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Management of Major Neurocognitive Disorders in African-Americans

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DOI: 10.31038/ASMHS.2017113

Abstract

This paper is a retrospective chart review study of African-American patients 55 years and older that were referred for psychiatric consultation after admission to a medical/surgical unit with integral psychiatric support at Jackson Park Hospital serving predominately African-Americans on Chicago’s Southside. Thirty-two percent (39/121) were found to have Computerized Tomography scan brain pathology (cerebral atrophy, cerebral ischemia, or cerebral infarction). Based on clinical judgment, these patients and others who had clinical findings necessitating a diagnosis of Major Neurocognitive Disorder, with and without Computerized Tomography scan brain pathology, were given Selective Serotonin Reuptake Inhibitors (chiefly Escitalopram starting at 5 mg every morning and increasing the dose until the patient responded rarely over 10 mg). Of these 39, 29 were more agreeable and had brighter affects, although the Sensorium and Cognition of their mental status examinations did not change, four showed absolutely no change, and six were lost to follow up, but who were well enough to be psychiatrically cleared for discharge.

Key Word

African-American, Neurocognitive disorders, Computerized tomography, Escitalopram, Point-prevalence, Major Depressive Disorder (MDD)

Introduction

The rates of Major Neurocognitive Disorder (MNCD) (specifically Alzheimer’s disease – AD) in African-Americans are reported to be twice as high as the rates in European-Americans. [1] The reasons for this health disparity are unknown, but that lack of understanding does not stop the influx of such patients to inpatient consultation and liaison services in general hospitals. Such patients are often referred for psychiatric evaluations from nursing homes because of aggressive behavior and a lack of cooperativeness. Unfortunately, the literature regarding African-American health and wellness is sparse and it is up to clinical research to fill this void until research that is more academic is available. [2] Further, clinical research often leads to the most pragmatic academic research. [3]

This brief report focuses on the prevalence and features of Neurocognitive Disorders in African-Americans admitted to Jackson Park Hospital – a hospital on Chicago’s Southside serving a predominately low-income African-Population. Previous research on this patient population revealed 98% of the patients Jackson Park Hospital services resided in one of the three zip codes (60617, 60619, and 60649) on Chicago’s South Side (Avalon Park, Burnside, Chatham, Greater Grand Crossing, and South Shore communities). [4] About 143,000 people live in these communities, and their median household income is $33,809. The patients sampled were hospitalized between May 1, 2017 to August 31, 2017.

Method

We sampled all patients admitted to Jackson Park Hospital’s Medical/Surgical – Psychiatric Inpatient unit from May 1 to August 31, 2017 who where 55 and up, and who were asked to have psychiatric consultations by the medical/surgical staff. The fore mentioned patients’ medical records were reviewed retrospectively, carefully examined and it was checked if a Head Computed Tomography (CT) scan without contrast was performed, as well as if Escitalopram or another Selective Serotonin Reuptake Inhibitor (SSRI) was utilized as part of the patient’s medical treatment plan. From there, the patient’s medical notes were further explored; the Head CT scans were viewed and examined in order to determine if the image demonstrated any pathology, such as cerebral atrophy, infarction and/or ischemia. Other factors were considered: 1) anti-psychotic use 2) employment of different selective serotonin reuptake inhibitors 3) if the patient was admitted from a nursing home and 4) if the patient was previously admitted to Jackson Park Hospital. The first author then conducted psychiatric evaluations for patients seeking services at the inpatient unit. The patients were admitted due to many different complaints, from aggressive behavior/altered mental status to unspecified “Dementia” (replaced in DSM-5 by Major Neurocognitive Disorder). Based on past clinical experience patients who were suspected of having central nervous system damage were given Escitalopram 5 – 10 mg, as it was the author’s clinical experience that patients with suspected central nervous system damage did well on this particular selective serotonin reuptake inhibitor. [5] Jackson Park Hospital’s Institution Review board approved the project as the data was archival and all patient identifiers were stripped from their files.

Results

Of 147 patient’s (55 years or older) records were reviewed but 26 subjects were lost to follow up leaving a total population of 121 patients over 55. Of these, 50 had clinical indications to get CT scans without contrast and they were given Escitalopram starting out at 5 mg and given up to 10 mg depending on their over-all health. [5] Based on clinical judgment, 39 of the 121 patients (32.2%) were given Escitalopram, usually starting out with 5 mg every morning, and these patients showed CT pathology (cerebral atrophy, cerebral ischemia, or cerebral infarction). Of these 39, 29 were more agreeable and had brighter affect, although the Sensorium and Cognition of their mental status examinations did not change, four showed absolutely no change, and six were lost to follow up, but who were well enough to be psychiatrically cleared for discharge. Seven patients were ordered to have a CT scan but the CT scans were not available for review; of these, four improved in being agreeable and their affect was noticeably brighter, but not in mental status Sensorium or Cognition; and three stayed the same. Fourteen patients showed CT pathology but were not given SSRIs. There were eleven patients who did not get CT scans, but who were given Escitalopram. Ten patients demonstrated improvement with Escitalopram similar to the patients described above, while one patient was lost due to discharge by the weekend psychiatric coverage. Additionally, five patients were given Escitalopram but were lost to follow up as they were discharged. Seven other patients were administered other selective serotonin reuptake inhibitors, and two patients showed improvement with Sertraline and Fluoxetine; while the other five were lost due to being discharged or no follow-up was deemed warranted (Table 1).

Table 1.

