for their imprisonment. These special rules are in the latest version called the “Bangkok” rules (named after the place where they had been drafted during an international expert meeting). They should be seen as a framework for conditions in all places of detention of women and their accompanying children, in addition to the more general “Minimum Standard Rules for the Treatment of Prisoners” (in the latest, revised version called also the “Mandela rules”). The Bangkok rules include specific provisions for the psychological, physical and medical needs of women such as those related to menstruation, protection against sexual violence, and others, and do not replace but extend the provisions of important further standards such as the Mandela rules or the UN Convention against Torture. Compliance with these rules is supervised by international bodies and organizations, such as the International Committee of the Red Cross, the UN Committee against Torture and the UN Special Rapporteur on Torture. Local NGO networks [1] in Syria have reported seven thousand women detainees, including 435 children, that are detained after arrest or kidnapping. They give also an estimate of about 8 thousand prison survivors with children under 10 years.

Torture is of course the probably most serious human rights offense, and is unfortunately highly common in prisons in many countries such as Syria [3] and Iran [4–6], in spite of an absolute prohibition of all forms of torture in all international standards (7). Torture is permitted under no circumstances whatever, even in national emergencies (such as war, “war on terror” or pandemics like Corona) and as such, the absolute prohibition of torture is a non “non-derogable” human right. Still, the reports of prison visits by the UN parties mentioned above and present scientific research have demonstrated that torture is frequently used [1], specifically to oppress women activists [8]. It frequently includes or is associated also with sexual violence [8], that has been demonstrated to have the most serious long-term psychological impact, in addition to additional physical sequels such as infections [9] or unwanted pregnancies that in turn again themselves lead to severe psychological suffering including increased suicide rates [10, 11]. Besides torture, witnessing atrocities including sexual abuse and torture, or the killing of other inmates, lack of access to health care with resulting chronic health problems, must be expected to contribute to both immediate and long-term physical and psychological suffering [7].

Psychological suffering is not only caused by these factors, but also by the indirect results such as awareness of the impact on the family, the inability to take care of one’s family members during imprisonment and the destruction of one’s professional career,- that is already difficult in many countries for women to maintain [8]. Survivors are also frequently stigmatized in their society and even in their families and in close relationships [7].

Medical doctors and other health care personnel in prisons are by their professional ethical standards obliged to recognize, document, report on and try to stop human rights violations such as torture or inhuman and degrading treatment, but are frequently unwilling or unable to do so [12,13]. This process is explained for example in a joint medical and legal standard by the United Nations, the Istanbul Protocol [14,15]. This task is obviously dangerous for health care professionals and is reportedly frequently neglected in Iran and Syria. In these countries doctors who dare to act are frequently persecute by the authorities [3, 12, 13, 16–19]. The present selective policy of releasing only non-political prisoners in a situation where the COVID 19 pandemic endangers especially prisoners under the adverse prison conditions in these countries must be seen as an aggravated form of persecution, especially as it affects especially political and women activists and imprisoned doctors as observed for example by Amnesty and by prominent Syrian human rights lawyer Anwar Al. Buni [1].

Survivors of human rights abuses but also their family members and communities and health care professionals who take care of them should keep in mind that psychological symptoms resulting from this long list of problems encountered by women in prison are in principal a normal reaction to an abnormal and abusive situation, and not a sign of weakness, stupidity or “madness” even if psychological symptoms in general are stigmatized in a society. The emotional and practical, unconditional support of survivors by their family members, partners and communities is therefore of crucial importance for the recovery of women prison survivors. Justice, redress and compensation, and the protection against future abuse are also important factors for psychological recovery (“therapeutic justice”), though in the face of the limited options of international bodies it might take a principal regime change to achieve this aims, that promoted by international organizations such as “Redress” in the UK.

In regard to psychological reactions, posttraumatic stress disorder (PTSD) related to specific events during imprisonment, such as torture, with intrusive memories, repeated nightmares, loss of normal sleep, anxiety, and avoidance of normal activities, is the most common specific reaction observed in many survivors [7, 11]. Depression [7] is also common, and both psychological reaction patterns can become illness with severe impact on the life of the survivor and indirectly also on other family members, which can mean that support might not be enough, but treatment by psychotherapy or for limited time by medication might be required. This would best be provided by specialized experts, in if possible multi-disciplinary treatment centers that have been set up in many countries. Chronic abuse of tranquilizers, pain medication, and, in some countries even alcohol or other drugs can be part of ill advised self help and are complications of the prison related reactive symptoms [7].

Further problems include chronic pain, especially in joints, as head-ache, or pain in the genital area, sexual problems especially after sexual violence or rape [6], and problems with blunt brain injuries after beatings, falls, or after having been pushed against walls and against objects [20–22].

Missing persons

The uncertain fate of those imprisoned and of other family members that frequently become “missing persons” forever, is an additional stress factor in this situation, also for those not imprisoned themselves that are “indirect victims”. Groups of persons listed as “missing” also of course include those abducted by both state actors as well as non-state actors, such as ISIS/DAESH, but also those killed in the war or (inter)national armed conflict.

Taking care of the surviving relatives of missing persons, mothers, wives, siblings and children, is a special challenge to be addressed especially in regions with a high number of missing persons such as Syria. Information on those who have been killed under torture, or died because of factors related to bad prison conditions, including COVID-19, by extra -legal executions, or also in war action, is frequently seen as an important supportive factor to provide psychological closure, and numerous forensic projects have been implemented to provide forensic evidence of persons killed, especially by the International Committee of the Red Cross. This is substantially supported by recent developments in DNA analysis [23] and new databases [24]. The special services of “naming the dead” of course also are a basis for accountability of perpetrators, and for the recovery of community history [25]. The identification of those killed and the circumstances of their deaths play an important role in transitional justice. This last process is often necessary to address and make public what has happened, and find a solution to offer justice to victims in the face of the often large numbers of perpetrators present in the aftermath of widespread human rights violations such as in Rwanda, Iran, or Syria.

In qualitative research we have conducted through focus groups with altogether 80 survivors in countries such as Peru and Uganda(26), three factors (categories) have been identified that surviving family members of those killed in prisons or massacres describe as helpful in psychological healing:

  1. confirmation, that it actually happened (which is important, as responsible governments or parties frequently deny that abuses ever happened, and in turn blame family members for false allegations of the government being responsible for disappearances),
  2. confirmation, that the action leading to the death was incorrect and not justified,
  3. Confirmation, that all steps will be taken, that it doesn’t happen again (which might include persecution of the perpetrators and an end to impunity).

International organizations such as the International Committee of the Red Cross (ICRC) have at least since the second world war developed strategies for the forensic identification of those missing persons killed, but also for those still alive, and recently have made use of the Internet and social networks to collect and distribute information on living survivors [1] bringing families and loved ones together again even in disorganised situations such as the war in Syria. While the identification of victims killed and discovered for example in mass the action leading to the death was incorrect and not justified in fact be an important factor in recovery and closure, psychological support should always be offered in addition to notification of victims identified on their manner of death. It must take into consideration that the process of mourning is usually a longer and complex one and re-confrontation with this type of information is not helpful in all steps of this process.

In general, mutual support and solidarity between direct and indirect survivors, is probably the most efficient supportive tool to be provided, as exemplified in the historical movement of the “mothers” (“madres de la plaza mayo”) (now grandmothers) in Argentine [27]. Similar organizations have now been set up by women prison survivors in Syria [2] to provide information, testimony and other forms of support in a critical situation. This has the benefit of reconfirming an active identity that does not depend on help received from third parties, well intentioned as it that might be. Further, new strategies such as “Universal Jurisdiction” have been developed, that provide for the option that criminal charges against perpetrators will be brought to third countries courts, for example in Europe, in a situation where a fair process, investigation or an international court cannot yet be implemented in a country where atrocities happened, as presently in Syria or Iran [28]. This process is intended to address the issues of impunity, redress, and serve the prevention of further abuses [29–31].

Conclusions

Imprisonment of women, especially of political activists and human rights defenders, should be closely monitored by independent bodies.

In cases where it constitutes part of political persecution, it should be stopped immediately especially in countries like Syria and Iran, where violations of human rights standards are common or even extreme.

Consistent support and protection for individuals but also survivor NGOs are a task also for the international community, especially in a situation where those imprisoned are suffering from sexual abuse and torture, and further are in prison endangered by selective exposure to COVID-19 pandemic. A comprehensive understanding of the problems and solutions as outlined in this article should in our opinion guide this process.

Acknowledgement

We are grateful to the Syrian Women’s International Initiative (Detained women’s) initiative for advice and information on the situation in Syrian prisons and to Nobel woman’s initiative for additional input.

References

  1. Sawasdipanich N, Puektes S, Wannasuntad S, Sriyaporn A, Chawmathagit C, Sintunava J, et al. (2018) Development of healthcare facility standards for Thai female inmates. Int J Prison Health. 14: : 163–74.
  2. Paynter MJ (2018) Policy and Legal Protection for Breastfeeding and Incarcerated Women in Canada. J Hum Lact 34: 276–81.
  3. Torture and ill treatment in Syria’s prisons. Lancet 388(10047): 842.
  4. Dehghan R (2018) The health impact of (sexual) torture amongst Afghan, Iranian anad Kurdish refugees: A literature review. Torture 28: 77–91.
  5. Busch J, Hansen SH, Hougen HP (2015) Geographical distribution of torture: An epidemiological study of torture reported by asylum applicants examined at the Department of Forensic Medicine, University of Copenhagen. Torture 25: 12–21.
  6. Mirzaei S, Hardi L, Wenzel T (2011) How to combat torture if perpetrators are supported by a religious “justification”. Torture 21: 173–7.
  7. Wenzel T (2007) Torture Curr Opin Psychiatry. 20: 491–6.
  8. Alsaba K, Kapilashrami A (2016) Understanding women’s experience of violence and the political economy of gender in conflict: the case of Syria. Reprod Health Matters 24: 5–17.
  9. Todrys KW, Amon JJ, Malembeka G, Clayton M (2011) Imprisoned and imperiled: access to HIV and TB prevention and treatment, and denial of human rights, in Zambian prisons. J Int AIDS Soc 14: 8.
  10. McColl H, Higson-Smith C, Gjerding S, Omar MH, Rahman BA, Hamed M, et al. (2010) Rehabilitation of torture survivors in five countries: common themes and challenges. Int J Ment Health Syst 4: 16.
  11. Wenzel T, Griengl H, Stompe T, Mirzaei S, Kieffer W (2000) Psychological disorders in survivors of torture: exhaustion, impairment and depression. Psychopathology 33: 292–6.
  12. Torture in Syria’s hospitals. Lancet 378(9803): 1606.
  13. Jones P (2019) Medical involvement in torture in Syria. Torture 29: 77–9.
  14. Robertson BW, Berger CE (2019) Interpreting Evidence of Torture. Med Law Rev 27: 687–95.
  15. R JH, Lin J, Modvig J, Nee J, Iacopino V (2019) The Istanbul Protocol: A global stakeholder survey on past experiences, current practices and additional norm setting. Torture 29: 70–84.
  16. Iran denies medical care to quell dissent (2012) Lancet. 379(9827): 1691–2.
  17. Ronaghy (1986) Persecution of doctors in Iran. Lancet 2(8505): 518.
  18. Nightingale EO, Stover E, Flockhart DA, Goering C (1984) Support urged for Syrian doctors. N Engl J Med 310: 803–4.
  19. Hampton T (2013) Health care under attack in Syrian conflict. JAMA 310: 465–6.
  20. Keatley E, d‘Alfonso A, Abeare C, Keller A, Bertelsen NS (2015) Health Outcomes of Traumatic Brain Injury Among Refugee Survivors of Torture. J Head Trauma Rehabil 30: E1–8.
  21. Mollica RF, Chernoff MC, Megan Berthold S, Lavelle J, Lyoo IK, Renshaw P (2014) The mental health sequelae of traumatic head injury in South Vietnamese ex-political detainees who survived torture. Compr Psychiatry 55: 1626–38.
  22. Keatley E, Ashman T, Im B, Rasmussen A (2013) Self-reported head injury among refugee survivors of torture. J Head Trauma Rehabil 28: E8-E13.
  23. Turingan RS, Brown J, Kaplun L, Smith J, Watson J, Boyd DA, et al. (2019) Identification of human remains using Rapid DNA analysis. Int J Legal Med.
  24. Hofmeister U, Martin SS, Villalobos C, Padilla J, Finegan O (2017) The ICRC AM/PM Database: Challenges in forensic data management in the humanitarian sphere. Forensic Sci Int 279: 1–7.
  25. Ubelaker DH, Shamlou A, Kunkle AE (2019) Forensic anthropology in the global investigation of humanitarian and human rights abuse: Perspective from the published record. Sci Justice 59: 203–9.
  26. Wenzel Tea (2020) Tools in transitional justice in human rights violations In: Wenzel T, Alksiri, R., editor. Women, safety and health in Asia. Cambridge Scholars Press: Newcastle
  27. MGB (2002) Revolutionizing Motherhood: The Mothers of the Plaza de Mayo. London: Rowman & Littlefield Publisher
  28. Wenzel T, Alksiri, R (2020) Folter und Menschenrechte im interdisziplinären Rahmen. In: Six-Hohenbalken M, editor. Vulnerabilität in Fluchtkontexten. Wien: Verlag der Akademie der Wissenschaften

Online Resources

https://www.unodc.org/documents/justice-and-prison-reform/Bangkok_Rules_ENG_22032015.pdf

https://www.ohchr.org/Documents/Publications/training8Rev1en.pdf

https://www.penalreform.org/issues/prison-conditions/standard-minimum-rules/

An Uncommon Cause of Bilateral Pulmonary Nodules in a Long-Term Smoker

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DOI: 10.31038/IMROJ.2020512

Abstract

Pulmonary Langerhans Cell Histiocytosis (LCH) in adults is a rare disease and no precise epidemiological data are available concerning its prevalence. Bilateral diffuse nodular infiltration without cystic changes could be one of the Langerhans Cell Histiocytosis (LCH) presentation depend on the stage of evolution of the process. We are reporting in this case an early possible manifestation of LCH that can mimic other wide deferential diagnosis especially among smokers.

