DOI: 10.31038/CST.2017264

Abstract

A detailed description of the clinical case of multivisceral resection in advanced gastric cancer is presented. The surgery included total gastrectomy, pancreatoduonenectomy, extended right colectomy, D2+ lymphadenectomy. After discharge from the hospital, the patient continues specific treatment in the form of adjuvant chemotherapy. During the nine months of follow-up, the patient did not find any recurrence of the disease. A brief review of the literature on the problem of multivisceral resections in advanced gastric cancer is presented.

Introduction

The necessity and possibility of multivisceral resections in locally advanced forms of malignant neoplasms in abdominal oncosurgery has been the subject of permanent discussion for several decades. At the same time, not only and not so much technical nuances of performing large-scale and super-large-scale surgical interventions as well as real patient tolerance of these operations and their expediency from the point of view of long-term results are discussed. At the same time, if multivisceral resections for malignant neoplasms of the large intestine and pelvic organs are currently considered as a standard version of the surgical manual, the extension of operations with locally advanced gastric tumors still raises a number of questions. This, in turn, is associated both with the characteristics of malignant neoplasms of the stomach (rapid local progression of the tumor process and its generalization, questionable efficacy of neoadjuvant and adjuvant therapy), and with topographic and anatomical features of the location of the stomach itself, determining the possibility of tumor invasion of the liver, pancreas, duodenum, colon, major vessels of the upper floor of the abdominal cavity. These circumstances, which in themselves dictate the necessity of performing multivisceral resections (of course with regional lymphadenectomy > D2) with very often occurring locally advanced gastric cancer, are certainly very important for deciding whether to perform this particular patient surgery with the radicality R0. On the other hand, factors that limit the possibility of carrying out operations in volumes equal to or exceeding gastrectomy with pancreatoduodenectomy are obvious: adequate anesthesia and resuscitation allowance for high risk of intra- and postoperative complications, technology of bloodless surgery and replacement of acute blood loss. At the same time, the integral indicator of the patient’s overall status in combination with these factors objectively determines an extremely high degree of operational and anesthetic risk and in the overwhelming majority of cases is today a reasoned basis for refusing a radical operation. Similarly, a very limited amount of observations of long-term results after multivisceral resections, which are an integral part of gastrectomy, do not allow most authors to make unequivocal judgments about the appropriateness of these interventions in terms of increasing the three- and five-year survival of patients.

Xin-Bao Wang et al. [1] report 17 cases of total gastrectomy with PDR performed in a group of 53 patients with synchronous tumor lesions of the stomach and pancreatoduodenal complex over a 9-year period. 3- and 5-year survival after multivisceral resection was 77 and 34%, respectively, in 59% of cases; local progression of the process was noted. The authors indicate that the predictors of satisfactory long-term results are the high degree of differentiation of adenocarcinoma and the radicality of the performed operation R0.

P. Roberts et al. [2] after analyzing Medline, EMBASE and Cochrane database, report a total of 27 total gastrectomies performed in combination with pancreatoduodenectomy for the period from 1985 to 2009. In the overwhelming majority of cases, surgical interventions were performed in patients with the T-test T3 and T4. In this case, the pre-operative or intraoperative IV stage of the oncology process was not the reason for refusing multivisceral resection. The indication for pancreatoduodenectomy (PDE) in stomach cancer was the spread of the tumor distal to the pylorus, the invasion of the tumor into the head of the pancreas, metastatic damage of the lymph nodes in the head of the pancreas. Neoadjuvant chemotherapy and radiation therapy was conducted in a limited number of observations, was not systematic and its results could not be subjected to statistical analysis. The authors indicate that the combination of gastrectomy with PDR significantly increases the number of postoperative complications (23.1 – 73.9%) compared to gastrectomy in a monovariant (3.2 – 31.9%). However, the authors do not report any fatal outcome after multivisceral resection. Analyzing the long-term results of surgical interventions, the authors point out that although there are no significant differences in 5-year survival in some reports, there is still a trend in the increase in 3- and 5-year survival in patients after multivisceral resections compared to only gastrectomy due to an apparently smaller number of R1 resection in patients of the first group.

O.I. Kit, et al. [3] provide data on 22 total gastrectomies combined with PDE for the period from 1983 to 2010. Multivisceral resections were accompanied by the development of complications of the early postoperative period in 73.3% of patients and 2 deaths. Subsequently, 5 patients required deferred reconstructive surgery. The authors indicate that PDE in combination with gastrectomy performed for common stomach cancer, increase the radicalism of the operation, which is reflected in an increase in 3-year survival in these patients. The authors emphasize that at the present stage of development of the PDD technique its combination with gastrectomy in the hands of an experienced oncologist, with adequate anesthesia and postoperative rehabilitation, is an acceptable method of treating patients with locally advanced gastric cancer without metastases to regional lymph nodes.