Initials Year of Birth CT (Y/N, If Y=(NL), (NA), (A), (IS), (IN) Lexap (Y/N, If Y = progress – other SSRI) Diagnosis Antipsychotic Use D/C NH (Y/N) Previous Admit Race
A.A. 1959 Yes = A, IS Yes (Other Psychiatrist cleared the patient) Psychosis NOS No Yes No Black
A.K. 1938 Yes = NA Yes(same) MNCD D/C risperidone Yes Yes Black
A.N. 1961 Yes = A, IS NO NOTE AVAILABLE Black
A.S. 1959 Yes = NL NO MDD Yes (ziprasidone, risperidone) No No Black
B.A. 1961 Yes = NL No Psychosis NOS ziprasidone by resident Yes No White
B.A. 1959 No No EtOH No No No Black
B.A. 1961 Yes = A, IS No Depression NOS No No No Black
B.B. 1944 Yes = A, IS Yes (Improved on previous admission) MNCD No Yes Yes Latino
B.B. 1949 Yes = A No Psychosis NOS Yes (Haloperidol) No Yes Black
B.B. 1957 Yes = NL No Deferred (then other Psychiatrist) Yes (Haloperidol) No No Black
B.B. 1955 Yes = A, IS Yes (Better) MNCD No No No Black
B.C. 1960 No No Paranoid Schizophrenia (not enough history Yes ( Loxapine0 No No White
B.D. 1959 Yes = NL No PTSD (by history) No No No Black
B.J. 1940 No No Schizoaffective Yes (risperidone) Yes No Black
B.J. 1962 No No EtOH No No No Black
B.L. 1946 Yes = NL No No Psychiatric Diagnosis No No No Black
B.R. 1956 No No Intellectual Disability No Yes No Black
B.R. 1932 Yes = A No MNCD (Other Psychiatrist) Yes (Quetiapine) Yes No White
B.T. 1940 Yes = A, IS No Metastatic HPC No No No Black
B.W. 1951 Yes = A, IS Yes (fine, no longer agitated) MNCD Lurasidone by attending physician Yes No White
B.W. 1940 No Yes (calm) Psychosis NOS No Yes Yes White
C.L. 1951 Yes = A Yes (calmer, less confused) MNCD Quetiapine was discontinued Yes No Black
C.L. 1951 Yes = NA Yes (lowered, still lethargic) MNCD No Yes No Black
C.M. 1958 No No Depression NOS Yes (risperidone) No No Black
C.P. 1955 No No (was given Paroxetine by other Psychiatrist) Major Depression by other Psychiatrist No No No Black
C.R. 1961 No Yes (by other Psychiatrist) Major Depression by other Psychiatrist No No No Black
C.S. 1954 Yes = NL No Adjustment No No Yes Black
C.W. 1939 Yes = NA Yes (well) Adjustment No Yes No Black
D.B. 1932 Yes=A, IS Yes (“brighter”, brighter, more energy) MNCD No Yes Yes Black
D.B. 1958 Yes = NL No Intellectual Disability Yes (Chloropromazine, risperidone) Yes No Black
D.G. 1951 Yes = IS, Volume Loss Yes (better, brighter) TBI No Yes Yes Black
D.J. was F.K. 1954 No Yes ( better) MNCD No No No Black
D.L. DECEASED
D.M. 1952  Yes = A, IS Yes (not talking) MNCD Haloperidol by Resident No No Black
D.P. 1961 No No Substance Abuse No No Yes Black
D.S. 1935 Yes = NL No Mood Disorder NOS Yes (Quetiapine) Yes No Black
D.W. 1934 Yes = A, IS Yes (Awake, better) MNCD D/C risperidone Yes Yes Black
E.A. 1936 Yes = A, IS Yes (“pretty good”) MNCD No No No Black
E.D. 1951 No No Acute Psychosis Quetiapine, ziprasidone (changed all to HS and D/C Benztropine) No No Black
E.E. 1956 Yes = A, IS Yes (little clamer) MNCD Clozapine (given by resident) Yes No White
E.G. 1959 Yes = NL No Intellectual Disability Quetiapine (given by resident) No No Black
E.J. 1935 Yes = A, IS Yes (Discharged) MNCD No Yes No Black
F.H. 1943 Yes = NA No Schizophrenia by other Psychiatrist, Psychosis NOS Lower Benztropine, risperidone by resident Yes Yes Black
G.B. 1958 Yes = IS, IN No MDD Loxapine No Yes Black
G.C. 1947 Yes=A, IS Yes (better, hungry) Depression NOS D/C Quetiapine Yes No White
G.D. 1937 Yes = Lacune Rt Basal Ganglia No Anxiety Disorder NOS No No No Black
G.E. 1942 Yes = A Yes (better. “think and realize”) Psychosis NOS No No Yes Black
G.G. 1961 Yes = NL Yes (refused0 Intellectual Disability No Yes No Black
G.J. 1950 Yes = IS No Adjustment No Yes No Black
G.M. 1941 Yes = A, IS Yes (“fine”) MNCD No Yes No Black
G.R. 1957 ? SI, HI; psych consult
G.T. 1953 Yes = NL No EtOH No No Yes Black
G.V. 1939 Yes = A, IS, IN No Psychosis NOS No Yes Yes Black
H.B. 1955 No No Schizophrenia Quetiapine (given by resident) Yes No Black
H.C. 1959 No No Substance Abuse No No No Black
H.D. 1957 No Yes (sleeping well) Anxiety, MDD Quetiapine (given by resident) No No Black
H.E. 1957 No Yes (much more responsive, whole new person) Organic Brain Damage from CVA No No No Black
H.J. 1958 Not available, Patient refused No
H.L. 1952 Yes = IS Yes (calmer) Heroin Abuse No No No Black
H.M. 1954 Yes = IN No EtOH No No No Black
H.P. 1952 Yes = NA Yes (much better) Anxiety Disorder NOS No Yes No Black
H.R. CURRENT
H.T. 1954 Yes = NL No Psychosis NOS Loxapine No No Black
H.W. 1931 Yes = A, IS Yes (more responsive) MNCD Olanzapine (given by resident) Yes Yes Black
J.A. 1944 Yes = A Yes MNCD (Other Psychiatrist) No Yes No Black
J.D. 1940 Yes = A, IS Yes (D/C Benzo, anxiety is gone & she’s happy) MNCD No Yes No Black
J.L. 1956 Yes = NA Yes (continues to refuse to talk) MNCD No Yes Yes Black
J.W. 1957 Yes = NL Yes (oriented and reasonable) TBI risperidone (given by resident) Yes Yes White
K.N. 1956 Yes = Severe Volume Loss, IS No Adjustment No Yes No White
K.W. 1937 Yes = NA Yes (well) Anxiety No No Yes Black
L.B. 1950 Yes = A, IS Yes (“fine”) MNCD No Yes No Black
L.G. 1961 Yes = consistent with MS Yes (same, calmer) Intellectual Disability No Yes No Black
L.L. CURRENT
L.R. 1936 Yes = A Yes (looks better) Psychosis NOS No Yes Yes White
M.A. 1946 Yes = IS No Psychosis NOS Loxapine Yes No Black
M.E. 1960 Yes = NA No Intellectual Disability risperidone by resident Yes No Black
M.F. 1925 Yes = A, IS ?????????
Geriartric Physician
M.H. 1959 Yes = A, IS Yes (better, more alert, not aggressive) MNCD (unknown) risperidone was lowered Yes Yes Black
M.J. 1944 Yes = A Yes (mood is okay) Intellectual Disability No No No Black
M.K. 1945 Yes = NL No (Mirtazapine) Major Depression by other Psychiatrist No No Black
M.L. 1957 No No EtOH No No No Black
M.M. 1961 Yes = NA No (Sertraline) Depression NOS Quetiapine No Yes Black
M.R. 1961 Yes = A No MDD, TBI Quetiapine No Yes White
M.R. 1955 Yes = IS, A Yes (Alert) Organic or MNCD No No No Black
M.R. 1947 Yes = NA No Psychosis NOS Olanzapine by resident Yes Yes Latino
M.S. 1956 Yes = Encaphalomalacia No Intellectual Disability, TBI No No Yes Black
M.V. 1952 No No Psychosis NOS No No No Black
M.W. 1957 Yes = NA No EtOH No No No Black
M.W. 1960 Yes = A, IN Yes (Alert, responsive) Organic Brain Damage No No No Black
N.C. 1962 No No Major Depression by other Psychiatrist No No Black
N.E. 1949 No Yes (better, thinking is much clearer) MNCD No No No Black
N.J. 1939 Yes = A, IS Yes (little better) MNCD Haloperidol by Resident Yes No Black
N.Z. 1954 Yes = A,IS ????? Chief complaint was acute psychosis, an attending physician patient Yes No
O.E. 1949 No No (Paroxetine by resident) TBI No Yes No White
O.F. 1961 No No Psychosis NOS Loxapine, d/c Olanzapine No No Black
O.J. 1961 No No Acute Psychosis Loxapine Yes No White
O.N. 1946 Yes = A, IS Yes (“allright”, better) MNCD No Yes Yes Black
O.V. 1956 Yes = NA Yes (did not get it) Depression NOS Continue Quetiapine No Yes Black
P.D. 1940 Yes = A Yes (no different) MNCD No Yes Yes White
P.H. 1956 Yes = IS No Heroin, MDD No No Yes Black
P.J. 1951 No No (fluoxetine) MDD ziprasidone by resident Yes No White
P.J. 1937 Yes = IN No Psychosis NOS Loxapine Yes No White
P.M. 1938 Yes = A, IS, IN Yes (other Psychiatrist cleared pt, “calm and coherent, no agitation or behavioral problems” MNCD No Yes No Black
P.N. 1948 Yes = IS No Psychosis NOS Loxapine refused Yes No Black
P.R. 1952 Yes = NL Yes (little better, flirts) Psychosis NOS risperidone Yes Yes Black
R.B. 1937 Yes = A, IS Yes (better) MNCD No Yes Yes White
R.B. 1948 No Schizophrenia by other Psychiatrist Quetiapine by resident Yes No Black
R.C. 1948 Yes = Hemorrhage in 2008 No MNCD secondary to CVA (BASED ON PREVIOUS ADMISSION No Yes Yes Black
R.D. 1953 No No EtOH, Paranoid Schizophrenia Quetiapine given by resident No Yes Black
R.F. 1953 Yes = A, IS Yes (no progress note) Organic/TBI D/C Quetiapine Yes Yes P Rican
R.I. 1947 Yes = A, IS, IN Yes (same, then increased to 10mg, then lost) MDD, Rule out MNCD No Yes Yes Black
R.J. 1953 Yes = NA Yes (calmer, not as rambuctious) Intellectual Disabilty, Depression NOS No No Yes Black
R.J. 1955 Yes = A, IS Yes (LOST) MNCD No No Black
R.J. 1930 No Yes (Prior admision was effective) MNCD No Yes No Black
R.S. 1943 Yes = NL in 2011 No Intellectual Disability Quetiapine by attending No No Black
S.E. 1948 Yes = NL No MNCD secondary to CVA No No No Black
S.G. 1958 No No Major Depression by other Psychiatrist No No No Black
S.G. 1961 Yes = NA No Mood Disorder NOS risperidone, Loxapine, Benztropine by resident Yes Yes White
S.M. 1959 Yes = NA No Epilepsy Haloperidol Deconoate No Yes Black
S.R. 1960 No Yes (little better, less voices) Depression NOS Haloperidol by Psychiatrist No No Black
S.R. 1952 Schizoaffectve (by other Psychiatrist)
S.R. 1947 Yes = NL in 2008 No (Sertraline by resident, discharged) Depression NOS Quetiapine by resident No Yes Black
S.S. 1957 Yes = A, IS Yes (“well”, polite but still delusional) Psychosis NOS D/C risperidone, Added Loxapine Yes No Black
S.S. 1949 Yes = A, IS, IN No Adjustment Disorder NOS No Yes No Black
S.T. 1958 No No Adjustment No Yes No White
T.A. 1955 No No EtOH Quetiapine No Yes Black
T.C. 1959 Yes = NL in 2012 No (fluoxetine by resident) Mood Disorder NOS No No No White
T.G. 1955 No Yes (no voices, no aggression) Acute Psychosis Lowered Benztropine, Loxapine Yes No Black
T.J. 1948 Yes = NA No (was stable) Paranoid Schizophrenia No Yes Yes Black
T.P. 1959 Yes = IN No EtOH No No No Black
T.R. 1962 No No Depression NOS risperidone by resident Yes No Black
T.R. 1953 Yes = A, IS Yes (slightly better, more alert) Psychosis NOS No No No White
T.R. 1958 No No Epilepsy Loxapine No No Black
T.R. 1953 Decreased, no psychiaric diagnosis, Guillain Bairre
V.A. 1957 Other Psychiatrist (In April for EtOH) No Yes
W.A. 1958 ? NO NOTE AVAILABLE Consult was ordered, EtOH
W.B. 1958 Yes = A, IS No (fluoxetine, much better) Heroin No No Yes Black
W.C. 1946 No Yes (much less cranky and was pleasant) MNCD No Yes No Black
W.D. 1957 No Intellectual Disability No No No Black
W.K. 1956 Other Psychiatrist
W.L. 1951 ?
W.M. 1928 Yes = A, IS, IN Yes (lethargic) MNCD No Yes No Black
W.P. 1953 No Yes (affect brighter) Psychosis NOS No Yes No Black
W.R. 1962 No Yes (better, clamer) Anxiety No No No Black
W.R. 1948 Yes = A, IS, IN Yes (same) MNCD, EtOH Quetiapine by resident Yes No White
W.T. 1961 Yes = A Yes (better) MNCD Quetiapine by resident Yes Yes White
Total Subjects = 147
Lost Subjects = 26
CT performed and given Escitalopram = 50,
CT path & given Escitalopram = 39; 29 showed improvement
CT path, given Escitalopram & showed no change = 4
CT path, given Escitalopram, but were lost = 6
CT was ordered but not available and given Escitalopram = 7 (4 with improvement, 3 were the same
CT with pathology but were not given Escitalopram or any type of SSRI = 14
Subject did not undergo CT but was given Escitalopram = 10
CT (Y/N, If Y=Normal(NL)
Not Available (NA)
Atrophy (A)
Ischemia (IS)
Infarction (IN)