Keywords

Smoking related lung disease, Interstial lung disease, Langerhans cell histiocytosis, Smoking

Case Report

58-year-old Irish male with previous medical history of psoriasis, which is controlled on topical treatment, was referred by his GP for Chronic cough and abnormal chest Xray. Patient gave history of chronic dry cough for the last 2 years. No dyspnea or wheezing and his mMRC score was Zero. Review of system was negative for weight loss, hemoptysis, joint pain or night sweat. Significant history of 80 pack-year smoking. Negative exposure to TB or asbestoses.

On examination, his temperature was 36.9°C, his blood pressure was 121/82 mmHg and his oxygen saturation was 97% in room air. There was no evidence of clubbing. No palpable lymphadenopathy. Normal breath sound.

Initial chest Xray showed multiple nodular densities in the both lungs. All his blood tests were normal, including: liver, renal function, calcium, white cell count, hemoglobin, platelet count, Anti-Nuclear Antibody (ANA), Anti-Neutrophil Cytoplasmic Antibodies (ANCA), Erythrocyte sedimentation rate (ESR) and ACE level. Quantiferon was negative.

Pulmonary Function test showed: FEV1: 92% (2.95L), 106% (4.2L), FEV1/FVC: 68%. Lung volumes: RV 116%, TLC 104%. DLCO 82% Kco 88%.

Urgent CT chest (figure 1a) showed: Innumerable predominantly less than 1cm pulmonary nodules in both lungs. The largest nodule in the left lower lobe 7mm.No significant hilar or mediastinal lymph nodes.

IMROJ-5-1-502-g001

Figure 1a. CT chest View.

Given his extensive smoking history, the likelihood of these abnormalities representing metastatic solid organ malignancy was very high. Other differential diagnoses to be considered include: multiple abscesses, septic emboli, fungal infection, non-inflammatory conditions like sarcoidosis, pneumoconiosis and inflammatory conditions like rheumatoid arthritis.

Bronchoscopy with BAL was done and that was negative for bacterial and MTB culture with normal differentials.

After Respiratory MDM discussion, CT guided biopsy of 7mm nodule in the left lower lobe was done. The core biopsy showed foci of perivascular and peribronchiolar interstitial cellular infiltrate of histiocytic cells with moderate amounts of pale cytoplasm and irregular nuclei. Also present were prominent eosinophils and some small lymphocytes. The large histiocytic cells were strongly positive for S100 and CD1a (figure 1b) and for Langerin confirming the morphological impression of Langerhan’s Cell Histiocytosis.

IMROJ-5-1-502-g002

Figure 1b.The histiocytic cells are positive for CD1a which also highlights the perivascular distribution of the infiltrate.

Discussion

Pulmonary LCH in adults is a rare disease and no precise epidemiological data are available concerning its prevalence. Pulmonary involvement with LCH can be observed in patients of any age. Systemic forms of the disease are usually seen in infants and children and pulmonary involvement is often not a prominent feature [1]. In contrast, isolated pulmonary LCH occurs predominantly in young adults with a peak frequency between 20 and 40 years of age. Patients with pulmonary LCH also tend to be heavy smokers [2, 3]. Approximately two thirds of patients present with respiratory symptoms, usually a dry cough, often associated with dyspnea on exertion [4].

The abnormalities seen on the chest radiograph are generally bilateral and symmetrical .More commonly, bilateral widespread cystic lesions may be identifiable.

The most striking characteristic on HRCT of this patient was bilateral diffuse nodular infiltration without cystic changes. That raises another presentation of pulmonary LCH depend on the stage of evolution of the process. Serial studies of individual patients with pulmonary LCH indicate that the lesions evolve as follows: nodules in early stage, cavitary nodules, thick walled cysts then thin walled cysts in late stages [5, 6].

References

  1. Howarth DM, Gilchrist GS, Mullan BP, et al. (1999) Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 15:2278-2290.
  2. Crausman RS, Jennings CA, Tuder RM, Ackerson LM, Irvin CG, et al. (1996) Pulmonaryhistiocytosis X: pulmonary function and exercise pathophysiology. Am J RespirCrit Care Med 153:426-435. [Crossref]
  3. Hance AJ, Basset F, Saumon G, Danel C, Valeyre D, et al. (1986) Smoking and interstitial lung disease.Ann NY AcadSci 465:643-656. [Crossref]
  4. Schönfeld N, Frank W, Wenig S, Uhrmeister P, Allica E, et al. (1993) Clinical and radiological features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 60: 38-44. [Crossref]
  5. Brauner MW, Grenier P, Moeulhi MM,Mompoint D, Lenoir S(1989) Pulmonary histiocytosis X: evaluation with high-resolution CT.Radiology172:255-258. [Crossref]
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Does a commensal relationship exist between coronaviruses and some human populations?

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DOI: 10.31038/JMG.2020323

Abstract

Coronaviruses enter lung tissue via the ACE2 receptor, which varies structurally among human populations. In particular, the Chinese population has fewer variants that bind weakly to the coronavirus S-protein. This global variation suggests that the ACE2 receptor has coevolved with different environments, some of which have favored susceptibility to infection of lung tissue by coronaviruses. It has been argued that respiratory viruses boost the immune response of lung tissue and thereby prevent more serious pulmonary diseases, like tuberculosis, pneumonia, and pneumonic plague. This preventive effect has been shown withother viral pathogens, notably γherpesvirus 68 and cytomegalovirus. Some human populations may have therefore gained protection from severe respiratory infections by becoming more susceptible to mild respiratory infections, such as those normally caused by coronaviruses. This commensal virus-host relationship would have been especially adaptive wherever respiratory pathogens could easily propagate, i.e., in crowded environments, where manypeople live in proximity not only to each other but also to animal sources of infection. In regions that have long had crowded environments, natural selection may have favored susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to deadly pulmonary diseases.

Keywords

ACE2, China, coronaviruses, respiratory viruses, tuberculosis

Coronaviruses were not considered highly pathogenic until the emergence of SARS in 2002. Although previous strains could be highly infectious, the infection itself was normally mild, i.e., a common cold. The current “novel” strain has raised concern because it is as contagious as the common cold but much more pathogenic.

Coronaviruses infect lung tissue via the ACE2receptor. This receptor varies structurally among human populations, notably in its ability to bind to such viruses and facilitate their entry into lung tissue. A study of 1,700 alleles in the ACE2 gene region found major differences in allele frequency not only between Asians and other human groups but also between different Asian groups. In particular, the Chinese population has fewer alleles that code for weak binding to the coronavirus S-protein [1]. Different ACE2 alleles are also associated with differences in susceptibility to diabetic retinopathy, an eye disease with a distinct global pattern of prevalence: 22% in Italy, 23% in China, 30% in the United Kingdom, and 40% in the United States [2].

Chinese lung tissue may therefore be especially susceptible to coronavirus infection, although the evidence remains controversial. One study, after identifying certain cells with high concentrations of the ACE2 receptor, showed that such cells were over five times more numerous in the lung tissue of an Asian donor than in the lung tissue of Euro American or African American donors; however, the entire sample had only one Asian donor [3]. Another study failed to find significant differences in ACE2 gene expression between Asian and Caucasian lung tissue [4]. Both studies suffer from the broadness of the term “Asian,” which covers a wide range of populations that differ from each other in many ways, notably in the structure of the ACE2 receptor.

Ethnic differences are also suggested by data on the prevalence of bronchiectasis, which is often caused by respiratory viruses [5]. In the United States, the prevalence is 2.5 to 3.9 times higher among Asian Americans than among Euro or African Americans [6]. Again, the term “Asian” is problematic. A high prevalence has likewise been found in Korean adults [7].

While it is not surprising that some human populations have adapted to the presence of certain pathogens by becoming more resistant, the population in this case has become less resistant, as if it actually benefits from infection by respiratory viruses. Some immunologists have suggested that such viruses boost the immune response of lung tissue and thereby prevent more serious pulmonary diseases, like tuberculosis, pneumonia, and pneumonic plague [8]. This preventive effect has been shown with other viruses. When mice are infected with γherpesvirus 68, which is similar to Epstein-Barr virus, there is production of large quantities of IFN-γ and activation of macrophages that protect against subsequent infection by Listeria monocytogenes, Mycobacterium tuberculosis, and Yersinia pestis [9,10]. Infection with cytomegalovirus likewise protects against Listeria monocytogenes and Yersinia pestis [9]. Other viruses may have similar commensal relationships with human hosts, but little is still known about the benefits the host would gain from their presence [11,12]. Recent work suggests that commensal viruses contribute to intestinal health [13].

Some human populations may have therefore gained protection from severe respiratory infections by becoming more susceptible to infection by coronaviruses, which are normally mild in their effects. This commensal virus-host relationship would have been especially adaptive wherever respiratory pathogens posed a major threat to health. As one team of researchers suggested: “human γHV-infection may be an important but unrecognized factor which modifies TB [tuberculosis] outcome, particularly in high TB burden countries where most children acquire EBV [Epstein-Barr virus] by 3 years of age” [10].

Tuberculosis has historically caused much mortality, particularly in crowded social environments:

Crowd diseases are generally highly virulent and depend on high host population densities to maximize pathogen transmission and reduce the risk of pathogen extinction through exhaustion of susceptible hosts. Many crowd diseases emerged during the Neolithic Demographic Transition (NDT) starting around ten thousand years ago (kya), as the development of animal domestication increased the likelihood of zoonotic transfer of novel pathogens to humans, and agricultural innovations supported increased population densities that helped sustain the infectious cycle. The marked expansion of MTBC [Mycobacterium tuberculosis complex] during the NTD, but not during earlier human expansion events, suggests that the success of this pathogen was primarily driven by increases in human host density, which is typical of crowd diseases [14].

Tuberculosis became prevalent at an early date in China, approximately six to eleven thousand years ago [14]. This time frame is consistent with China’s expansion of agriculture, domestication of animals for food, and emergence of large communities. In a crowded environment, where many people live in proximity not only to each other but also to animal sources of infection, natural selection would favor different ways to boost the immune response of lung tissue. One way would be to increase susceptibility to mild respiratory infections, such as those normally caused by coronaviruses. This commensal relationship may explain why China was less affected by the Spanish flu of 1918-1920 [15]. Since that time, the Chinese population may have unknowingly become less resistant to severe respiratory infections because mild respiratory infections have become less prevalent, through improvements in public health and reduction of household size.

This kind of gene-culture coevolution probably happened not only in China but also in other regions with a long history of animal domestication and crowded environments, such as the Indo-Gangetic Plain, the Fertile Crescent of the Middle East, and the Mediterranean Basin [16]. In all of these regions, natural selection may have increased susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to deadly respiratory pathogens.

Perhaps this commensalism explains why COVID-19 has been more severe in southern Europeans than in northern Europeans. One might expect the opposite: the severity of infection would increasewith increasing latitude. After all, arespiratory virus should be more contagious under conditions of lower temperature, lower humidity, and lower solar UV. Northern Europeans, however, have coevolved with animal domestication and crowded environments for a shorter time.The virus may be more contagious among them, but its entry into lung tissue is not facilitated to the same extent.

References

  1. Cao Y, Li L, Feng Z, Wan S, Huang P et al. (2020) Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov6:11.[crossref]
  2. Adams N (2020) Cracking the code to the 2019 novel coronavirus (COVID-19): Lessons from the eye. Eye Reports 6 : 1.
  3. Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y et al. (2020) Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCoV.bioRxiv2020.01.26.919985
  4. Cai G. (2020) Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov.medRxiv2020.02.05.20020107
  5. Gao YH, Guan WJ, Xu G, Lin ZY, Tang Y et al. (2015) The role of viral infection in pulmonary exacerbations of bronchiectasis in adults: a prospective study. Chest 147: 1635-1643. [crossref]
  6. Seitz AE, Olivier KN, Adjemian J, Holland SM, Prevots DR (2012) Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest142: 432-439. [crossref]
  7. Kwak HJ, Moon JY, Choi YW, Kim TH, Sohn JW et al. (2010) High prevalence of bronchiectasis in adults: analysis of CT findings in a health screening program. Tohoku J Exp Med222: 237-242. [crossref]
  8. Shekhar S., Schenck K., Petersen F.C. (2017) Exploring host-commensal interactions in the respiratory tract. Front Immunol8: 1971. [crossref]
  9. Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M et al. (2007) Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447: 326-329. [crossref]
  10. Miller HE, Johnson KE, Tarakanova VL, Robinson RT (2019) γ-herpesvirus latency attenuates Mycobacterium tuberculosis infection in mice. Tuberculosis 116: 56-60. [crossref]
  11. Griffiths P (1999) Time to consider the concept of a commensal virus? Rev Med Virol 9: 73-74. [crossref]
  12. Vu DL, Kaiser L (2017) The concept of commensal viruses almost 20 years later: redefining borders in clinical virology. ClinMicrobiolInfec 23: 688-690. [crossref]
  13. Minton K (2019) Commensal viruses contribute to gut health. Nat Rev Immunol19: 721. [crossref]
  14. Comas I, Coscolla M, Luo T, Borrell S, Holt K.E et al. (2013) Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 45: 1176-1182. [crossref]
  15. Langford C. (2005) Did the 1918-19 influenza pandemic originate in China? PopulDev Rev31: 473-505.
  16. McNeill WH (1998) Plagues and Peoples. New York, Anchor Books.