Discussion

Serious scientific research has failed to show any serious prevention strategies for Alzheimer’s disease. [6] However, as previously mentioned, African-Americans have been reported to have twice the Alzheimer’s disease as European-Americans. [1] Apolipoprotein E is a risk allele for late onset Alzheimer’s disease and compared with Caucasians, the allele frequency is higher among African Americans, and thus thought to be a significant risk factor for the development of Alzheimer’s disease. [7] Unfortunately, as this was a retrospective study, the authors did not have a measure of the APOE genotype of all the study participants. Point prevalence studies on the prevalence of coma in African-American populations reveals high rates of coma in this population. [8] Having a loss of consciousness resulting in a coma from a traumatic brain injury is another risk factor for the development of Alzheimer’s disease that is of interest to researchers, but which has yet to show a conclusive link between the two. [9] Other studies have shown that Alcohol-related Organic Brain Syndromes have been predisposed to misdiagnosis. [10] A review of the literature on coma illustrates this phenomena is frequently found in African-American communities and was hypothesized to contribute to the high rates of violence seen in such communities. [11-13] Another study that is more recent has revealed a high prevalence of Neurobehavioral Disorders associated with Prenatal Alcohol Exposure (ND-PAE) are found in poor African-American communities. [4] Accordingly, nearly 1/3 of this predominately low-income African-American population having a Major Neurocognitive Disorder from cerebral atrophy, cerebral ischemia, or cerebral infarction is not surprising. However, these patients’ extremely positive response to Escitalopram is surprising. Past experience with patients who had Alzheimer’s disease, Cerebrovascular infarcts, or traumatic brain injuries leads one to believe there is not much that can be done for such patients. Escitalopram and other SSRIs do not improve their cognition. They reduce the patient’s anxiety helping them to be less of a management problem for staff, while, at the same time, not leaving the patient lethargic and sleepy. Most times these patients’ affects were noticeably brighter and they were more socially engaged despite not knowing the year or the president.

Much to the author’s astonishment selective serotonin reuptake inhibitors (SSRIs) have been shown to reduce amyloidal deposits in brain, [14] and they do more to help patients with Major Neurocognitive Disorders than the usual donepezil or memantine which are seen as an unnecessary waste. It may well be that SSRI’s are more effective at reducing and preventing amyloid formation in the damaged brain than the medications that have been approved for treating Alzheimer’s disease. As the SSRI’s are being prescribed for the patient’s anxiety, they are not being used off label.

Another interesting long-term prevention strategy involved the use of prenatal choline. There is some indication that giving choline to pregnant women may prevent the development of Alzheimer’s disease as well as other neurodevelopmental disorders. [15, 16] The schizophrenia research group at the University of Denver is recommending prenatal choline to prevent schizophrenia, autism and ADHD. [17, 18] Recently, the American Medical Association’s House of Delegates provided advocacy to included recommended adequate doses of choline during pregnancy. [19] As of yet, there are no solid links between the high rates of ND-PAE and the high rates of Alzheimer’s disease in African-Americans, but by virtue of the reality that adequate doses of prenatal choline are protective against both neuropsychiatric disorders, it would not surprise us.

Conclusions

Elderly African-American patients (55 years and older) referred for psychiatric consultation on a medical/surgical unit with psychiatry as an integral part of the treatment team often have cerebral pathology resulting in a diagnosis of Major Neurocognitive Disorders. In many instances the cerebral pathology can be documented by a CT scan without contrast. Although the congitive and sensorium of such patients is not significantly altered with an SSRI (most notably Escitalopram), there is a vast improvement in these patient’s anxiety resulting in brighter affect and more agreeable behavior.

References

  1. Alzheimer’s Association (2014) African Americans and Alzheimer’s disease: The Silent Epidemic. Chicago: USA.
  2. Mental Health: Culture, Race, and Ethnicity: A Supplement to Mental Health (2001): A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, US Public Health Service.
  3. Bell CC (2016) Commentary on the Usefulness of Clinical Research. Abnormal and Behavioural Psychology 2.
  4. Bell CC, Chimata R (2015) Prevalence of Neurodevelopmental Disorders in Low-Income African-Americans at a Family Medicine Clinic on Chicago’s Southside. Psychiatr Serv 66: 539–542. [Crossref]
  5. Bell CC (2015) Managing major neurocognitive disorder in African Americans, Clinical Psychiatry News 43: 16.
  6. Daviglus ML, Bell CC, Berrettini W, Bowen PE, et al. (2010) NIH State-of-the-Science Conference: Preventing Alzheimer’s disease and Cognitive Decline. Ann Intern Med 152: 176–181.
  7. Yu L, Lutz MW, Wilson RS, Burns DK, et al. (2017) APOE e4- TOMM40 ‘523 haplotypes and the risk of Alzheimer’s disease in older Caucasian and African Americans. PLoS ONE 12: e0180356. [Crossref]
  8. Bell CC, Thompson B, Shorter-Gooden K, Shakoor B, Dew D, et al. (1985) Prevalence of coma in black subjects. J Natl Med Assoc 77: 391–395. [Crossref]
  9. Julien J, Joubert S, Ferland MC, Frenette LC, Boudreau-Duhaime MM, et al. (2017) Association of traumatic brain injury and Alzheimer disease onset: A systematic review. Ann Phys Rehabil Med 60: 347–356. [Crossref]
  10. Bell CC (1985) Alcohol-Related Organic Brain Syndromes-Frequently Misdiagnosed as Schizophrenia. Bulletin of the New York State Chapter of the National Black Alcoholism Council, Inc 4: 3–4.
  11. Bell CC (1986) Coma and the etiology of violence, Part 1. J Natl Med Assoc 78: 1167–1176. [Crossref]
  12. Bell CC (1987) Coma and the etiology of violence, Part 2. J Natl Med Assoc 79: 79–85. [Crossref]
  13. Bell CC, Kelly R (1987) Head Injury with Subsequent Intermittent, Non-schizophrenic, Psychotic Symptoms and Violence. J Natl Med Assn 79: 1139–1144. [Crossref]
  14. Sheline YI, West T, Yarasheski K, Swarm R et al. (2014) An Antidepressant Decreases CSF Aß Production in Healthy Individuals and in Transgenic AD Mice. Sci Transl Med 6: 236re4. [Crossref]
  15. Bell CC (2017) Can prenatal choline lead to prevention of Alzheimer’s? Clinical Psychiatry News 45: 10–11.
  16. Strupp BJ, Powers BE, Velazquez R, Ash JA, et al. (2016) Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer’s Disease. Curr Alzheimer Res 13: 97–106. [Crossref]
  17. Freedman R1, Ross RG1 (2015) Prenatal choline and the development of schizophrenia. Shanghai Arch Psychiatry 27: 90–102. [Crossref]
  18. Ross RG, Hunter SK, Hoffman MC, McCarthy L, et al. (2016) Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. Am J Psychiatry 173: 209–516. [Crossref]
  19. Bell CC (2017) AMA’s stance on choline, prenatal vitamins could bring staggering results. Clinical Psychiatry News.

Proposal on Cooperation on 100 Novel Drug Formulas

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Forgotten Volkmann Operation (Modified Radical Mastectomy) and its Value in Modern Combined Treatment of Breast Cancer

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DOI: 10.31038/CST.2017263

Abstract

Objective: We have an insufficient scientific data about pre-Halstedian period of breast cancer (BC) history, and about the results of BC treatment. The aim of this article to present authentic scientific data about pre-Halstedian (1867 – 1894) period of BC history, to introduce techniques and results of BC operations.

Materials And Methods: This article based on the original papers of the European, and the American scientists of the end of XIX -beginning of the XX century In 1894, Cheyne, Halsted, and Meyer introduced radical mastectomy for the treatment of BC. Since the end of XIX century and to the second half of the XX century radical mastectomy become the gold standard for treatment of BC. In 1960s, Auchincloss, Madden presented technique of modified radical mastectomy (MRM). In 1972, Madden, introducing MRM wrote: “MRM is not a new technique and it was popular about century or more ago“. In 1875, Volkmann introduced his technique for treating BC; he removed the breast, pectoral fascia, performed axillary nodes dissection.

Results During 25 years, 3–yeasr results of Volkmann operation were significantly improved from 17. 8 %-23 % in 1880/1881 to 35%-45 % in 1891/1900. According to presented data, in pre-Halstedian period, Volkmann operation, become the standard of BC treatment.

Conclusions The period of pre-Halstedian BC history (1867-1894), the results of Volkmann breast operation, the names of prominent European and American surgeons and scientists were forgotten, and our duty to reintroduce it.

Key words

Breast cancer, pre-Halstedian period, Volkmann operation, 3-years results

Introduction

In 1894, Cheyne, Halsted, and Meyer introduced radical mastectomy for the treatment of BC [1, 2, 3]. Since the end of XIX century and to the second half of the XX century radical mastectomy become the gold standard for treatment of BC. In 1960s, Auchincloss, Madden presented technique of MRM (total mastectomy, preservation of the pectoral muscles, axillary dissection) for the treatment of BC [4, 5]. In 1970s, American Cancer Society and NIH Consensus Panel declared : total mastectomy with axillary dissection should be recognized as the current treatment standard [6, 7]. Today MRM is the most commonly performed technique of mastectomy in combined treatment of locally advanced BC. Madden introducing MRM, wrote : MRM is not a new technique and it was popular about century or more ago [5]. The aim of this article is to present authentic scientific data of pre-Halstedian period of BC, to introduce techniques and results of BC operations.

Materials and Methods

This article based on the original papers, and the authentic manuscripts of the European, and the American scientists of the end of XIX – beginning of the XX century.

Charles Hewitt Moore (1821–1870)

Moore was a British surgeon, Vice President of the Royal Medical and Surgical Society of London.

In 1867, More [8] presented the paper about local recurrences of BC after inadequate breast operations. In his paper Moore wrote: It is not sufficient to remove the tumour, or any portion only of the breast in which it is situated; mammary Cancer requires the careful extirpation of the entire organ. Diseased axillary glands should be taken away by the same dissection as the breast.

Summary

  1. Moore was one of the first, who stressed the importance of removig of whole breast in all cases of BC
  2. Moore removed the breast and performed axillary dissection in case of diseased lymphnodes

Richard von Volkmann (1830-1889) (Figure 1)

CST2017-232-ValerijusOstapeko_F1

Figure 1. R. Volkmann

Volkmann was the one of the most prominent German surgeons and scientists, Professor of Surgery and head of the Department of Surgery at the University of Halle

A. Original Volkmann breast cancer operation

In 1875, Volkmann introduced new technique for treating breast cancer; he removed the entire breast, liberal piece of skin, pectoral fascia, performed axillary nodes dissection in cases of their enlargement. I make it a rule never to do a partial amputation for cancer of the breast, but remove entire breast, even for a smallest tumors, and at the same time I take away a liberal piece of skin. The skin- defect is, of course, very great when operates in this manner, and the wound, requires a long time for healing; the fascia of the muscle is, accordingly, entirely removed. Volkmann stressed the scientific background of operation: I was led to adopt this procedure because on microscopical examination I repeatedly found when I had not expected it that the fascia was already carcinomatous, whereas the muscle was certainly not involved. It seems to me, therefore, that the fascia serves for a time as a barrier, and is able to bring to a halt the spreading growth of the carcinoma [2, 9]. In his book Beck wrote: Since Volkmann found, on microscopic examination, that even in small and superficially located carcinomatous growths of the mammary gland, the fascia was generally involved, he was naturally led to the conclusion that removal of the tumor alone was an insufficient procedure. [10] According to Halsted and Rodman Volkmann probably was the first to remove the pectoralis muscles-major, in a series of thirty-eight cases, minor in a much smaller number [2, 11]. In 1883, during the 12th Congress of the German Surgical Society, Gussenbauer, Langenbeck and Winiwater, discussing Küster’s presentation, stated: a routine axillary dissection should be done in all patients regardless of the presence or absence of palpable nodes. [4] (Figure 2).

CST2017-232-ValerijusOstapeko_F2

Figure 2. Mastectomy by Gross Tumors of the breast.
Rights: Public Domain, Google-digitized.

Volkmann operation with routine axillary dissection

Since 1883, Volkmann operation with routine axillary dissection becomes the classic operation for treatment of BC. According to our classification of mastectomy, the original Volkmann operation was simple or total mastectomy, in case of axillary dissection – MRM.

 In 1894, Halsted wrote: So convinced was Volkmann of the accuracy of his observations and of the truth of his theory that he prescribed a method of operating, which he followed until his death, and which has been adopted by almost every good surgeon up to the present time; his (Volkmann) operation is a classical one [2]. According to Volkmann, “radical cure” was applied to cases that have remained alive and free from recurrence for at least three years after operation [12].

Summary

  1. In 1875, original Volkmann operation (removal of the breast, pectoral fascia, axillary nodes dissection in cases of their enlargement) was inroduced.
  2. Since 1883, Volkmann operation with routine axillary dissection become the standard of BC treatment in Germany.

Samuel Weissel Gross (1837-1889)

Gross was a prominent American scientist and surgeon, a President of the Pathological Society of Philadelphia, Vice-President of the Philadelphia Academy of Surgery

In 1880, in his book Gross described new technique of operation: …Within the past seven months , however, I have adopted the principles which I have just enunciated, that is to say, I removed the mamma and its coverings bodily, dissected off the pectoral fascia, and cleaned out the axilla in five cases, and all recovered [13]. In 1888, Gross wrote: The rule to remove the axillary contents in every case should be absolute. I have obtained 21. 05 %, of cures [14].

In his book Rodman stressed: It should not be forgotten, however, that Gross advised and practised removing the pectoral fascia in 1879, and that Volkmann had done so in 1875 [15].

Summary

  1. In 1879, Gross introduced new technique for treatment BC in the USA.
  2. Gross removed the breast, dissected the pectoral fascia, performed routine dissection of the axilla. It was a Volkmann operation with routine axillary dissection.

Sir William Mitchell Banks (1842–1904)

Banks (1842–1904) was a Scottish surgeon and scientist, Professor of Anatomy Liverpool University, and Vice-Presidents of section of surgery British Medical Association

In 1882, Banks wrote: About three years ago (1879), I came to the conclusion, that, in every case where the breast is removed, the axilla should be cleared [16]. Butlin emphasized the main propositions of Banks’s techniques: “In every case of BC the operation should comprise removal of the whole mamma, of the skin covering it, and of the fascia over the pectoral muscle. The axilla should be opened and the contents cleared out, whether enlargement of the glands can be detected or not [17]. In 1900, Banks described the main points of the complete operation technique, presented results of treatment, published the intraoperative images made by his house-surgeon Dr. Arkle: Now, the first four series comprise 175 patients and of these 108 have remained free from local recurrence. Of the 108 there have lived 73 over three years (three-year survival – 67. 6 %) [18, 19]. (Figure 3).