Bier Block Regional Anesthesia versus Conscious Sedation in Pediatric Forearm Fracture Management: Clinical Outcomes and Costs

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DOI: 10.31038/IJOT.2020312

Abstract

Background: Bier block, or intravenous regional block (IVRB), and Conscious Sedation (CS) can be used for pediatric forearm fracture reductions. This study compares the two.

Questions/Purposes: Of the two options (IVRB vs CS) of anesthesia for pediatric fracture reduction, is one safer and more cost efficient?

Patients and Methods: Arkansas Children’s Hospital charts were reviewed for pediatric forearm fractures treated in the ED between 2005 and 2014. Patient age, sex, fracture type, mechanism of injury, need for further reduction, initial complications, long-term complications, number of follow-up visits, need for further operative reduction, and total weeks of care were gathered. Patient from ages 4–7 were included in the study due to the tendency of using CS for younger patients. ED room costs were compared between 18 IVRB patients and 19 CS patients.

Results: Total length of care for IVRB was 5.9 weeks versus 5.6 for CS with 2.8 follow-up appointments for IVRB versus 2.7 for CS. IVRB cost $423 less than CS. There were no complications in either group.

Conclusion-IVRB: Is safe and cost effective method for pediatric forearm fracture reduction compared to CS.

Clinical Relevance: Eliminating the need for sedation and stream-lining fracture treatment in the pediatric ED is both safe and efficient when using IVRB. Patients are not required to be NPO and do not require prolonged recovery in the ED.

Introduction

Developed in 1908, the Bier block technique, also known as Intravenous Regional Block (IVRB), utilizes the retrograde intravenous flow in an extremity with a tourniquet in place proximal to the fracture to deliver local anesthetic to the extremity for regional anesthesia. Our institution is an academic children’s medical center where the Bier block is routinely used as the sole anesthesia for closed reduction of pediatric forearm fractures. This method of anesthesia has a long historical record of safety and efficacy, and does not require the patient to have an empty stomach as is required for conscious sedation [1–4, 5]. Conscious sedation is also well-described and widely used in managing pediatric forearm fractures requiring a closed reduction in the emergency room [3, 4] The aim of this study is to compare the short- and long-term clinical and radiographic outcomes of Bier block anesthesia and conscious sedation in the setting of pediatric patients treated for isolated forearm fractures treated with closed reduction in the emergency department. A cost comparison between the two anesthesia methods is also performed.

The Bier block has proven to be a very safe method of regional anesthesia for over 100 years [1–4, 5]. The method involves placement of an Intravenous (IV) catheter in the patient’s injured extremity while another IV catheter is placed in an unaffected extremity. Routine monitoring of blood pressure, heart rate and rhythm monitoring are instituted. A tourniquet is then placed proximal to the fracture site on the affected extremity. Some have advocated using a double tourniquet to address tourniquet pain [6]. By injecting local anesthetic intravenously in the affected extremity, the retrograde blood flow allows the anesthetic to be distributed throughout the extremity without entering the systemic vasculature. Some have advocated exsanguinating the extremity prior to the procedure although this is not routinely done at our institution. [7]. Once the tourniquet is inflated, 0.5% lidocaine without epinephrine is injected into the IV catheter in the affected extremity. The dose is determined based on patient weight. The average dosing is 3mg/kg of 0.5% lidocaine without epinephrine in the pediatric patient.

We currently use the formula [weight (kg) × 0.6 = volume (ml) of 0.5% lidocaine]. The maximum recommended dose is 30ml. Often the lidocaine injection is followed by an injection of 10 mL of injectable saline as this can help push the volume of lidocaine into the tissues to improve the anesthesia. The tourniquet must be left inflated for 30 minutes and then slowly released monitoring for any signs or symptoms of lidocaine toxicity. This has proven to be a very simple, effective and safe procedure for fracture reduction. The benefits include adequate analgesia, simplicity of technique, low cost, low complication rate, and decreased post-procedure monitoring time [1–4, 5]. Blasier et al. found ninety-nine percent of patients undergoing Bier block anesthesia in upper-extremity fracture care had adequate anesthesia for closed fracture reduction. There were no complications noted. Specifically, there were no incidents of hypotension, tachycardia, seizures or arrhythmias, which have been reported as adverse events in past series [8]. Less than 2% required a general anesthetic in the operating room for further treatment [3]. Still, this procedure is not widely utilized in the U.S. A survey of 63 orthopedic surgeons and 69 emergency medicine physicians in the U.S. and Canada found that only 20% use IVRB routinely for closed reduction of pediatric forearm fractures [9]. However, it is gaining popularity with recent publications presenting the safety and benefits of the procedure along with the relatively lower cost and decreased time spent in the emergency department as compared to conscious sedation [1].

Materials and Methods

IRB approval was granted for a retrospective review of patient charts at our institution. Patient charts from 2005–2014 were reviewed, and those with patients who had isolated closed forearm fractures that required only closed reduction in the emergency department under either Bier block regional anesthesia or conscious sedation were selected for possible inclusion in the study. Patients were excluded if there were other fractures or injuries noted or there was inadequate follow-up. Patient age, sex, fracture type, mechanism of injury, need for further reduction, initial complications, long-term complications, number of follow-up visits, need for further operative reduction, and total weeks of care were gathered.

Due to the tendency of our institution to conduct Bier blocks for most forearm fractures and reserve conscious sedation for younger patients, we further limited eligibility of study patients to those between 4 and 7 years of age. Statistical analyses were conducted with SAS v 9.4 (The SAS Institute, Cary, NC) and Excel 2013 (Microsoft Corporation, Redmond, WA). Patient characteristics at presentation (age, sex, year of injury, bone fractured, position of fracture on the bone, mechanism of injury, and days to reduction) were compared between anesthesia groups via Cochran-Armitage trend tests and chi-square tests. The same patient characteristics at presentation were entered together into a logistic-regression model to estimate each subject’s probability or “propensity” to receive Bier block instead of conscious sedation, and the resulting propensity scores were then used to stratify subjects into quintiles. To examine how propensity-score stratification affected the differences in patient characteristics between anesthesia groups, we calculated each characteristic’s standardized difference as the difference in group means divided by the pooled estimate [7] of the groups’ common Standard Deviation (SD). Unadjusted standardized differences were calculated this way across the entire study population, whereas propensity-adjusted standardized differences were calculated as the average across propensity-score quintiles of the standardized difference within each quintile. To compare outcomes between anesthesia groups, we used Fisher’s exact test, the Cochran-Mantel-Haenszel (CMH) correlation chi-square test, and the Wilcoxon Rank-Sum (WRS) test for unadjusted comparisons, and stratified versions of the CMH and WRS tests (with propensity-score quintiles as strata) for propensity-adjusted comparisons. An alpha=0.05 significance level was employed for all statistical comparisons. From the patients who met all eligibility criteria, we gathered the emergency department’s total visit cost for two randomly selected subsamples consisting of 19 conscious-sedation patients and 18 Bier-block patients. This data was used for average cost comparisons between the groups via WRS test.

Results

A total of 1616 patient charts were initially reviewed, and 128 charts met all eligibility criteria. This included 66 patients (52%) who received Bier block anesthesia and 62 patients (48%) who received conscious sedation. Table 1 shows the distribution of patient characteristics at presentation in each group. On average, Bier-block patients were 1.1 years older than conscious-sedation patients (P<0.0001). Additionally, the median year of injury was 2013 in the Bier-block group compared to 2010 in the conscious-sedation group (P=0.0003), due in part to the fact that no Bier blocks (versus 10 conscious sedations) were performed in 2005 or 2006 in the study population. None of the other patient characteristics at presentation (sex, bone fractured, fracture position, injury mechanism, and days to reduction) were significantly different between groups.

Table 1. Patient Demographics

Baseline Characteristic

Overall
(N=128)

Bier Block
(N=66)

C. Sedation
(N=62)

P*

Age in years, N (%A):
4
5
6
7
       Mean (SDB)

28 (22%)
36 (28%)
36 (28%)
28 (22%)
5.5 (1.1)

3 (5%)
14 (21%)
27 (41%)
22 (33%)
6.0 (0.9)

25 (40%)
22 (35%)
9 (15%)
6 (10%)
4.9 (1.0)

<0.0001†

Sex, N (%):
Female
Male

51 (40%)
77 (60%)

30 (45%)
36 (55%)

21 (34%)
41 (66%)

0.18‡

Year of Injury, N (%A):
2005–06
2007–08
2009–10
2011–12
2013–14
       Median

10 (8%)
37 (29%)
9 (7%)
29 (23%)
43 (34%)
2011

0 (0%)
20 (30%)
1 (2%)
10 (15%)
35 (53%)
2013

10 (16%)
17 (27%)
8 (13%)
19 (31%)
8 (13%)
2010

0.0003†

Bone+Position, N (%A):
Radius, Proximal
Radius, Mid-
Radius, Distal
BBFAC, Proximal
BBFAC, Mid-
BBFAC-, Distal

4 (3%)
6 (5%)
18 (14%)
2 (2%)
20 (16%)
78 (61%)

3 (5%)
3 (5%)
12 (18%)
0 (0%)
10 (15%)
38 (58%)

1 (2%)
3 (5%)
6 (10%)
2 (3%)
10 (16%)
40 (64%)

–––‡‡

Bone fractured, N (%A):
Radius
BBFAC

28 (22%)
100 (78%)

18 (27%)
48 (73%)

10 (16%)
52 (84%)

0.13‡

Fracture position, N (%A)
Distal
Mid- or Proximal

96 (75%)
32 (25%)

50 (76%)
16 (24%)

46 (74%)
16 (26%)

0.84‡

Mechanism of Injury, N (%A):
FOOSHD
All other mechanisms

99 (77%)
29 (16%)

48 (73%)
18 (20%)

51 (82%)
11 (11%)

0.20‡

Days to Reduction, N (%)
zero days
one or more days

120 (94%)
8 (6%)

63 (95%)
3 (5%)

57 (92%)
5 (8%)

0.41‡

Table 2 shows the distribution of outcomes between groups, and shows both the unadjusted and propensity-adjusted P-values for the outcome differences. There were no initial or long-term complications in either group. Only one Bier-block patient (2%) and three conscious-sedation patients (5%) required more than one attempt at closed reduction. One patient from each group required an operative intervention. The Bier-block patient required Open Reduction Internal Fixation (ORIF) and the conscious-sedation patient required closed reduction under general anesthesia in the operating room. Both additional interventions were needed due to loss of reduction during follow up. The two groups had nearly equal lengths of total care, with an average of 5.9 weeks in the Bier-block group versus 5.6 weeks in the conscious sedation group (propensity-adjusted P=0.82; Table 2 and Figure 2). The number of follow-up visits were also nearly equal between groups, with an average of 2.8 visits in the Bier-block group versus 2.7 visits in the conscious sedation group (propensity-adjusted P=0.54; Table 2 and Figure 1). Table 3 shows that, when the ED visit costs were compared, Bier block was found, on average, to be $423 (26%) less expensive than conscious sedation. The average ED visit cost was $1,601 for conscious sedation versus only $1,177 for Bier block (P=0.0003) [Table 3].

IJOT-2020-303_F1

Figure 1: Number of visits distributions between both smethods.

IJOT-2020-303_F2

Figure 2: Length of care distribution between both methods.

Table 2. Patient Outcomes between the Two Groups.