CST2017-232-ValerijusOstapeko_F3

Figure 3. W Banks in public domain

Summary

  1. In 1879, Banks introduced new operation for treatment breast cancer in the UK
  2. Banks removed the breast, dissected the pectoral fascia, performed routine dissection of the axilla. It was Volkmann operation with routine axillary dissection

Frederic Shepard Dennis (1850-1934)

Surgeon, Professor of Principles and Practice of Surgery, Bellevue Hospital Medical College, President of the American Surgical Association

In 1891, Dennis described the main steps of his technique: I am removing in every case, the entire breast with pectoral fascia and the lymphatic glands [20].

In 1896, Dennis published a summary of all BC cases operated no later than 1891: Of the 74 cases of pure carcinoma of the breast, the subsequent history of 41 is known, and 3 of these have not yet reached the three years’ limit of time. In these 38 cases there are 17 cases in which a permanent recovery has taken place, allowing the three years’ standard of time to have been reached. This gives 45%, of permanent cures…and a little over 5 per cent of local recurrences. Since the publication of the last statistics in 1891; he has had 15 cases of pure carcinoma of the breast, with no mortality from the operation itself. There are, therefore, 12 cases in which the full subsequent histories are known; two of them suffered from a recurrence of the disease and the remaining 10 have passed the three years’ limit of time. This gives 83 %, of permanent cures in cancer of the breast in the last 15 consecutive cases [21] (Figure 4).

CST2017-232-ValerijusOstapeko_F4

Figure 4. Removed breast [18]

Summary

  1. Dennis removed the entire breast with pectoral fascia and the lymphatic glands. It was Volkmann operation with routine dissection of axillae

Meeting of the American Surgical Association (ASA) in 1891

In 1891, during the meetings of the ASA well known European, Canadian and American surgeons took part in the discussion on recurrence of BC. Dennis presented a key lecture, in which he said: 75 % of recurrences is high, but it represents approximately the general average, if all the cases are taken into consideration. These figures include cases where incomplete operations performed, that is to say, where the axilla was not open. I am a strong advocate of always removing in every case, to which there is no exception, the entire breast, with the pectoral fascia and the lymphatic glands, as the minimum operation in the most insignificant scirrhus…Dr. Halsted has beautifully demonstrated that the pectoral fascia is involved in many cases of carcinoma of the breast, although to the naked eye, or to the sense of touch, this infiltration may not be apparent… In order to secure immunity from the disease in every case, it is necessary to adopt a radical operation as routine treatment in all cases… Chiene takes a flap from the arm to cover the wound. Stiles, assistant to the Professor of Surgery Chiene suggested a new and reliable method of testing the radical character of an operation by acidum nitrictim, for about ten minutes… The recurrence of carcinoma of the breast influenced by the histological type of the carcinoma itself… A study of the cases of recurrence of carcinoma of the breast shows it to occur „under or close to the scar. Von Winiwarter has also demonstrated that in Billroth’s cases the recurrences originated in the scar tissues. . [20] (Figure 5).

CST2017-232-ValerijusOstapeko_F5

Figure 5. Dissected axillae [19].

Summary

  1. In 1891, during ASA meeting participants stressed the necessity of the removing of whole breast, pectoral fascia, and of regular cleaning of axillae. It was Volkmann operation with routine dissection of axillae

In the end, we would like to present the original scan from the article, published by Dowd (President of the New York Surgical Society) in 1894. In article the authentic name of Volkmann’s operation, is presented. [22]

CST2017-232-ValerijusOstapeko_F6

Results

The initial (1880-1881) 3-years results of Volkmann operation without routine dissection of axillae operation were not impressive: Volkmann (1880) -17. 8%, Kuster (1881)-21. 5%, Konig (1881)-22. 5 % [12, 23]. In 1883-1894, after introducing Volkmann operation with regular cleaning of axillae, 3-years results were significantly improved: Dennis – 45. 0 % (1891), May – 35. 0 % (1893), Dennis-77. 0 % (1895), average of Rotter, Helferich, Cheyney – 42. 5 % (1896), Banks – 67. 59 % (1900) [22, 23].

Retrospectively, the latest results of Volkmann’s operations with regular dissection of axilla were similar with the results of radical Halsted mastectomy.

The pre-Halstedian period of BC history was chracrerized by significantly high scientific level. The results of BC treatment, techniques of operations, the causes of recurrencies, recommendation on early detection were published, analyzed and discussed; new technique of mastectomies were introduced; prominent European surgeons and scientists presented their innovations in the meetings of ASA. In 1965, Madden presented modified radical mastectomy with removing breast, pectoral fascia, dissection of axillae and preserving pectoral muscle and reintroduced Volkmann’s operation. Even today, 142 years after it introduction, MRM – Volkmann’s operation is a standard of breast cancer management.

Conclusions

The period of pre- Halstedian BC history, Volkmann breast operation, the names of prominent European and American surgeons were forgotten, and our duty to reintroduce it.

Funding: All of authors have no conflicts of interest to disclose.

Competing interests: The authors declare that they have no competing interests.

Authors’ contribution VO is the main author: AO- contributed to the review of manuscript. EO-carried out the literature search. All authors read and approved the final manuscript.

Highlights

  1. The pre-Halstedian period of Breast cancer history was chracrerized by significantly high scientific level
  2. The Volkmann’s operations with regular dissection of axilla was the gold standard of breast cancer treatment
  3. This period of breast cancer history, Volkmann breast operation, the names of prominent European and American surgeons were forgotten.

References

  1. Cheyne WW (1894) An Address on the Treatment of Cancer of the Breast: Delivered before the Harveian Society of London. Br Med J 1: 289–291. [crossref] 
  2. Halsted WS (1894) The results of operation for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Ann Surg 20: 497–55.
  3. Meyer W (1894) An improved method for the radical operation for carcinoma of the breast. Med Rec NY 46: 746–49.
  4. Madden JL, Kandalaft S, Bourque RA (1972) Modified radical mastectomy. Ann Surg 175: 624–634. [crossref] 
  5. Achincloss H (1963) Significance of location and number of axillary metastases in carcinoma of the breast: a justification for a conservative operation. Ann Surg 158: 37–46.
  6. Policy Statement on Surgical Treatment of Breast Cancer American Cancer Society (1973) CA Cancer J Clin 23: 341–43.
  7. The treatment of primary breast cancer: management of local disease (1979) NIH Consens Statement Online 2: 29–30.
  8.  Moore CH (1867) On the Influence of Inadequate Operations on the Theory of Cancer. Med Chir Trans 50: 245–280. [crossref]
  9. Dennis FS (1896) Diseases of the female breast.In: Dennis FS, Billings JS, editors. System surgery, v. IV, New York and Piladelphia: Lea Brothers 927–928.
  10. Beck C (1907) Diseases of the breast.In: Beck C, editor. Surgical disease of the chest, Philadelphia: P Blakistone’s Son 321.
  11. Rodman WL (1908) Diseases of the breast, with special reference to cancer. Philadelphia: P Blakiston’s Son
  12. Williams WR (1894) Treatment of acinous cancer. In: Williams WR editor. Monograph on diseases of the breast their pathology and treatment with special reference to cancer. London: John Bale and Sons 364.
  13. Gross SW (1888) Tumors of the breast. In: Mann MD editor. A system of gynecology by American authors.v.2, Philadelphia: Lea Brothers 314.
  14. Gross SW (1888) Tumors of the breast. In: Mann MD editor. A system of gynecology by American authors.v.2. Philadelphia: Lea Brothers 311–318.
  15. Rodman WL (1908) Diseases of the breast, with special reference to cancer. Philadelphia: P Blakiston’s Son: 273
  16. Banks WM (1882) On free removal of mammary cancer with extirpation of the axillary glands as a necessary accompaniment. Br Med J 2: 1138–41.
  17. Butlin HT (1887) On the operative surgery of malignant diseases. London J. & A. Churhill 359–388.
  18. Banks W (1900) The Lettsomian Lectures being Practical Observations on Cancer of the Breast: Delivered before the Medical Society of London. Br Med J 1: 817–24.
  19. Banks WM (1902) A Brief history of the operations practiced for cancer of the breast. Br Med J 1: 5–10.
  20. Dennis FS (1891)Recurrence of carcinoma of the breast. Transactions of the American Surgical Association 9: 221 – 29.
  21. Dennis FS (1896) Diseases of the female breast. In: Dennis FS, Billings JS editors. System surgery, v. IV, New York and Piladelphia: Lea Brothers 931–32.
  22.  Dowd CN (1898) III. A Study of Twenty-nine Cases of Cancer of the Breast submitted to Operation. Ann Surg 27: 285–302. [crossref]
  23. May B (1897) The Ingleby Lectures on the Operative Treatment of Cancer of the Breast. Br Med J 149: 1456–58

Lymphoma Involving the Heart and Inferior Vena Cava: Radiological and Pathological Approach

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DOI: 10.31038/CST.2017262

Abstract

Primary Cardiac Lymphoma (PCL) is a very rare condition accounts for 2% of all primary cardiac tumours. This is a case report of a 76 year old male patient with shortness of breath, cough and pyrexia of unknown origin for 2 months. In the initial diagnostic workup, echocardiography revealed aortic and mitral regurgitation with no pericardial effusion. With the development of right sided pleural effusion about one month after the initial presentation, ultrasound scan guided pleural fluid aspiration performed. Pleural fluid culture revealed no bacterial growth. Second echocardiography showed no flow in the Superior Vena Cava (SVC) and suspected of a thrombus. Contrast enhanced Computed Tomography scan of the chest demonstrated a mass lesion in the right heart and distal inferior vena cava (IVC). The lesion was compressing the SVC without complete obstruction. The pericardium was intact with no pericardial effusion. No mediastinal lymphadenopathy identified. Initial differential diagnosis was leiomyosarcoma of the distal IVC extending in to the right heart. As there was no pericardial involvement, possibility of lymphoma was made as a remote cause. Subsequently digital subtraction angiography guided biopsy performed from the mass in the distal IVC and right atrium. Diffuse lymphoma was confirmed on histology. As there were no Hodgkin cells in the sample, probable diagnosis of Non-Hodgkin’s lymphoma was made. Subsequently patient died due to cardiovascular compromise before starting specific therapy.

Keywords

Cardiac lymphoma, Inferior vena cava, Radiological imaging, Histological diagnosis

Introduction

Primary Cardiac Lymphoma (PCL) is a very rare condition usually of B-cell non-Hodgkin’s type. They account for 2% of all primary cardiac tumours and 1% of extranodal lymphomas [1, 2]. They are usually diffuse large cell lymphomas manifest as an ill-defined, infiltrative mass [3]. PCL are more commonly seen in immunocompromised states, either iatrogenic including those associated with solid organ or bone marrow transplantation or HIV related and these are usually associated with EBV infection. Lymphomas in immunocompetent individuals are extremely rare [4]. As there are no specific clinical symptoms, the clinical diagnosis of the condition is difficult. Typically when B symptoms develop, (fever, weight loss, fatigue common in lymphoid malignancies), progressive heart failure will ensue in these patients [5]. However advanced cross sectional imaging modalities allowed early and accurate detection of primary cardiac malignancies [6]. The definitive diagnosis of the condition needs histological evaluation of the tumour. One of the accessible diagnostic method is transoesophageal echocargiography-guided transjugular biopsy, which has a relatively low risk of complications [7]. Endomyocardial biopsy via percutaneous cardiac approach is also another approach for histological diagnosis [8].

We present a case of lymphoma arising in the heart with extension in to the superior and inferior vena cava.

Case Report

A 76 year old male was initially investigated for shortness of breath and cough of 2 months duration in a specialized hospital for respiratory disease. On initial presentation the patient was not dyspnoeic but found to have 94% of saturation of oxygen in blood. Bilateral ankle oedema was evident at that time. The blood pressure was normal on admission to the hospital. During hospital stay patient develops mild fever episodes intermittently. Sputum culture and blood culture were negative during the febrile illness. Subsequently patient underwent trans oesophageal echocardiography suspecting infective endocarditis, and it revealed grade ii aortic regurgitation and mitral regurgitation. There was no evidence of pericardial effusion or features of congestive cardiac failure Figure 1.

CST2017-235-Srilanka_f1

Figure 1.

About a month following initial presentation the patient develops right sided pleural effusion and then ultrasound scan guided pleural fluid aspiration was performed. There were 3.8g/dl of protein and 80% of lymphocytes in the pleural fluid. However there was no evidence of bacterial growth or acid fast bacilli in the pleural fluid.

Again patient was send for cardiology opinion and underwent 2 dimensional Echocardiogram which revealed no flow in the Superior Vena Cava (SVC) with suspicion of a thrombus in the SVC extending in to the right ventricle. Right atrium was dilated at that time. Then the patient was transferred to the National Hospital of Sri Lanka (NHSL) for further evaluation and management Figure 2.

CST2017-235-Srilanka_f2

Figure 2.

A contrast enhanced Computed Tomography (CT) scan of the chest performed in the NHSL and detected a contrast enhancing mass lesion with few hypodence areas within the lesion involving the distal inferior vena cava (IVC), right atrium and right ventricle. The lesion was appear to compress the distal SVC without complete obstruction of the lumen. Right main pulmonary artery was pushed superiorly by the mass lesion without significant luminal narrowing. The pericardium was not involved by the lesion and there was no pericardial effusion. There was bilateral pleural effusion on CT scan. There was no significant hilar or mediastinal lymphadenopathy. In conclusion differential diagnosis of leiomyosarcoma of the distal IVC extending in to the right atrium and right ventricle was made. As there was no pericardial effusion or pericardial involvement by the mass lesion, the possibility of lymphoma was made as a remote possibility Figure 3.

CST2017-235-Srilanka_f3
CST2017-235-Srilanka_f3b

Figure 3.

Subsequently the patient referred for digital subtraction angiography guided biopsy of the mass lesion in the distal IVC and right atrium. With right femoral vein puncture the venous access gained and IVC catheterization was performed. Five biopsy samples were obtained using 10 F guiding catheter and an Alligator forceps Figure 4.

CST2017-235-Srilanka_f4

Figure 4.

On histological assessment with haematoxylin and eosin staining there were sheets of discohesive medium to large lymphoid cells with enlarged hyper chromatic nuclei and narrow rim of cytoplasm. Mitoses were frequently found. Immunohistochemistry (IHC) with Leukocyte Common Antigen (LCA) revealed strong membranous positivity in all lymphocytes. Diffuse lymphoma was confirmed by histology. As there were no Hodgkin cells in the biopsy, probable diagnosis of Non-Hodgkin type lymphoma was made [Figure 5 & 6].

CST2017-235-Srilanka_f5

Figure 5.

CST2017-235-Srilanka_f6

Figure 6.

Subsequently the patient was transferred to The National Cancer Institute, Sri Lanka for further management. However the patient died from cardiac arrest before starting specific therapy.

Discussion

Primary cardiac lymphoma (PCL) is a very rare condition. On histology they are usually of B-cell non-Hodgkin’s type lymphoma. The most frequent location of PCL is the right atrium, followed by the pericardium. Signs and symptoms are non-specific and depend on the location and extent of the tumour; these include right-sided heart failure, precordial pain, arrhythmias, conduction disorders and cardiac tamponade [7]. In literature there is a case of atypical presentation of ischemic hepatitis in a young adult with PCL, which highlights the wide variety of clinical manifestations of this rare tumour [9].

In our patient the initial presentation was nonspecific and the disease progressed rapidly. Radiological imaging played major role in the identification and sampling of the tumour. The diagnosis of diffuse lymphoma was confirmed by histology with probable diagnosis of Non-Hodgkin lymphoma.

The most effective treatment method for cardiac lymphoma is chemotherapy. Palliative surgery may be necessary to correct haemodynamics when venous blood flow to the lungs is disturbed [10]. Guilherme HO, et al. concluded in their study that cardiac lymphomas had worse survival compared with extra-cardiac lymphomas [11].

Unfortunately this patient died due to cardiovascular compromise before starting chemotherapy or palliative surgery.

Take home message: Primary cardiac lymphoma is a rare entity with nonspecific clinical presentation which may mislead the early diagnosis and prompt treatment. Radiological and histological evaluation plays major role in the diagnosis of this condition.

Limitation: In our local setting immuno-histochemical analysis was not available freely and therefore the diagnosis of definite subtype of the lymphoma was limited.

Ethical Consideration: Informed consent was taken from the relatives of the patient for publication of the case report.

References

  1. Fernandes F, Soufen HN, Ianni BM, Arteaga E, Ramires FJ, et al. (2001) Primary neoplasms of the heart. Clinical and histological presentation of 50 cases. Arq Bras Cardiol 76: 231–237. [crossref] 
  2. Lam KY, Dickens P, Chan AC (1993) Tumors of the heart. A 20-year experience with a review of 12,485 consecutive autopsies. Arch Pathol Lab Med 117: 1027–1031. [crossref] 
  3. Jean Jeudy, et al. (2012) From the Radiologic Pathology Archives, Cardiac Lymphoma: Radiologic Pathologic Correlation. RadioGraphics 32:1369–1380
  4. Bagwan IN, et al. (2009) Unusual presentation of primary cardiac lymphoma. Interactive CardioVascular and Thoracic Surgery 9: 127–129
  5. Shah K, Shemisa KA (2014) “low and slow” approach to successful medical treatment of primary cardiac lymphoma. Cardiovasc Diagn Ther 4:270–273
  6. Seok JR, Byoung WC, Kyu OC (2001) CT and MR findings of primary cardiac lymphoma: Report upon 2 cases and review. Yonsei Medical Journal 42: 451–456
  7. Angela FC, et al. (2003) Primary Cardiac Lymphoma: Diagnosis by transjugular biopsy. Rev Esp Cardiol 56:1141–4
  8. Jung YC, et al. (2009) Extensive primary cardiac lymphoma diagnosed by percutaneous endomyocardial biopsy. J Cardiovasc Ultrasound 17:141–144
  9. Yuan JS, et al. (2012) Acute ischemia hepatitis as a major clinical presentation of the primary cardiac lymphoma. J Emerg Crit Care Med 3: 118–23.
  10. Jonavicius K, et al. (2015) Primary cardiac lymphoma: two cases and a review of literature. Journal of Cardiothoracic Surgery 10:138
  11. Guilherme HO, et al. (2017) Characteristics and Survival of Malignant Cardiac Tumors: A 40-Year Analysis of Over 500 Patients.