Outcome

Overall
(N=128)

Bier Block
(N=66)

C. Sedation
(N=62)

Unadjusted P*

Propensity-adjusted P*

Initial Complications, N (%A):
None

128 (100%)

66 (100%)

62 (100%)

–––

–––

Long-term Complications, N (%A):
None

128 (100%)

66 (100%)

62 (100%)

–––

–––

Number of attempts, N (%A):
1 attempt
2 attempts
3 attempts

124 (97%)
3 (2%)
1 (1%)

65 (98%)
0 (0%)
1 (2%)

59 (95%)
3 (5%)
0 (0%)

0.66†

0.36†

Need for OR, N (%A):
No
Yes

126 (98%)
2 (2%)

65 (98%)
1C (2%)

61 (98%)
1D (2%)

1.00€

–––

Number of follow-ups, N (%A):
2 visits
3 visits
4 visits
5 visits
6 or 7 visits
#visits, Mean (SDB)
#visits, Range

66 (52%)
36 (28%)
19 (15%)
5 (4%)
2 (2%)
2.8 (1.0)
2.0–7.0

33 (50%)
15 (23%)
13 (20%)
5 (8%)
0 (0%)
2.8 (1.0)
2.0–5.0

33 (53%)
21 (34%)
6 (10%)
0 (0%)
2 (3%)
2.7 (1.0)
2.0–7.0

0.32§

0.54§

Total length of care, N (%A):
3 weeks
4 weeks
5 weeks
6 weeks
7 weeks
8 weeks
9–12 weeks
13–17 weeks
       #weeks, Mean (SDB)
#weeks, Range

10 (8%)
53 (41%)
17 (13%)
18 (14%)
5 (4%)
9 (7%)
9 (7%)
7 (5%)
5.8 (3.0)
3.0–17.0

4 (6%)
27 (41%)
7 (11%)
11 (17%)
2 (3%)
4 (6%)
8 (12%)
3 (3%)
5.9 (3.0)
3.0–17.0

6 (10%)
26 (42%)
10 (16%)
7 (11%)
3 (5%)
5 (8%)
1 (2%)
4 (6%)
5.6 (3.1)
3.0–16.0

0.32§

0.82§

Table 3. Cost Distribution Analysis

IVRB1

CS2

Mean (SD3)

$1,177.34 ($253.61)

$1,600.98 ($339.19)

Median

$1,101.71

$1,531.77

Quartiles

$982.26 – $1,318.48

$1,309.91 – $1,923.62

Range

$846.75 – $1,726.27

$1,063.76 – $2,233.47

WRS4 test result

P=0.0003

Discussion

The two main aims of this study were to determine if Bier block regional anesthesia is a safe, effective, and cost-efficient method of anesthesia for pediatric forearm fracture reduction in the emergency department, and to compare the short- and long-term complications and outcomes of Bier-block patients with those of conscious-sedation patients chosen for their overlapping age range. Our institution has a long experience with using Bier blocks in these patients, and we have had found the procedure in children to be both safe and effective. Bier block anesthesia was found to be as safe as conscious sedation in our final study group. Neither final study group had any instance of short-term or long-term complications; specifically, no instances of lidocaine toxicity, compartment syndrome, need for hospital admission for pain control after the procedure, nerve palsy or growth arrest. No child required conversion from Bier block anesthesia to conscious sedation due to inadequate pain control or anxiety despite having a younger group of patients ranging from 4 to 7 years of age. This is a common concern with using Bier block anesthesia in the younger awake child. In our institutional experience, the need for conversion from Bier block to conscious sedation due to inadequate anesthesia or anxiety is very rare. Our emergency department has child life specialists available who can assist in the procedure if needed in the more anxious children by providing distraction and entertainment in the form of reading or tablet usage for games.

One of the aims of this study was to assess follow up data for these two groups. With the rising costs in providing medical care, minimizing the need for, and number of, follow up clinic appointments is valuable. We found that both groups had nearly equal follow up time length and number of follow up visits and both were quite low. Certainly patients in our study’s age group are considered to have very wide tolerances for what constitutes an acceptable fracture reduction due to their tremendous ability to remodel deformity but our data shows that these two methods are equally effective at preventing patients from requiring surgical intervention. One patient in each group did require operative intervention due to inadequate reduction in the emergency department or loss of reduction in follow up, resulting in a 2% rate in each group of a need for surgical intervention in the operating room. The Bier block patient required ORIF and the conscious sedation patient required further closed reduction without internal fixation under general anesthesia.

Some weaknesses of our study include the small patient group sizes. We found it necessary to restrict the age range from the original data that included all patients with forearm fractures, and limit the study to patients who were between 4 and 7 years old. This was due to several factors. First, the majority of patients at our institution receive a Bier block as their form of anesthesia for forearm fracture reduction in the emergency department. If conscious sedation is performed, it is usually reserved for younger patients or the more anxious patients who we perceive may not tolerate a Bier block as well. We were unable to effectively compare the two larger, more inclusive groups due to the large number of Bier-block anesthesia patients and low number of conscious-sedation patients overall and the age differences between the two groups. By lowering and narrowing the age range, we were able to obtain an average age of 6 years in the Bier block group and 5 years in the conscious sedation group. This allowed for more clinically useful comparable data points, but limited the number of patients we were able to compare.

Distributions of the total number of follow-up visits in the Bier-block and conscious-sedation groups, showing that the two groups have very similar distributions. See Table 2 for the means, SDs, and ranges of the distributions.

Distributions of the total length of care in weeks for the Bier-block and conscious-sedation groups, showing that the two groups have similar distributions. See Table 2 for the means, SDs, and ranges of the distributions.

An additional weakness of the study was the probable violation of the “no unmeasured confounders” assumption required for valid propensity-score-based analysis. In addition to each patient’s age and year of injury, we collected their sex, the bone fractured and position of the fracture on the bone, the mechanism of injury, and the number of days to reduction, but not the patient’s race. Race is a pervasive confounder in health-care research that can lead to treatment disparities, not only through provider biases or income disparities, but also through the perceptions and comfort levels of the patients and their parents. Thus, race could easily have been confounded with the choice of anesthesia method in our study. However, it should be said that ours is an equal-access institution where all patients are treated the same regardless of race or socioeconomic background, and this fact should reduce some (if not all) of the unmeasured confounding of race with anesthesia method.

Emergency department visit cost analysis was included in this study for the reason of fiscal responsibility. Bier block anesthesia has been shown to be safe and effective with less total time in the emergency department compared to conscious sedation [7]. We also show an average cost savings of $423 in using Bier block anesthesia compared to conscious sedation. Bier block anesthesia also has the added benefit of not requiring significant specialized post-procedural monitoring that requires trained emergency-department staff that could otherwise be treating another patient. Bier block anesthesia patients do not require any further monitoring after the reduction, which allows for staff to be freed up and, in theory, diminish patient room utilization time. In a high-volume pediatric hospital, decreasing visit time is essential for having an efficient emergency department. We attempted to prove this theory in our study comparing time data between the conscious sedation and Bier block groups, but there were significant limitations with our ability to do that accurately. These limitations included incomplete charting regarding admit and discharge time and NPO status of those patients receiving conscious sedation affecting the wait time before reduction.

Bier block anesthesia is a safe and cost-effective form of anesthesia for pediatric forearm fracture closed reduction in the emergency department in patients between 4 and7 years of age. It has continued to be proven to be safe throughout the years and continues to be shown to be more time and cost effective. Short-term and long-term complication rates are low and are similar to those seen in patients treated with conscious sedation. Follow up time and number of visits are similar between the two groups as well. However, Bier block anesthesia was found to cost significantly less than conscious sedation in our series. We theorize that there are additional indirect cost savings with Bier block compared to conscious sedation as a result of (1) the diminished need for specialized and lengthy monitoring of the patient after the procedure, (2) the NPO status of the patient having no effect on our ability to perform and timing of proceeding with the Bier block, and (3) the efficiency with which one can perform the Bier block in an emergency department setting, although we did not attempt to prove that in this study. Continued research in this field will continue to shed light on this useful method of emergency room treatment of pediatric forearm fractures.

Conflict of Interest

The authors declare that they have no conflict of interest.

Statement of Human and Animal Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). No identifying information was included in this study.

Statement of Informed Consent

Informed consent was not obtained due to the retrospective nature of this study with no identifying patient information presented in the study. All data was collected under IRB institutional guidelines.

Statement of Funding

No funding was received by any authors for this study.

References

  1. Aarons CE, Fernandez MD, Willsey M, Peterson B, Key C, et al., (2014) Bier block regional anesthesia and casting for forearm fractures: safety in the pediatric emergency department setting. J Pediatr Orthop 34: 45–49.
  2. Barnes CL, Blasier RD, Dodge BM (1991) Intravenous regional anesthesia: a safe and cost-effective outpatient anesthetic for upper extremity fracture treatment in children. J Pediatr Orthop 11: 717–720. [Crossref]
  3. Blasier RD, White R (I1996) Intravenous regional anesthesia for management of children’s extremity fractures in the emergency department. Pediatr Emerg Care 12: 404–406.
  4. Colbern E (1970) The Bier block for intravenous regional anesthesia: technique and literature review. Anesth Analg 49: 935–940.
  5. Mohr B (2006) Safety and effectiveness of intravenous regional anesthesia (Bier block) for outpatient management of forearm trauma. CJEM 8: 247–250.
  6. Perlas A, Peng PW, Plaza MB, Middleton WJ, Chan VW, et al., (2003) Forearm rescue cuff improves tourniquet tolerance during intravenous regional anesthesia. Reg Anesth Pain Med 28: 98–102. [Crossref]
  7. Yang E (2017) Green’s Operative Hand Surgery. 2: 10–11.
  8. Constantine E, Steele DW, Eberson C, Boutis K, Amanullah S, et al., (2007) The use of local anesthetic techniques for closed forearm fracture reduction in children: A survey of academic pediatric emergency departments. Pediatr Emerg Care 23: 209–211. [Crossref]
  9. Guay J (2009) Adverse events associated with intravenous regional anesthesia (Bier block): A systematic review of complications. J Clin Anesth 21: 585–594.
  10. Mendenhall W, Beaver RJ, Beaver BM (2009) Introduction to Probability and Statistics 13th Edition, Cengage Learning, [multiple cities and countries], ISBN-10: 0495389536, Page 403.

GNRB (Medical Device) vs MRI on Anterior Cruciate Ligament (ACL) Tears with Arthroscopic Validation

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DOI: 10.31038/IJOT.2020311

Florian Beaurain

SMQ engineer

Master 2 « Medical Device: Design and assessment » (University of Lille, France)

Objective: Comparison of GNRB® versus MRI in the diagnosis of different patterns of anterior cruciate ligament tears.

Requirements: Patients operated for ACL tears or ACL tears + meniscus.

Exclusion Criteria: all patients without isolate ACL tears (without other ligament and bone injuries), patients were not get primary surgery.

Collection of Data

Database of Dr Henri ROBERT (surgeon, specialist on ACL surgery: Operative report, MRI (1.5 T) report and GNRB database for all patients).

Group of Patients

2 groups:

  • Patients with complete ACL tears
  • Patients with partial ACL tears

Statistical Test

We use sensibility like an indicator for average method

Binary Criteria: ACL tears (partial or complete)

Acceptability

For MRI report, if it required interpretation, it shall be null. It must be clearly mentioned complete or partial tears in the conclusion report.

For GNRB, if delta for both knees >3 mm = complete tears and if 1.5 mm ≤ delta <3 mm, partial tears.

Non Inferiority Test

Estimate value: Pr (MRI’s sensibility [1]) by Πr = 0.57

Estimate value: Pe (GNRB’s sensibility [2,3]) by Πe = 0.84

It set α = 5 % unilateral, β = 10 % and δ = 10%.

IJOT-2020-302_e1

For estimation by confidence interval (CI) of difference of proportions

With Pe = GNRB’s sensibility and Pr = MRI’s sensibility and Ne = Nr

–nr, ne ≥ 30

–nrpr, nr(1–pr), nepe, ne(1–pe) ≥ 5

IJOT-2020-302_e2

Pattern

IJOT-2020-302_f1

Difference of Proportions Test

– Difference test at δ ≠ 0

IJOT-2020-302_e3

Results

This study was performed on data from previous years and two years before for 200 operated patients in total. After exclusion of 64 medical files (one of the 3 data is missing: GNRB, MRI or arthroscopic report), 62 tears were partial and 74 complete with arthroscopy report [Table 1, 2, 3].

Table 1: Table of IRM’s and GNRB’s sensibility with arthroscopy for reference.

MRI vs Arthroscopy for Complete ACL

MRI vs Arthroscopy for Partial ACL

GNRB vs Arthroscopy for Complete ACL

GNRB vs Arthroscopy for Partial ACL

Number

47

22

45

46

Number of Subject

62

74

62

74

Sensibility

0,76

0,30

0,73

0,62

Table 2: Sensibility and specificity of GNRB in the literature.

Complete ACL

Partial ACL

Sensibility

Specificity

Sensibility

Specificity

Robert H [5]

70%

99 %

80%

87%

Klouche S [3]

92%

96 %

92%

98%

Di Ioro A

72%

85%

Lefevre N

84%

81%

87%

87%

Beldame J

62%

75%

Beaurain F

73%

 62%

Table 3: Sensibility of MRI in the literature.

Complete ACL

Partial ACL

Beldame J [1]

 57%

Steltzlen C [4]

32%

For complete tears, MRI’s sensibility was 0.76 and GNRB’s sensibility 0.73. For partial tears, MRI’s sensibility was 0.30 and GNRB’s sensibility 0.62.

For Complete Tears

For estimation by Confidence Interval (CI) of difference of proportions

Conditions for application are verified.

IJOT-2020-302_e4

For Partial Tears [4]

For estimation by Confidence Interval (CI) of difference of proportions

Conditions for application are verified.

IJOT-2020-302_e5

Discussion

This results shows equivalence for ACL’s complete diagnostics (for MRI and GNRB reports) with the literature and for incomplete ACL tears, it’s slightly lower than literature.

Sensibility’s results (for MRI and GNRB reports) for this study are equivalent for complete and partial tears diagnostic in the literature.

Conclusion

Sensibility of GNRB laximetry is quite the same than MRI for complete tears but superior for partial tears.

References

  1. Beldame J (2009) Etude radio-clinique du ligament croisé antérieur [Thèse de Doctorat en Médecine]. [France]. Université de Rouen Normandie.
  2. Lefevre N, Bohu Y, Naouri JF, Klouche S, Herman S (2014) Validity of GNRB® arthrometer compared to TelosTM in the assessment of partial anterior cruciate ligament tears. Knee Surg Sports Traumatol Arthrosc 22: 285–290. [Crossref]
  3. Klouche S, Lefevre N, Cascua S, Herman S, Gerometta A, Bohu Y (2015) Diagnostic value of the GNRB® in relation to pressure load for complete ACL tears: A prospective case-control study of 118 subjects. Orthop Traumatol Surg Res 101: 297–300. [Crossref]
  4. Steltzlen C, Lefevre N, Bohu Y, Herman S (2011) Évaluation clinique d’une série continue de 55 cas de ligamentoplastie partielle du ligament croisé antérieur par la technique TLS (greffe courte aux ischio-jambiers). Rev Chir Orthopédique Traumatol 97: 493.
  5. Robert H, Nouveau S, Gageot S, Gagnière B (2009) A new knee arthrometer, the GNRB: Experience in ACL complete and partial tears. Orthop Traumatol Surg Res 95: 171–176. [Crossref]

Current Treatment of Traditional Chinese Medicine for Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Our Research

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DOI: 10.31038/JCRM.2020314

Introduction

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a male pelvic floor dysfunction, which usually manifests as urogenital pain, lower urinary tract symptoms, sexual dysfunction and psychological problems [1]. In China, a national survey shows that the prevalence of CP/CPPS in 2009 was 4.5% [2]. The treatment options of CP/CPPS includes antibiotics, α-blockers, anti-inflammatory medications and so on, but we have to admit that patients and doctors are highly dissatisfied with the treatment of this disease [3]. Therefore, it is not surprising that patients often seek other forms of treatment.

In China, it is becoming more and more popular for patients to seek Traditional Chinese Medicine (TCM) treatment. To our knowledge, a systematic review of acupuncture treatment of CP/ CPPS was published in 2016 [4]. A systematic review of the efficacy and safety of moxibustion in the treatment of CP/CPPS was published in 2019[5]. In terms of drug treatment, although phytotherapy such as quercetin [6] and pollen extract [7] are reported to have a certain effect in the treatment of CP/CPPS, Chinese doctors use more compound prescriptions of TCM. There are few reports on oral TCM in the treatment of CP/CPPS, so we focuses on the current treatment of TCM in the treatment of CP/CPPS, as well as our research on the use of GuiHuang prescription in the treatment of CP/CPPS.

Treatment of CP/CPPS with TCM

In an open, multicenter, pre-and post-controlled clinical trial, 240 patients with type III prostatitis who met the diagnostic criteria of the National Institutes of Health (NIH) were treated with Longjin Tonglin capsule, 3 tablets per time, 3 times a day for 12 weeks. Taking NIH chronic prostatitis symptom index (NIH-CPSI) as the main curative effect index, the curative effect was compared before and after treatment. It was found that the total CPSI scores of patients with type III A prostatitis were 23.12 ±6.99(before treatment), after treatment4, 8 and 12 weeks were 18.22 ±6.39,14.12 ±5.88,12.36 ±6.04respectively (P< 0.0l). Before treatment and 4, 8 and 12 weeks after treatment, the total CPSI scores of patients with type III B prostatitis were 23.12 ±6.99,18.22 ±6.39,14.12 ±5.88,12.36 ±6.04 respectively. No abnormal liver and renal function and adverse events were found in the test.

It shows that Longjin Tonglin capsule is safe and effective in the treatment of type III prostatitis [8].

A systematic review on the efficacy and safety of the compound prescription of TCM for clearing away heat and promoting diuresis in the treatment of chronic prostatitis.Meta analysis showed that the compound prescription of traditional Chinese medicine for clearing away heat and promoting diuresis was superior to Prostat(RR1.26,95%CI1.13~1.41), and subgroup analysis showed that this compound was superior to Qianliekang(RR1.32,95%CI1.19~1.45) and quinolone antibiotics (RR1.34,95%CI1.15~1.57). There was no significant difference between heat-clearing and diuresis-promoting TCM and quinolone antibiotics alone (P< 0.01), and there was no serious adverse reaction reported [9]. No serious adverse reactions were reported.

A study was conducted to evaluate the safety and efficacy of Qianlie Shule granule in the treatment of chronic prostatitis. 66 patients with chronic prostatitis were enrolled in a multicenter, open, self-controlled clinical study. The patients were treated with Qianlie Shule granule 1 bag per time, 3 times a day for 6 weeks. The efficacy of the treatment was evaluated with the NIH-CPSI as the main evaluation index, TCM syndrome as the secondary efficacy index, urine routine and liver and kidney function indexes before and after treatment to evaluate its safety, and adverse events were recorded. The Results showed that NIH-CPSI before treatment was significantly higher than that after 6 weeks treatment (P<0.05), and the score of TCM syndrome waiting score was 11.15 ±8.54 before treatment and 3.56 ±3.83 after 6 weeks treatment, and the difference was also statistically significant (P<0.05). Qianlie Shule granule can relieve the urinary system related symptoms of patients with chronic prostatitis (kidney and spleen deficiency, qi stagnation and blood stasis syndrome), reduce NIH-CPSI and TCM syndrome score, the clinical effect is significant [10].

Our research

The rich clinical experience handed down by the ancestors of TCM for thousands of years, should also seriously evaluate the curative effect of TCM in accordance with the principle of evidence-based medicine. For this reason, we carried out the clinical study of GuiHuang prescription in the treatment of CP/CPPS. This study was randomly divided into two groups: treatment group (GuiHuang prescription group, n=33) and control group (Tamsulosin group, n=33). The patients were treated for 6 weeks and followed up for 2 weeks according to NIH-CPSI score and TCM symptom score. To observe the safety and efficacy of GuiHuang prescription in the treatment of CP/CPPS with dampness-heat stasis. The project was reviewed by the Medical Ethics Committee of Xiyuan Hospital on June 21, 2019, and obtained the ethical approval (batch number: 2019XLA019-3). The project was registered by the China Clinical trial Center (Registration No.: ChiCTR1900026966) on October 27th, 2019. At present, the project is still recruiting. The composition of GuiHuang prescription includes: Angelica 12g, Phellodendron chinense 12g, honeysuckle 15g, turmeric 10g, frankincense 5g, myrrh 5g, Angelica dahurica 10g, tangerine peel 10g, plantain 15g, Hedyotis diffusa 15g, which has the effect of clearing heat and removing dampness, removing blood stasis and relieving pain.

Comment

The best treatment for CP/CPPS has yet to be determined, and the basic strategy is based on symptom control and anxiety relief. The UPOINT phenotypic system (Urinary symptoms, Psychosocial dysfunction, Organ specific, Infection, Neurologic dysfunction and Tenderness of muscles ) play an important role in guiding the clinic [11]. At the same time, it reflects the individual differences of patients, with different phenotypes of different drugs, which is similar to the syndrome differentiation and treatment of TCM. It appears that a tailored treatment strategy addressing individual patient characteristics is more effective than one single therapy[12].

The use of TCM compound prescription, need syndrome differentiation addition and subtraction, according to the different physique and symptoms of patients, will use different prescriptions, there will be a patient a treatment prescription, which is not conducive to evidence-based research. In order to avoid insufficient, we fixed the composition of GuiHuang prescription, studied the patients in accordance with this prescription (damp-heat stagnation type), and we did not add or subtract the prescription. This can ensure the accuracy of the research results, and we are full of expectations for the results.

The compound prescription of TCM, which has been used clinically, such as Ningmitai capsule[13], which is a commercial formula, has been reported to have a good therapeutic effect and is safe. In clinical practice ,the use of TCM compound alone, or combined with western medicine is our Strategy for the purpose of clinical efficacy. There are also external uses of TCM, such as enema, TCM sitz bath.

The use of TCM compound prescription in the treatment of CP/ CPPS is very common. In our department, the proportion of patients taking oralTCM is more than 80%, but unfortunately, our reports are relatively few. The characteristics of TCM are often the first clinical use, such as GuiHuang prescription, we have used for more than a decade, the clinical effect is accurate, and then we are in clinical observation and research, have obtained a higher level of evidence, and then carry out mechanism research. However, we have some shortcomings, there are 10 herbs in the prescription, and the exact mechanism of the effect is not clear. At present, many studies are published in Chinese, which is not conducive to international promotion, and the recognition of research is affected. More published English-language clinical trials are needed to prove its effectiveness. We believe that TCM can be used as a supplementary treatment option for CP/CPPS.

Acknowledgement

This work was financially supported by Xiyuan Hospital Project, Grant number 2019XYMP–23

References

  1. Rees J, Abrahams M, Doble A, et al. (2015) Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline[J]. BJU Int, 116(4):509-525.[crossref]
  2. Liang CZ, Li HJ, Wang ZP, et al. (2009)The prevalence of prostatitis-like symptoms in China. J Urol182:558–63.[crossref]
  3. Anothaisintawee T , Attia J , Nickel J C , et al. (2011) Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome A Systematic Review and Network Meta-analysis[J]. JAMA The Journal of the American Medical Association, 305(1):78-86.[crossref]
  4. Qin Z, Wu J, Zhou J, et al. (2016) Systematic review of acupuncture for chronic prostatitis/chronic pelvic pain syndrome. Medicine (Baltimore) 95:e3095[crossref]
  5. Cao Q, Zhou X, Chen J, et al. (2019) Efficacy and safety of moxibustion in patients with chronic prostatitis/chronic pelvic pain syndrome: A systematic review protocol[J]. Medicine, 98(20):e15678.[crossref]
  6. Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. (1999) Quercetin in men with category III chronic prostatitis.Urology.54(6):960-963. [crossref]
  7. Wagenlehner FM, Schneider H, Ludwig M, et al. (2009) A pollen extract (Cernilton) in patients with inflamma-tory chronic prostatitis-chronic pelvic pain syndrome.EurUrol. 56(3):544-551. [crossref]
  8. Shang X J, Geng Q, Duan J M, et al. (2014) [Efficacy and safety of Longjintonglin Capsule for the treatment of type III prostatitis].[J]. 20(12):1109-12.[crossref]
  9. Ming-xingQiu, Guo-bingXiong, Shi-yi Zhou, et al. (2007)Qingrelishi-category Chinese medicine for chronic prostatitis: a systematic review[J]. National Journal of Andrology, 13(4):370-377.
  10. Zhoushaohu，Guojun，Cuigang，et al. (2019) Qianlieshule Granules for chronic prostatitis: A multicenter self-controlled clinical trial[J]. Chinese Journal of Andrology.33(05):48-51.
  11. Shoskes D, Robert D, Nickel C.(2010) 798 phenotypically directed multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome: a prospective study using upoint[J]. The Journal of Urology, 183(4):e312.[crossref]
  12. ThunyaratAnothaisintawee, John Attia, J Curtis Nickel,et al.(2011) Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome A Systematic Review and Network Meta-analysis[J]. Jama, 305(1):78-86.[crossref]
  13. Jin C, Chen Z, Zhang J.(2018) Meta-analysis of the efficacy of Ningmitai capsule on the treatment of chronic prostatitis in China.Medicine (Baltimore). 97(33):e11840.[crossref]

On the Muricid snail, Plicopurpura pansa, in the Pacific coast of Central America

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DOI: 10.31038/AFS.2020213

Abstract

The Muricid snail, Plicopurpura pansa, in Central America has been studied, and the secretion of hypobanchial gland and its utilization are discussed. P. pansa exudes a few drops of secretion in the gland at being picked up. The secretion has been used historically in various forms for dyeing. There is no other region where the dyeing by drops has been carried out. It is noteworthy that the shell is not hammered or cracked, and the snail is released or put back at the same place where it was. The name of “Pacific purple” is proposed for the dye and its color. A decreasing the stock population and the smaller individuals in size are reported. The Pacific coast of Central America is a unique area of artisanal textile culture, and intensive investigations on the species are now required for biological and cultural conservation.

Keywords

Muricid, Plicopurpura pansa, Central America, purple dye, dyeing method, Pacific purple, secretion, hypobranchial gland, 6,6’-dibromoindigo

Secretion of the gland and dyeing

The present study of Plicopurpura pansa focuses on the secretion in hypobranchial gland and a utilization of that, and reviews the result of field studies in El Salvador. Little comparative study among the species in other regions was conducted.

 The Muricid snails are characterized by the hypoblanchial gland, and its secretion makes it possible to dye textiles. The dying activities are reported historically in the Pacific coast of Central America and in Mediterranean region, especially at Phoenicia [1, 2]. In European countries, the dye and its color has been called Tyrian purple, Royal purple, Phoenician purple, and so on [2,4]. The color pigment was revealed to be 6, 6’-dibromoindigo, and the chemical structure is shown (Figure 1) [3].