Evaluation of an Inverse Molecular Design Algorithm in a Model Binding Site as An In silico predicted and computer-aided molecular designed HIV-1 protease CTLA-4 blockador for the increasement of the antigen-specific W191G mutant of cytochrome c peroxidase CD8+ T-cells to the inprevaccinated patients with melanoma using new cluster of algorithms for Large-Scale Protein-Ligand Docking experiments

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Abstract

Computational molecular design is a useful tool in modern drug discovery. Virtual screening is an approach that docks and then scores individual members of compound libraries. In contrast to this forward approach, inverse approaches construct compounds from fragments, such that the computed affinity, or a combination of relevant properties, is optimized. We have recently developed a new inverse approach to drug design based on the dead-end elimination and A* algorithms employing a physical potential function. This approach has been applied to combinatorially constructed libraries of small-molecule ligands to design high-affinity HIV-1 protease inhibitors [M. D. Altman et al. J. Am. Chem. Soc. 130: 6099–6013, 2008]. Here we have evaluated the new method using the well studied W191G mutant of cytochrome c peroxidase. This mutant possesses a charged binding pocket and has been used to evaluate other design approaches. The results show that overall the new inverse approach does an excellent job of separating binders from non-binders. For a few individual cases, scoring inaccuracies led to false positives. The majority of these involve erroneous solvation energy estimation for charged amines, anilinium ions and phenols, which has been observed previously for a variety of scoring algorithms. Interestingly, although inverse approaches are generally expected to identify some but not all binders in a library, due to limited conformational searching, these results show excellent coverage of the known binders while still showing strong discrimination of the non-binders. Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential forimmunogenicity and may produce an effector memory T-cell response. It has been previously determined the effect of CTLA-4 blockador on antigen-specific responses following vaccination. In-depth immune monitoring was performed on three ipilimumab-treated patientsprevaccinated with gp100 DNA (IMF-24), gp100209–217 and tyrosinase peptides plus GM-CSFDNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11). In previous studies it was shown that peripheral blood mononuclearcells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culturewith HLA-A*0201-restricted gp100209–217 (ITDQVPFSV), tyrosinase369–377 (YMDGTMSQV),or 20-mer NY-ESO-1 overlapping peptides, respectively. It has also been evaluated on the PDBbind v2012 core set where istar platform combining with RF-Score manages to reproduce Pearson’s correlation coefficient and Spearman’s correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. Here, we have discovered for the first time an in silico predicted and computer-aided molecular designed CTLA-4 (YMDGTMSQV) mimic blockador for the increasement of the antigen-specific CD8+ T-cells to the inprevaccinated patients with melanoma.

Keywords

Evaluation, Inverse Molecular Design Algorithm, Model Binding Site, In silico predicted, computer-aided molecular designed CTLA-4 blockador, increasement, antigen-specific CD8+ T-cells, inprevaccinated patients, melanoma, new cluster, algorithms, Large-Scale Protein-Ligand Docking experiment, inverse design, scoring function, protein-ligand interaction, cytochrome c peroxidase, dead-end elimination, drug design.

Quantum mechanically derived AMBER-compatible Algebraically in silico discovery of a multi-epitope mimic poly-pharmacophore to Multiple Peptides Derived from Cancer-Testis Antigens as a promising anti-tumor pharmaco-agent for the maintance of a Specific T-cell Response in Long-term Vaccinated patients Advanced Biliary Tract Cancer using a parallel Cloud computing for protein-ligand binding site comparison for structural proteome-wide ligand-binding site comparisons

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Abstract

Molecular mechanics (MM) methods are computationally affordable tools for screening chemical libraries of novel compounds for sites of P450 metabolism. One challenge for MM methods has been the absence of a consistent and transferable set of parameters for the heme within the P450 active-site. Experimental data indicates that mammalian P450 enzymes vary greatly in the size, architecture, and plasticity of their active sites. Thus, obtaining x-ray based geometries for the development of accurate MM parameters for the major classes of hepatic P450 remains a daunting task. Our previous work with preliminary gas-phase quantum mechanics (QM) derived atomic partial charges, greatly improved the accuracy of docking studies of raloxifene to CYP3A4. Different patterns for substrate docking are also observed depending on the choice of heme model and state. Newly parameterized heme models are tested in implicit and explicitly solvated MD simulations in the absence and presence of enzyme structures, for CYP3A4, and appear to be stable on the nanosecond simulation timescale. The new force field for the various heme states may aid the community for simulations of P450 enzymes and other heme containing enzymes. The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and thereare only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response,and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus ontheir fluctuations during long-term vaccination until the disease had progressed. A unified statistical model to support local sequence order independent similarity searching for ligand-binding sites and its application to genome-based drug discovery. Bioinformatics, 25, i305–i312.]. These algorithms have been extensively benchmarked and shown to outperform most existing algorithms. Moreover, several predictions resulting from SMAP-WS have been validated experimentally. Thus far SMAP-WS has been applied to predict drug side effects, and to repurpose existing drugs for new indications. SMAP-WS provides both a user-friendly web interface and programming API for scientists to address a wide range of compute intense questions in biology and drug discovery. Here, we have for the first time discovered a multi-epitope mimic poly-pharmacophore to Multiple Peptides Derived from Cancer-Testis Antigens for the maintance of a Specific T-cell Response in Long-term Vaccinated patients with Advanced Biliary Tract Cancer using the BiogenetoligandorolTM based SMAP-WS chemical informatic parallel web service for structural proteome-wide ligand-binding site comparison.

Keywords

Algebraically in silico discovery, multi-epitope, mimic, poly-pharmacophore, Multiple Peptides, Cancer-Testis, Antigens, anti-tumor, pharmaco-agent, Specific T-cell Response, Long-term, Vaccinated patients, Advanced Biliary Tract Cancer, parallel web service, structural proteome-wide, ligand-binding site, comparison, Cytochrome P450 enzymes, heme force field parameters, molecular mechanics, RESP charges, AMBER, drug-metabolism,

Evaluation of an Inverse Molecular Design Algorithm in a Model Binding Site in silico designed dosimetric autologous living vaccine consisting of with Multiple Wilms’ Tumor 1 WT1-ConSynthetic–Restricted Peptide mimotopic Epitopes RMFPNAPYLP pulsed dendritic cells on a personalized Active Network analysis for asymptomatic or minimally symptomatic metastatic Pancreatic Cancer

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Abstract

Computational molecular design is a useful tool in modern drug discovery. Virtual screening is an approach that docks and then scores individual members of compound libraries. In contrast to this forward approach, inverse approaches construct compounds from fragments, such that the computed affinity, or a combination of relevant properties, is optimized. We have recently developed a new inverse approach to drug design based on the dead-end elimination and A* algorithms employing a physical potential function. This approach has been applied to combinatorially constructed libraries of small-molecule ligands to design high-affinity HIV-1 protease inhibitors [M. D. Altman et al. J. Am. Chem. Soc. 130: 6099–6013, 2008]. Here we have evaluated the new method using the well studied W191G mutant of cytochrome c peroxidase. This mutant possesses a charged binding pocket and has been used to evaluate other design approaches. The results show that overall the new inverse approach does an excellent job of separating binders from non-binders. For a few individual cases, scoring inaccuracies led to false positives. The majority of these involve erroneous solvation energy estimation for charged amines, anilinium ions and phenols, which has been observed previously for a variety of scoring algorithms. Interestingly, although inverse approaches are generally expected to identify some but not all binders in a library, due to limited conformational searching, these results show excellent coverage of the known binders while still showing strong discrimination of the non-binders. An in silico designed dosimetric autologous living vaccine consisting of with Multiple Wilms’ Tumor 1 WT1-ConSynthetic–Restricted Peptide mimotopic Epitopes RMFPNAPYLP pulsed dendritic cells on a personalized Active Network analysis for asymptomatic or minimally symptomatic metastatic Pancreatic Cancer.