AFS_2020-Hiroshi KITANI_F1

Figure 1. Chemical structure of 6,6’-dibromoindigo, and the process of reduction, leuco- 6,6’-dibromoindigo (Sawada 2014)

The distribution of P. pansa in El Salvador is limited at headland area with breaking water and rocky shore, not sand beach or stone beach, and the dyeing activities have been carried out in there.

The present study groups the dying methods into the two (Figure 2). The one (A) is the method by the drops of secretion and the second (B) by the tissues cut out of the gland. The former has been introduced only in Central America.

AFS_2020-Hiroshi KITANI_F2

Figure 2. Dyeing methods by the secretion of Muricid snail

It is observed that P. pansa exudes a white liquid of secretion at being picked up, which means that the white liquid flows out in the shell aperture, and it’s volume is about 0.3ml or 3 drops per individual of 3cm/shell length. However no comparative study about the relation between the volume and the body weight/size was conducted, the volume of the secretion of P. pansa is supposed to be too much than that of other Muricid. It is a characteristic of the species, and other Muricid requires a cracking the shell and cutting the tissue out of the gland for extracting dye pigment.

The method by drops (A) is very efficient for dyeing directly. The present study confirmed a stocking of fresh drops in refrigerator for a few days, which is very convenient for laboratory works. At flowing out the white liquid into the aperture, it is possible then to drop the liquid and dye directly the cotton yarn in the hand. The color of drops changes gradually from milky white, white green, and finally to purple color in 15 minutes under the sunlight.

The second (B) requires a process of cutting the tissue out of hypobranchial gland. After grinding the tissue in a bowl to be a watery paste, it is now possible to use it directly for painting or dying textiles (B1). Furthermore, the cut-out tissue is applicable for extracting the dye by chemical reductant (B/B2, B3) (Figure 2). After obtaining the paste (B), an adding water makes it possible to filter the fluid, and then the dye pigment, 6,6’-dibromoindigo, is extracted in the liquid filtered. It is now possible to reduce the liquid by adding the reductant such as sodium hydrosulfite (Figure 1). Then, the dyeing textile is possible in a dark room and then after under the sunlight for coloring. In this case, a volume of textile can be dyed smoothly. Powdered dye is also available after drying the filtered liquid, and then the dyeing is introducible at any place and at any time under the same procedure of B1. The method by reduction (B) has not been introduced in Central America.

The dye and its color have been called in general Tyrian purple [2,4], but it is considered to be a product by reduction. That product has not been introduced in Central America, neither Tyrian purple. The dyeing method by the pure secretion and that by reduction are not the same, however the color pigment 6,6’-dibromoindigo is the same among the species. The present study names it “Pacific purple” for the dye and its color originated from the drops of P. pansa, which shows a better distinctiveness of the dyeing.

Biology

The functions of the secretion have been unclear. Some observations reported a toxic or anesthetic substance against the prey. Muricid such as oyster drills is a well known predator and a possible user of secretion to oysters. It is observed in laboratory that Rapana sp. uses the secretion against bivalves. The present study observed P. pansa preying on a smaller snail, Littorina sp.. It is experienced that the whole meat stimulates or irritates the tongue at eating and is inadequate for seafood, however some large sized snails such as Conchalepas sp. in Chile and Peru, and also Repana sp. in Turkey are important sea foods, but the secretion of these species are not utilized currently.

The habitat of P. pansa in El Salvador is limited on the rock surface or in a crack of rock, and stays for days at 3–5 m over the water line, where is a zone of without or less water. Video movies in Mexico show the collecting snails and dyeing at water line, which is a remarkable difference of the habitat. The behavior and habitat induce an assumption that the secretion would effective for a respiration while staying over the water line, because it is supposed that the water stocked inside the shell may be insufficient for staying days over the water line. It is supposed that Muricid in the water does not need additional oxygen, and secretes successively little volume of secretion. No conclusive study has been conducted on the secretion, but the present observation on P. pansa concludes that the releasing snails after dyeing should be returned to around the water line, not the same place where it was.

It is reported also that the Muricids lay eggs in capsules and it is reported that damaged capsules show a dark purple color, which suggests that the liquid in the capsule would contain the color pigment or the secretion. The biological study on egg capsule would be effective for larval production in laboratory.

There are little biological and ecological studies such as growth, reproduction, larval development, habitat, daily and seasonal movement, stock population, regional difference of the species, ad so on, which seem to be obstacles for the advanced developments and studies of P. pansa.

Development and conservation

Central America is the only place where the dyeing by secretion of Muricid is carrying out. It is a traditional culture for a long time [1], and the Pacific purple has been popular among the local people, however a limited production due to unstable dyeing works at seashore. No evidence of symbol color of authority or status has been reported as was Tyrian purple in Europe.

The dyeing textile by drops is very efficient and there would be no local need for improving the method or developing a new utilization. The present study has observed that a general interest in the natural purple is fading away, but a high interest exists also in enjoying the dye and its color by different ways from the past, specially in mysterious color changing every second, saying “palm-top miracle and wonder”.

The present study suggests new utilizations such as a body painting, nail art, painting on the T-shirts, tourisms, traditional dyeing, biological/chemical study for younger generations, as well as a possible pharmaceutical and cosmetic use, and so on. The chemical product of 6,6’-dibromoindigo has been developed synthetically in Japan and it is reported that the examination of the fatness such as rubbing, washing, perspiration, and against light shows a better grade than those of indigo [3].

There seems to be little technical obstacles for utilizing the drops, but exists biological obstacles mentioned previously. Furthermore, some articles [1, 5] reported a possible fade-out of the culture and a heavy exploitation of the resources in the past.

The textile culture in Central America is very unique, and the tradition of living together with the resources of Pacific purple is highly praised. The present study emphasizes the necessity of effective biological and cultural conservation programs for the regional assets before being forgotten.

References

  1. Secretaría de Educación Pública(SEP) (1988) El caracol púrpura, Una tradición Milenaria en Oaxaca, Mexico,ISBN 968-29-1867-7 (in Spanish)
  2. Takako Terada (2005) Fieldwork on shellfish purple, Kwassui bulletin 48, p51–61. Kwassui Women’s University. (in Japanese)
  3. Tadanobu Sawada, Hiroyuki Ishii, Harue Senou, Toyotoshi Ueda (2014) Color Fastness of Ancient Purple 6,6’-Dibromoindigo after Dyeing. The Journal of Silk Science and Technology of Japan.  22: 57–63.
  4. Ludwig CA, Naegel, Federico A. Garcia-Dominguez (2006) Reproductive cycle of the purple snail Plicopurpura pansa (Gould 1853) from two locations at Baja California Sur, Mexico. Journal of Shellfish Research 25: 925–933

Clinical Evidence on Apatinib in Treating Chemotherapy-Refractory Metastatic Esophageal Squamous Cell Carcinoma

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DOI: 10.31038/JCRM.2020313

Abstract

Majority Chinese esophageal cancer patients are squamous cell carcinoma (ESCC) and with metastasis at initial diagnosis. Treatment for metastatic ESCC who failed first-line chemotherapy is an unmet medical need. Targeting human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor 2 (KDR) have been approved to be effective for esophageal adenocarcinoma (EAC). We explored the clinical relevance of these molecular signaling in ESCC cohorts and collected clinical evidence on applying apatinib, a Chinese FDA-approved KDR inhibitor for late-stage gastric carcinoma, in 26 patients with chemotherapy-refractory metastatic ESCC. The clinical response rate and disease control rate of these patients to apatinib 500mg once daily regimen was 12% and 60%, respectively. The patients’ median progression-free survival time (PFS) was 3.2 months (95% CI, 2.23-4.17 months) and overall survival time (OS) was 5.3 months (95% CI, 4.46-6.14 months). The commonest grade 3-4 treatment related adverse events included leukopenia (7.7%) and anemia (7.7%). No drug-related death occurred. In conclusion, apatinib has favorable activity and acceptable safety, and could be a new treatment option for patients with chemotherapy-refractory metastatic ESCC.

Keywords

apatinib, chemotherapy-refractory, metastatic, esophageal squamous cell carcinoma

Introduction

In China, esophageal carcinoma (EC) is the third most frequent cancer and the fourth leading cause of cancer death [1]. As it’s different from western countries where esophageal adenocarcinoma (EAC) is more common, 95% of the clinical pathological type of Chinese EC is squamous cell carcinoma (ESCC)[1]. Approximately 130,000 new cases of ESCCs are diagnosed annually in China and most of them are with metastasis at initial diagnosis [1]. Even for patients undergo surgery at an early stage, more than half of ESCCs proceed recurrence or metastases within 2-3 years [2]. Treatment of ESCC has not really changed for 30-40 years and primarily consists of chemotherapy [3]. Platinum or fluorouracil-based regimens are the first-line treatment for metastatic ESCC, with a median progression-free survival (PFS) less than 6 months [4]. No chemotherapeutic regimen has been defined for those who failed first-line chemotherapy.

Several targeted therapies have been approved for the treatment of EAC by the US Food and Drug Administration (FDA), including trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive esophageal or gastric adenocarcinomas, and the anti-vascular endothelial growth factor (VEGF) receptor 2 (KDR) antibody ramucirumab either as a single agent or in combination with paclitaxel in the second-line setting. To explore the scientific rationale of these targeted strategy in ESCC, we did a comprehensive analysis of the expressions of HER2, KDR and VEGF in clinical ESCC cohorts in comparing to normal esophagus tissue. The results indicate that KDR and VEGF are consistently over-expressed in multiple ESCC cohorts, while the expression of HER2 is even downregulated in ESCC, suggesting a potential anti-KDR strategy for ESCC.

Apatinib was approved by Chinese FDA in 2014 for patients with latestage gastric carcinoma through targeting KDR. It has been reported to inhibit VEGF-mediated tumor microvascular density and tumor growth in ESCC cell lines and xenograft mice [5]. Some patients with advanced EC have tried various targeted drugs as a subsequent line treatment including apatinib [6, 7]. However, most of the studies were not stratified according to tumor histology, a systematic study focusing on the efficacy and safety of apatinib for the ESCC patient with chemotherapy-refractory metastasis is barely reported. In this regard, we conducted a retrospective study and investigated the efficacy and toxicity of apatinib in treating 26 patients with chemotherapy-refractory metastatic ESCC.

Methods

Bioinformatics data mining

GSE23400 dataset including 53 ESCC tumor samples and 53 adjacent paired normal esophagus samples [8] and GSE20347 dataset including 17 ESCC micro-dissected tumor samples and 17 matched samples from adjacent normal esophagus tissue [9] were used to analyze the mRNA expression and DNA copy number of HER2, KDR and VEGF in ESCC. GSE13898 dataset including 75 EAC samples from 64 patients and 28 paired normal esophageal samples [10] and GSE36458 dataset including 112 EAC and 45 normal tissue [11] were used to analyze HER2, KDR and VEGF expression in EAC. Analyses were performed using GEO2R with default settings.

Patients

This single-institution single-arm retrospective study was approved by the Ethics Committees of Henan Cancer Hospital and carried out in accordance with the Declaration of Helsinki. All patients provided written informed consent before participating in the study. Patients with chemotherapy-refractory metastatic ESCC received apatinib as subsequent line treatment between December 2015 and December 2016 were included. ESCC was confirmed histologically, and was surgically unresectable or recurrent. Metastasis in these patients were examined in lymph nodes, liver, lung or mediastinum. Patients had to have first-line chemotherapy failure before participating in the study. Treatment failure was defined as intolerable adverse effects or disease progression during treatment. Additional enrollment criteria were as following: at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; a life expectancy of >12 weeks; and acceptable hematologic, hepatic, and renal function. Patients with uncontrolled blood pressure with medication (140/90 mmHg), or with bleeding tendency, or receiving thrombolytics or anticoagulants were excluded.

Treatment

Patients received oral apatinib 500 mg (Hengrui Pharmaceutical Co., Ltd., Shanghai, China) in tablet form once daily. A treatment cycle was 28 days. No local radiotherapy or interventional therapy was offered during apatinib dosing. Dose reduction was allowed one time to a dose level not lower than 250mg once daily. Dose re-escalation was not permitted. Patients continued treatment until disease progression or experienced intolerable toxicity or withdrew consent from the study.

Statistical analysis

Response was assessed according to the RECIST version 1.1 as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) in patients with measurable lesions. Tumor assessments took place every 8 weeks using computed tomography. Progression free survival (PFS) was measured from the initiation of apatinib to the occurrence of progression, or death without evidence of progression. Overall survival (OS) was measured from the first day of apatinib administration to the day of death or to the final day of the follow-up period. Survival curves for OS and PFS were estimated using the Kaplan-Meier method. Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Safety analysis set consisted of all patients who received at least one dose of apatinib and completed the required safety data collection. Primary end points were safety and PFS. The last follow-up was performed on May 1, 2017.

Results

Gene expression of HER2, KDR and VEGF in EC cohorts

There are much less clinical annotated gene profiling datasets of EC than other common cancers. We chose four most comprehensive datasets (GSE23400, GSE20347, GSE13898 and GSE36458) with relative large sample size to evaluate the gene expression of HER2, KDR and VEGF in ESCC and EAC cohorts. As shown in Figure 1, EAC cohorts have consistently increased mRNA expression and DNA copy number of HER2 (P=0.038 and 8.51E-04, respectively), while only have over-expressed KDR (P=0.007) but not VEGF (P=0.194). In contrast, ESCC cohorts have consistently over-expressed KDR and VEGF (P=0.019 and 1.44E-07, respectively) but even downregulated mRNA and DNA copy number of HER2 (Log2 fold change = -1.037, and -2.164, respectively) (Figure 2). These results not only provided scientific supports to the anti-HER2 treatment strategy for EAC, but also may indicate the potential of anti-KDR strategy for ESCC.

JCRM-3-1-1-g001

Figure 1.Expression of HER2, KDR and VEGF mRNA or DNA copy number in EAC vs. normal esophageal tissue in the GSE13898 (10) and GSE36458 (11) datasets. A. HER2 mRNA expression in EAC tissue (n=75) is significantly higher than that in the normal esophageal tissue (n=28). Log2 FC=1.032, P=0.038. B. HER2 DNA copy number in EAC tissue (n=112) is significantly higher than that in the normal esophageal tissue (n=45). Log2 FC=1.100, P=8.51E-04. C. KDR mRNA expression in EAC tissue (n=75) is significantly higher than that in the normal esophageal tissue (n=28). Log2 FC=1.077, P=0.007. D. VEGF mRNA expression in EAC tissue (n=75) and normal esophageal tissue (n=28). Log2 FC=1.038, P=0.194.

JCRM-3-1-1-g002

Figure 2.Expression of HER2, KDR and VEGF mRNA or DNA copy number in ESCC vs. normal esophageal tissue in the GSE23400 (8) and GSE20347 (9) datasets. A. KDR mRNA expression in ESCC tissue (n=51) is significantly higher than that in the normal esophageal tissue (n=51). Log2 FC=1.072, P=0.019. B. VEGF mRNA expression in ESCC tissue (n=51) is significantly higher than that in the normal esophageal tissue (n=51). Log2 FC=1.368, P=1.44E-07. C. HER2 mRNA expression in ESCC tissue (n=51) and normal esophageal tissue (n=51). Log2 FC= -1.037, P=0.867. D. HER2 DNA copy number in ESCC tissue (n=51) and normal esophageal tissue (n=51). Log2 FC= -2.164, P=1.00.

Patient characteristics

Between December 2015 and December 2016, 26 patients were enrolled in this study, and 5 patients were excluded because of ineligibility. The median age was 64 years (range: 48–75 years). Nineteen patients (73.1%) had good performance status, with an ECOG score of 0 or 1. Eight patients had esophagectomy and 18 patients had un-resectable primary ESCC. All patients had metastasis and the most common metastatic sites were lymph nodes (80.8%), liver (46.2%), lung (38.5%) and mediastinum (34.6%). All patients were failed to prior treatment: 17 patients received first-line chemotherapy and the other 9 patients received second-line chemotherapy. The baseline characteristics are summarized in Table 1.

Table 1.Baseline Patient Characteristics

N=26

Characteristic

No.

%

Sex

Male

17

65.4

Female

9

34.6

Age, years

Range

48-75

Median

64

ECOG Performance status

0

8

30.8

1

11

42.3

2

7

26.9

Prior chemotherapy

First line

17

65.4

Second line

9

34.6

Third line

0

0

Metastases

Lymph nodes

21

80.8

Mediastinum

9

34.6

Lung

10

38.5

Liver

12

46.2

Bone

4

15.4

Others

5

19.2

Esophagectomy

Yes

8

30.8

NO

18

69.2

Radiotherapy

Yes

12

46.2

NO

14

53.8

Abbreviations: ECOG: Eastern Cooperative Oncology Group

Toxicity

A total of 26 patients received at least one dose of apatinib and were included in safety analyses. All grade adverse events are listed in Table 2.

Table 2.Adverse Events graded based on CTCAE 4.0

Apatinib(N=26)

Adverse Events

Grade 1/2, n(%)

Grade 3, n(%)

Grade 4, n (%)

Hematologic

Leukopenia

8(30.8)

1(3.8)

 1(3.8)

Neutropenia

6(23.1)

1(3.8)

−

Thrombocytopenia

4(15.4)

−

−

Anemia

10(38.5)

2(7.7)

−

Non-hematologic

Proteinuria

3(11.5)

−

−

Hypertension

6(23.1)

1(3.8)

−

Bleeding

2(7.7)

−

−

Esophageal fistula

−

1(3.8)

−

Fatigue

6(23.1)

1(3.8)

−

Appetite loss

9(34.6)

−

−

Nausea

7(26.9)

−

−

Vomiting

5(19.2)

−

−

Abdominal pain

  4(15.4)

−

−

Diarrhea

6(23.1)

−

−

Hand-foot skin reaction

3(11.5)

−

−

Hypoproteinemia

3(11.5)

−

Hypocalcemia

2(7.7)

1(3.8)

−

Liver function

Hyperbilirubinemia

4(15.4)

−

−

Elavatedtrasaminase

5(19.2)

−

−

Renal disorder

Creatinine clearance decrease

2(7.7)

−

−

Hypothyroidism

4(15.4)

1(3.8)

−

Others

 Heart failure

−

1(3.8)

−

Abbreviations: CTCAE, Cancer Institute’s Common Terminology Criteria for Adverse Events

The most common adverse events are grade 1 to 2 and manageable. For seven patients, apatinib was reduced to 250mg daily. The main reasons for dose reduction were appetite loss, fatigue, hypertension, hypothyroidism and renal function impairment. The most common grade 3 side effects included hypertension (3.8%), fatigue (3.8%), esophageal fistula (3.8%), hypocalcaemia (3.8%), hypothyroidism (3.8%) and heart failure (3.8%). Two patients withdrew the study because of grade 3 esophageal fistula and acute heart failure. Except for 1 patient who had grade 4 leukopenia, no other grade 4 toxicities were observed. One patient died of injuries after receiving 24 days of apatinib treatment. No drug-related death was observed.

Treatment efficacy

Of the 25 evaluable patients, PR was observed in 3 patients (12%) and SD was observed in 12 patients (48%). No patients met CR. Ten patients (40%) experienced disease progression. The overall response rate (ORR) and disease control rate (DCR) was 12% and 60%, respectively (Table 3). The median PFS of all 26 patients was 3.2 months (95% CI, 2.23-4.17 months) (Figure 3) and OS was 5.3 months (95% CI, 4.46-6.14 months) (Figure 4). We noted that the metastatic tumors were well responsive to the apatinib treatment in the 15 patients with PR or SD. As shown in Figure 5, metastatic tumors in lung and lymph nodes of one patient were ~50% reduced after one cycle apatinib treatment; in another patient apatinib killed ~80% liver metastatic tumors. Even in the patients experienced tumor progression for their primary ESCCs, 8 of the 10 patients showed mild shrinkage or no-change for the metastatic tumors after the apatinib treatment.

Table 3. Analysis of clinical efficacy

Apatinib

Efficacy

Number of patients (N=25)

%

Complete response

0

0

Partial response

3

12

Stable disease

12

48

Disease progression

10

40

Disease control rate (%)

 60

Overall response rate (%)

 12

JCRM-3-1-1-g003

Figure 3.Kaplan-Meier curve of progression free survival (PFS) of patients with apatinib treatment.

JCRM-3-1-1-g004

Figure 4.Kaplan-Meier curve of overall survival (OS) of patients with apatinib treatment.

JCRM-3-1-1-g005

Figure 5.CT images of two ESCC patients with lung and lymph node metastasis (Pt 1, A) and liver metastasis (Pt 2, B).

Discussion

Prognosis of patients with metastatic ESCC after progression on first-line chemotherapy is poor, further cytotoxic chemotherapy provides little benefits and with significant treatment-related toxicity.

Therefore, it’s always under an urgent need to discover novel targeted therapies, which are more effective and less toxic than traditional chemotherapy options. It’s known that EAC and ESCC have completely different molecular biological characteristics. Although there have been several approved targeted therapy for EAC, whether they are beneficial to ESCC patients need exploration. In the current study, we provided both scientific and clinical evidence on apatinib through targeting the VEGF-KDR signaling in chemotherapy-refractory metastatic ESCC patients and with well-tolerated side effects.

Data from our study suggests a promising beneficial effect of apatinib in managing the metastatic ESCC patients after failed to chemotherapy. Overall, we observed a profound inhibition on metastatic tumor growth in the cohort, including tumor shrinkage at metastatic sites in all 15 patients with PR or SD, and effective controlling of tumor growth at metastatic sites in 8 of the 10 patients experienced tumor progression for their primary ESCCs. In comparing with EAC, metastatic ESCC patients have higher activations of VEGFKDR signaling in tumor tissue and blood [12], and tumor lesions at metastatic sites are more VEGF-KDR dependently angiogenic [13]. Apatinib has been shown in several tumor metastasis models in inhibiting angiogenesis and has superior anti-tumor effects [14-16]. Ideally, we would perform a tissue correlative study to compare the expression of KDR in the before- vs post-treated tumor samples. However, in these advanced and heavily-treated patients, multiple re-sampling of tumor tissue is almost impossible, and we didn’t have chance to obtain any tissue from the post-treated tumors. Anti-angiogenesis agents usually do not directly induce tumor cell cytotoxicity. Thus a prospective study in combining apatinib with switched chemotherapy is planned in our hospital.

We also observed a median PFS of 3.2 months and OS of 5.3 months in the cohort, and a 12% clinical response rate and 60% disease control rate, which is consistent with a recent study of apatinib in advanced ESCC patients [7]. Other anti-VEGFR inhibitors including sorafenib and sunitinib have been explored in advanced EC patients [17, 18], suggested their ability to stabilize chemotherapy-refractory disease. However, these studies were not exclusive to ESCC and 80% of the enrolled populations were EAC, thus the results were not stratified according to histology. In addition, we examined similar or less toxicities of apatinib than sorafenib or sunitinib in the study cohort. Grade 3/4 toxicities of single sorafenib in patients with advanced EC included a relative high percentage of rash/hand-foot reaction, even causing treatment discontinuation [17]. Combination of sunitinib with paclitaxel in advanced EC patients demonstrated more serious toxicities than single apatinib or sorafenib [18]. Grade 3/4 toxicities included high percentages of leukopenia/neutropenia (25%) and anemia (18%). Several grade 5 toxicities were even observed including upper gastrointestinal hemorrhage and esophageal fistula [18]. Our study suggests a favorable safety profile of apatinib in comparison with these anti-angiogenic agents for chemotherapy refractory metastatic ESCC patients.

We strongly agree that successes of targeted therapies depend on biomarker-driven patient selection. There has been no conclusion on biomarkers for all anti-angiogenic drugs. A biomarker study of apatinib in patients with breast cancer showed that high expression of phosphorylated KDR in tumor tissue could predict treatment efficacy [19]. For metastatic tumors, circulating VEGF might be more revealing than tissue analyses. A clinical correlative study in further investigating circulating VEGF and tissue KDR expression as potential biomarkers to predict the efficacy of apatinib in metastatic ESCC patients is undergoing in our hospital.

In conclusion, apatinib has demonstrated favorable activity and acceptable safety, and could be a new treatment option for patients with chemotherapy refractory metastatic ESCC. For further study, apatinib 500 mg once daily is the recommended dose. The prospective phase II trial including circulating biomarkers to predict treatment response is ongoing (NCT03170310).

Acknowledgement

This work was supported by National Natural Science Foundation of China (grant number 81201954).

References

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Heparan Sulfate-Modifying Enzymes: Intriguing Players in Cancer Progression

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DOI: 10.31038/CST.2020513

 

Heparan sulfate (HS) is a sulfated glycosaminoglycan that is deposited in human tissue matrices at specialized sites [1,2]. HS interacts with diverse extracellular matrix (ECM) components with HS binding sites, including inflammatory cytokines, and heparin-binding growth factors (HBGFs) [3,4]. Within the ECM and in the cell surface glycocalyx, HS-proteoglycans (HSPGs) act as reservoirs for cytokines and HBGFs, and as cofactors for surface receptors where they stabilize active signaling complexes [5–7]. The bioavailability and activity of HBGFs stored on HSPGs are primarily regulated by HS-modifying enzymes that act on HSPGs, such as perlecan, the syndecans and the glypicans [8,9]. Therefore, HSPGs and their enzymic modifiers are crucial for tissue homeostasis, both in normal biology, as in development and wound healing, and in pathological processes such as fibrosis and cancer biology [1,10,11]. To date, studies have identified three key extracellular enzymes that modulate HS function and growth factor signaling: tissue heparanase (HPSE) and the extracellular endosulfatases SULF1 and SULF2. HPSE is an endoglycosidase that cleaves HS chains yielding diffusible HS fragments [12] that often still retain bound growth factors (Fig. 1A). HS-bound growth factors can subsequently bind to surface receptors to form HS-HBGF-receptor ternary complexes (Fig. 1B) [12]. Like HPSE, SULFs are secreted but, for the most part, stay peripherally associated with the cell surface through the interaction with HSPGs in the glycocalyx, primarily syndecans and glypicans [13,14]. Enzymatic activity of SULFs involves selectively removing 6-O-sulfate groups from HS polymers (Figure 1A) [14,15]. Because many HBGFs require 6-O-sulfate for high-affinity binding to HSPGs or surface coreceptors [3,15,16], SULFs release HBGFs in a form free from HS chains. Freed HBGFs can bind subsequently to cognate cell surface receptors to form signaling complexes, or they may rebind to distant unmodified HSPGs that retain 6-O-sulfate. Therefore, both HPSE and SULFs are crucial enzymes that define activation parameters of HS-independent signaling networks in both positive and negative ways that often are context-dependent [17,18].