Keywords

Evaluation, Inverse Molecular Design Algorithm, Model Binding Site, in silico designed, dosimetric, autologous living vaccine, Multiple Wilms’ Tumor 1 WT1-ConSynthetic–Restricted, Peptide, mimotopic Epitopes, RMFPNAPYLP pulsed, dendritic cells, personalized, Active Network, analysis, asymptomatic, minimally, symptomatic metastatic, Pancreatic Cancer, inverse design, scoring function, protein-ligand interaction, cytochrome c peroxidase, dead-end elimination, drug design,

Experimental superposition of orders of quantum gatesAn in silico designed dosimetric autologous living vaccine consisting of with Multiple Wilms’ Tumor 1 WT1-ConSynthetic–Restricted Peptide mimotopic Epitopes RMFPNAPYLP pulsed dendritic cells on a personalized Active Network analysis for asymptomatic or minimally symptomatic metastatic Pancreatic Cancer

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Abstract

Quantum mechanics has long been recognized as a counter-intuitive theory, with ideas such as wave-particle duality, quantum superposition and entanglement defying our natural way of thinking. In recent years, these sorts of uniquely quantum properties are being exploited to develop revolutionary technologies, such as quantum cryptography, quantum metrology and perhaps the most well-known example, quantum computation. In the field of quantum computation, the circuit model was used to show that universal quantum computation is possible1, and the circuit model has since been an incredibly successful tool, leading to important quantum algorithms which greatly outperform their classical counterparts2. The circuit model takes advantage of the fact that quantum mechanics allows for the superposition and interference of quantum bits (qubits) in different states to achieve a computational speed-up. However, in addition to the superpositions of states, quantum mechanics also allows for the superposition of quantum circuits3,4—a feature which is not used in the standard quantum circuit model. Nevertheless, such superpositions of quantum circuits are rapidly becoming central to several foundational research programs studying the role of time and causality in quantum theory5,6,7,8,9. These superpositions of quantum circuits (sometimes called a ‘superposition of causal orders’) give rise to new counter-intuitive quantum predictions, and it has recently been predicted that they could provide quantum computers with even further computational advantages8,10. In particular, superimposing quantum circuits, each with a different gate ordering, can allow one to accomplish a specific computational task with fewer quantum gate uses than a quantum computer which has a fixed-gate order10. Quantum computers achieve a speed-up by placing quantum bits (qubits) in superpositions of different states. However, it has recently been appreciated that quantum mechanics also allows one to ‘superimpose different operations’. Furthermore, it has been shown that using a qubit to coherently control the gate order allows one to accomplish a task—determining if two gates commute or anti-commute—with fewer gate uses than any known quantum algorithm. Here we experimentally demonstrate this advantage, in a photonic context, using a second qubit to control the order in which two gates are applied to a first qubit. We create the required superposition of gate orders by using additional degrees of freedom of the photons encoding our qubits. The new resource we exploit can be interpreted as a superposition of causal orders, and could allow quantum algorithms to be implemented with an efficiency unlikely to be achieved on a fixed-gate-order quantum computer.An in silico designed dosimetric autologous living vaccine consisting of with Multiple Wilms’ Tumor 1 WT1-ConSynthetic–Restricted Peptide mimotopic Epitopes RMFPNAPYLP pulsed dendritic cells on a personalized Active Network analysis for asymptomatic or minimally symptomatic metastatic Pancreatic Cancer.

Keywords

Experimental superposition of orders of quantum gatesAn in silico designed dosimetric autologous living vaccine consisting of with Multiple Wilms’ Tumor 1 WT1-ConSynthetic–Restricted Peptide mimotopic Epitopes RMFPNAPYLP pulsed dendritic cells on a personalized Active Network analysis for asymptomatic or minimally symptomatic metastatic Pancreatic Cancer.

Experimental simulation of Novel procedure quantum tunneling in small Computational Scaffolding systems on tumorigenic stem cell bacterial infected hybrids for the in silico rescaffolding and side-chain optimization on the neutrophil immune defense CAP37 protein

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Abstract

It is well known that quantum computers are superior to classical computers in efficiently simulating quantum systems. Here we report the first experimental simulation of quantum tunneling through potential barriers, a widespread phenomenon of a unique quantum nature, via NMR techniques. Our experiment is based on a digital particle simulation algorithm and requires very few spin-1/2 nuclei without the need of ancillary qubits. The occurrence of quantum tunneling through a barrier, together with the oscillation of the state in potential wells, are clearly observed through the experimental results. This experiment has clearly demonstrated the possibility to observe and study profound physical phenomena within even the reach of small quantum computers. Quantum simulation is one of the most important aims of quantum computation ever since Feynman studied the likelihood of simulating one quantum system by another1. Recent years have witnessed fruitful results in the development of quantum computation, and it has been demonstrated that quantum computers can solve certain types of problems with a level of efficiency beyond the capability of classical computers2,3,4,5,6, among which the simulation of the dynamics of quantum systems is especially attractive because of the exponential improvement in computational resources and speeds. Quantum simulation has become a subject of intense investigation and has been realized in various situations, such as system evolution with a many-body interaction Hamiltonian7,8,9,10, the dynamics of entanglement11,12, quantum phase transitions13,14, and calculations of molecular properties15,16,17,18,19. Since we live in a dirty environment, we have developed many host defenses to contend with microorganisms. The epithelial lining of our skin, gastrointestinal tract and bronchial tree produces a number of antibacterial peptides, and our phagocytic neutrophils rapidly ingest and enzymatically degrade invading organisms, as well as produce peptides and enzymes with antimicrobial activities. Some of these antimicrobial moieties also appear to alert host cells involved in both innate host defense and adaptive immune responses.RNAs fold into intricate and precise secondary structures. In this study for the first time we have been evaluted experimental simulation of Novel procedure quantum tunneling in small Computational Scaffolding systems on tumorigenic stem cell bacterial infected hybrids for the in silico rescaffolding and side-chain optimization on the neutrophil immune defense CAP37 protein.

Keywords

Novel procedure Computational Scaffolding, tumorigenic stem cell, bacterial infected hybrids, in silico rescaffolding, side-chain optimization, neutrophil immune defense, CAP37 protein, Experimental simulation, quantum tunneling, small systems.

Demonstration of quantum permutation algorithm with a single photon ququart on Combinatorial learning procedures and graph transformations for the discovery of tumor-like cardiomyocyte derived eletroporated combined hybrids on a Meta-Dynamic Meta-node stemness reconstructing approach for the in silico generation of a anti-(JAM-A) drug-construct

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Abstract

As quantum counterpart of classical computer, quantum computer reveals incredible efficiency to execute arithmetic tasks and threatens the security of classical communication. Quantum algorithm is the sole of quantum computation, which shows the amazing power of quantum parallelism and quantum interference. It attracts particular concern to develop new quantum algorithms in recent years. The concept of simulating physics progresses with quantum computers was originated in Richard Feynman’s observation that computers built from quantum mechanical components would be ideally suited to simulating quantum mechanics1. Since then, the first efficient quantum algorithm was proposed by Deutsch in 19852 and generalized by Deutsch and Jozsa in 19873. Lately, an increasing number of practical programs were presented, such as factoring large integer4, Grover’s searching algorithm for database5 and Simon’s exponential acceleration algorithm for the black box problem6. What’s more, Harrow et al. came up with a quantum scheme to decrease the computational complexity of solving linear system of equations from O(n) to log(n) , and this was the first quantum algorithm to work out the most fundamental problems in engineering science7. Some quantum algorithms have been demonstrated in different physical systems, such as ion traps8,9,10,11, superconducting devices12,13,14, optical lattices15,16, quantum dots17,18, and linear optics19,20,21,22,23,24,25. Due to its good scalability, easy-handling and high stability, linear optical system is a good candidate for implementing quantum algorithms.We report an experiment to demonstrate a quantum permutation determining algorithm with linear optical system. By employing photon’s polarization and spatial mode, we realize the quantum ququart states and all the essential permutation transformations. The quantum permutation determining algorithm displays the speedup of quantum algorithm by determining the parity of the permutation in only one step of evaluation compared with two for classical algorithm. This experiment is accomplished in single photon level and the method exhibits universality in high-dimensional quantum computation.Combinatorial learning procedures and graph transformations for the discovery of tumor-like cardiomyocyte derived eletroporated combined hybrids on a Meta-Dynamic Meta-node stemness reconstructing approach for the in silico generation of a anti-(JAM-A) drug-construct.

Keywords

Demonstration, quantum permutation algorithm, single photon, ququart, Combinatorial learning procedures, graph transformations, discovery tumor-like cardiomyocyte, eletroporated, combined hybrids, Meta-Dynamic, Meta-node, stemness, reconstructing, approach, in silico, generation, anti-(JAM-A), drug-construct.