CST 2020-502-Daniel D. Carson_F1

Figure 1. HS-modifying enzymes HPSE and SULFs release HBGFs with outcomes that are influenced by context. A. HPSE directly cuts HS chains to increase availability of HBGFs bound to HS fragments, while SULFs remove 6-O-sulfate residues (light blue circles) and release HBGFs free of HS. B. HS can act as a cofactor and stabilize HBGF binding to receptors via ternary complexes, while other factors transduce their signals via binary complexes. C. Spatial distribution of HPSE and SULFs produce opposing signaling effects when these enzymes act at the cell surface versus release factors bound in the ECM. At the cell surface, SULFs can disrupt ternary complex formation by HS desulfation, inhibiting downstream signaling. D. Infiltration and activation of tumor-associated cells, both TAMs and CAFs, contribute to regulation of HPSE and SULF expression and enrich the tumor milieu with HSPGs and HBGFs.

Better understood than the SULFs, HPSE generally is regarded as a tumor promoter. Cleavage of HS by HPSE releases and increases the availability of HBGFs, including vascular endothelial growth factors, hepatocyte growth factors [19–22] and fibroblast growth factors [23–26], thereby improving their access to their cell surface receptors and enabling downstream growth signaling. Consequently, HPSE can stimulate pro-tumorigenic processes including neoangiogenesis, tumor cell proliferation and invasion, inhibition of apoptosis, and metastasis, all among the well-accepted hallmarks of cancer [27,28]. Because of the intricacies from potential outcomes of SULF activity, predicting their impact on complex microenvironments, a priori, such as tumors, is more complicated. Numerous studies have implicated the SULFs as significant players involved in critical aspects of cancer progression, including proliferation, invasion and metastasis [1,15]. The expression of these intriguing enzymes is abnormal in many carcinoma cells, yet no consensus conclusion has been made as to whether they support or inhibit general cancer progression. Some of this confusion may be attributed to differences in regulation of gene expression between SULF1 and SULF2. For example, tumor necrosis factor α (TNFα) [29] and Wilm’s tumor transcriptional factor [30] stimulate SULF1 expression to a greater extent than SULF2. In contrast, SULF2, but not SULF1, is a p53 target [31]. A comparison of potential transcription factor binding sites (TFBS) in the SULF1 and SULF2 promoter regions in silico revealed that ~50% of TBFS were not shared between these two genes [32]. Therefore, dysregulated transcriptional programs and different transcriptional targeting in SULF genes both in cancer cells and cells in the tumor microenvironment may partially explain some of the apparently contradicting data concerning SULF functions in tumorigenesis.

A review of studies focusing on SULFs and published in the past twenty years reveals contrasting expression levels and opposing effects on tumor growth depending on the type of cancer and the surrounding microenvironment. For instance, an analysis of SULF1/SULF2 in various cancer cell lines suggested a mostly tumor-suppressing role of SULFs [33]. In contrast, other researchers demonstrated that high SULF1 or SULF2 levels correlate with poor prognosis in a wide range of tumor types [34]. Additionally, contrary to SULF2, SULF1 can exert a tumor suppressor effect in cancers, including myeloma, ovarian, head and neck, breast, liver, and pancreatic [33,35–39] cancers, despite being upregulated in others [40]. The paradox of how SULFs, sharing essentially identical target specificity, have different biological functions remains an open research question. In seeking to reconcile these observations, an essential point to consider is the signaling context. Most of the studies mentioned above solely focused on the cancer compartment, where cultured cells respond to artificially supplied HBGFs. However, there is overwhelming evidence that associated “bystander” stromal cells play a vital role in the regulation of tumor growth [41–13]. Cancers with reduced expression of HPSE or the SULFs still may be impacted by the actions of these enzymes in scenarios where they are being produced by cancer-associated fibroblasts (CAFs) and/or tumor-associated macrophages (TAMs). In recent years, the role of immune cells in cancer progression has gained increased attention. TAMs stand out as a major cell population in the tumor stroma [44] where they can, together with CAFs, modulate the expression of matrix remodeling enzymes, HSPGs, and HBGFs via pro- and anti-inflammatory cytokines [45–48] (Fig. 1D).

Also part of the signaling context controlling cell behavior are the specific ligands and their binding preferences to various HS modifications, spatial distribution of the enzymes themselves, cellular composition of the microenvironment, and the combination of HBGFs and cytokines present. Examples of such variations include whether: 1) ligands require HS fragments as cofactors for ternary complex signaling (Fig. 1B); 2) desulfation results in HBGF release or disruption of cofactor potential; 3) the enzymes are more abundant at the cell surface or in the ECM (Fig. 1C); 4) a robust reactive stroma response supporting cancer progression is present. While SULFs have been shown to suppress signaling at the cell surface through disruption of coreceptor functions, their release of HBGFs from fibroblasts in a desmoplastic stroma might favor growth. To date, studies exploring the influence of these different aspects of the signaling context are scarce, primarily from a lack of in vitro model systems that can reproduce the convoluted tumor microenvironment. Recent improvements in bioengineered cancer tissues are changing this, and new insights are on the horizon. While several HPSE inhibitors have reached and/or are currently undergoing clinical trials [49,50], no drug targeting the SULFs specifically has reached the clinic. Given the diverse nature of SULF expression and opposing activity in different contexts, as discussed above, targeting SULFs for cancer therapy is a complex endeavor. A key concern relates to the consequences of potentiating or inhibiting SULF activity. While silencing SULFs can lead to anti-tumor effects in some cancers, in others where they act as tumor suppressors, SULF inhibition could enhance tumorigenicity. A significant amount of pre-clinical work is needed to understand the full repertoire of pro- and anti-tumor activities of the SULFs such that SULF-based therapies can be designed with confidence. Nonetheless, the undeniable involvement of HPSE and SULFs in regulating cancer progression makes these enzymes attractive both as therapeutic targets and prognostic indicators of tumor progression.

Acknowledgements

This work was supported by P01CA098912 from the National Institutes of Health and the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES).

Keywords

Heparin-binding growth factors, Heparan sulfate-Proteoglycans, Matrix-remodeling enzymes

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Malignant Urinary bladder paraganglioma in 12 year old boy

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DOI: 10.31038/EDMJ.2020415

Introduction

Paraganglioma of the urinary bladder is rarely encountered and its biological behavior is uncertain. Paragangliomas are extra-adrenal neoplasms of the neural crest derivation, and if hormonally active, they are termed pheochomocytoma. They account for less than 0.05 % of all bladder tumors and less than 1 % of all pheochromocytomas [1]. In the genitourinary tract, the urinary bladder is the most common site (79.2 %), followed by the urethra (12.7 %), pelvis (4.9 %), and ureter (3.2 %) [2,3]. Haematuria and intermittent hypertension during micturition are among the usual clinical signs along with generalised symptoms due to raised catecholamines such as headache, blurred vision, heart palpitation and flushing. Furthermore, the consequences of hypertension itself may muddle the initial diagnostic picture of these patients. Patients often seek medical attention only when their hypertension has become so advanced as to cause syncope, retinopathy or intracranial haemorrhage. In addition, symptoms and signs of urethral obstruction may occur when the tumour is within the vicinity of the urethral opening(4).However, 27 % of pheochromocytoma of the urinary bladder do not feature any hormonal activity [3]. The pheochromocytoma of the bladder was first described by Zimmermann in 1953 [5], and a little more than 100 cases have been spotted since then [1].

Treatment strategies for these tumours are not well-defined because of their rare incidence. We present a rare case of paraganglioma of the urinary bladder where a partial cystectomy was performed.

Case report

12yr old boy presented with history of episodic severe headache for 2 months duration; severe, holocranial associated with vomiting episodes. Headache was often accompanied with diaphoresis, anxiety and nervousness. He also had history of left retinal detachment one year back .On evaluation he was found to be hypertensive, BP – 200/170 mm Hg. There was no history of any familial disorder (MEN syndrome) or family h/o hypertension. Biochemical assessment revealed an elevated 24-hour normetanehrine of 3863/24 hours (<600).Initial localization of the paraganglioma was through contrast enhanced computed tomography (CT) of the abdomen and pelvis which revealed intensely enhancing lesion (4.5 x 2.7 cm) at superior border of urinary bladder with loss of fat planes; two more similar lesions (? Lymph nodes) were present in peri-vesicle locations along iliac vessels. GA 68 – DOTANOC PET scan confirmed disease limited to urinary bladder and Bilateral iliac lymph nodes. After an extensive effort to control his blood pressure with prazosin and Metoprolol, excision of the tumour along with pelvic lymph node excision was performed under general anaesthesia. Prior cystoscopic examination extrinsic compression at dome of bladder with increased vascularity. Bilateral ureteric catheterisation (5 Fr) was performed in view of identification of ureters during pelvic lymph node dissection. Partial cystectomy with pelvic lymph nodal dissection was successfully performed with minimal fluctuation of his blood pressure. The post-operative period was uneventful and histopathological examination confirmed the diagnosis of pheochromocytoma of the urinary bladder. All anti-hypertensive medications were discontinued immediately after the operation. Micturating Cysto-Uretherogram (MCU) done on 10th post-operative day reveal satisfactory bladder capacity (250 ml) with no leak or residual volume. Histopathological report was malignant paraganglioma with lymph node metastasis.  Two external iliac lymph nodes were positive for metastatic deposits.

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Image 1 – CT scan images showing transverse sections at level of urinary bladder showing enhancing mass lesion(4.5cm x 2.7 cm) at superior border of Urinary border.

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Image 2 – CT scan showing coronal and saggital images of lesion at superior border of urinary bladder along with two similarly enhancxinglesions (lymph nodes) in perivesical location.

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Image 3 – Gallium – 68 DOTANOC PET scan showing somatostatin expressing urinary bladder mass lesion with bilateral external iliac lymph nodal involvement.

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Image 4 – Surgical specimen showing Bladder paraganglioma(5x5xcm,inner surface seen) and bilateral external iliac lymph node ( about 3x 2cm , 3 in number, largest – 3×2 cm, firm).

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Image 5 – Low power view of tumor. Tumor shows nests of cuboidal cells separated by vascularised fibrous septa. This pattern of arrangement of tumor cells is k/a Zellballen.

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Image 6 – High power view Shows zellballen formation and tumor cells with moderate amount of cytoplasm.

Discussion

The commonest bladder tumor in children is rhabdomyosarcoma. (Huppmann AR, Pawel BR. Polyps and masses of the pediatric urinary bladder: a 21-year pathology review. Pediatr Dev Pathol. 2011; 14(6): 438-44.) Paragangliomas of the urinary bladder are rare tumors that can present at any age (range 11–84 years) with a mean age of 45 years and with slight female sex predilection [1]. In the pediatric population they are extremely rare, with just over 12 cases reported in the literature [6]. The commonest site within the bladder is the trigone and the posterior wall [8].The lateral wall has also been cited as a common site [7].As many as 50% of the paragangliomas are hereditary and may be associated with familial paraganglioma, neurofibromatosis type 1, von Hippel- Lindau disease, and the Carney triad [9].Histologically, they are characterized by cells arranged in discrete nests separated by a prominent sinusoidal network. Malignant paraganglioma of the urinary bladder constitutes 10% of all the bladder paragangliomas [10, 12]. No reliable histologic criteria exist to distinguish malignant from benign neoplasms. Differentiation from benign bladder paragangliomas is based on local invasion, lymph node involvement, or distant metastases [10]. Approximately 30 malignant cases have been reported so far in the literature [11].

Suspected cases of paraganglioma should first be investigated by measuring the levels of catecholamine and metabolites such as metanephrine and vanillylmandelic acid secretion in either blood or urine. However, in cases of nonfunctional paragangliomas, the metabolites may be normal. Imaging can be used to evaluate the primary tumor as well as metastatic lesions. MR imaging is highly useful for imaging extra-adrenal pheochromocytomas. It may reliably differentiate pheochromocytoma from the more common epithelial neoplasms of the bladder which are characteristically poorly enhancing. On MR imaging paragangliomas are typically more hyper intense on both T1- and T2-weighted images.[13]

Bladder Pheochromocytomas is mainly treated by surgical excision. Preoperative catecholamine blockade is necessary for functional tumors. Metastatic or recurrent tumors are treated with palliative therapy [1]. Cystoscopic examination prior to the excision helps to delineate the exact location of the lesion, especially with regard to the depth of invasion and the involvement of the ureters. Biopsy should be avoided. On cystoscopy, pheochromocytomas appear as solid reddish brown granulated and lobulated lesions with or without ulceration [14]. Since the sympathetic plexus of the bladder is scattered between all the layers of the bladder, transurethral resection alone is associated with a high rate of recurrence and partial cystectomy is the standard of care where bladder can be preserved or else a total cystectomy is done. Open approach is preferred [14, 15, 16] although laparoscopic approach, as reported by Kozlowski et al, has recently been shown to be feasible [17].

References

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