In the monograph “Combined operations for stomach cancer”, published in 2005 under the editorship of prof. V.F. Kasatkin [4], the reasons for really single observations of a combination of gastrectomy with PDE are indicated: significant operational trauma, duration of surgery and anesthesia, removal of an extensive drug with the formation of a “tissue volume deficit” in the abdominal cavity, lack of a large epiploon as plastic material and a “biological” tampon, two dangerous in terms of development of insolvency of the anastomosis (pancreatic and esophageal). These circumstances are a natural cause of the complicated course of the postoperative period in almost 80% of patients. The authors provide information on two cases of expansion of the multivisceral resection volume to a combination of gastrectomy and PDE with right-sided hemicolectomy. The same authors give data on the operation of A.F. Chernousov (2000) combined gastrectomy, PDE and resection of the transverse colon. At the same time, the authors of the monograph argue reasonably enough about the feasibility of performing such operations: “Aware of the high risk of death, they relied on the idea of improving the patient’s condition and the illusory hope of recovery. The support was the fact that most of the operated ones were brought to their full desperation by their ailment, and realizing that the only real chance for prolonging life is surgery, literally demanding surgical intervention “[5-7].

Performing surgical interventions for stomach cancer in our Hospital, we very often face the need to expand the volume of surgery to a combination of subtotal resection or gastrectomy with distal or subtotal distal resection of the pancreas, resection of the colon, atypical or anatomical resection of the liver. However, with the need to perform multispecial resection in the amount of gastrectomy, PDE and extended right colectomy, we first encountered. Considering the aforementioned small number of observations of operations of this volume available in the literature, we considered it possible to describe this clinical case.

Clinical case

Patient N., 39 years old female, mother of three children, applied for consulting assistance to the Department of Abdominal Surgery of the Clinical Hospital 1 (Volynskaya) of the Hospital 1 Office of the President of the Russian Federation on 07.12.2016 with complaints about the inability to eat solid food, almost constant feeling of overflow in epigastria, regurgitation and periodic vomiting of food eaten. These symptoms were first noted by the patient in July 2016. In case of an out-patient examination in September 2016, during the esophagogastroduodenoscopy, “deformation and cicatricial-ulcerative stenosis of the pylorobulbar zone” was detected, a biopsy was taken. The histological examination of the biopsy specimen turned out to be uninformative. Due to increasing phenomena of gastric emptying, the patient again applied for an outpatient care to a gastroenterologist in November 2016. The patient received an outpatient X-ray of the stomach with contrast, at which the subcompensated stenosis of the pylorobulbar zone was diagnosed without specifying its etiology. From the end of November 2016, the patient noted the appearance of weakness, stool retention for 2 to 4 days, periodically the appearance of melena. The patient indicated the fact of the total mass loss for 4 months per 10 kg. In the history of the patient, there are three caesarean sections, the latter with a ligation of the fallopian tubes.

Upon examination, the patient’s condition was regarded as moderate. Patient was of normostenic physique, BMI 22.9. Clinically significant violations of the overall status, including peripheral lymphadenopathy, were not identified. Attention was drawn to the presence of palpable, limitedly displaced, painless volume formation in the epigastric region. In the rectal finger examination, traces of feces of black color were detected.

In case of esophagogastroduodenoscopy (Figure 1) circular tumor infiltration of the antral part was detected with proximal propagation along the small curvature 2 cm above the angle of the stomach, distally on the bulb of the duodenum and postbulbar region, with ulceration in the antrum 2 × 2.5 cm, in the bottom of which the plaque of hydrochloric acid hematin; multifocus biopsy was performed. Histological examination of the endoscopic biopsy specimen: a low-grade adenocarcinoma with the presence of signet-ring cells.

The patient was hospitalized in the Department of Abdominal Surgery of the Clinical Hospital 1 (Volynskaya) of the Hospital 1 Office of the President of the Russian Federation on 08.12.2016. At the time of hospitalization, laboratory indicators were within the physiological norm (including Hb 128 g/l, WBC 7.6, total protein 66 g/l). When multispiral computed tomography (MSCT) was performed with bolus contrasting, it was revealed (Figure 2): the upper part of the stomach was stretched with contents, in which a hyper-sensitive suspension was detected (probably, barium residues); the walls of the antrum are thickened to 15 mm, around the antrum there are quantitatively enlarged lymph nodes 9-12 mm in size, the pyloric department merges with the bulb of the duodenum without clear boundaries, the lumen in it is not traced; thickness of the walls of bulb and postbulbar part of the duodenum up to 7mm, the rest of the intestinal wall is not thickened; the walls of the stomach and the duodenum adjacent to the head of the pancreas without convincing signs of tumor’s invasion; the spleen is not enlarged, homogeneous; pancreas with clear contours, not enlarged, homogeneous structure; pancreatic duct is not enlarged; sites of pathological accumulation of contrast substance parenchyma of the gland is not revealed; liver is not enlarged, homogeneous structure; intra- and extrahepatic bile ducts are not dilated, gallbladder is in usual size, thin-walled, in the lumen – homogeneous liquid contents; there were signs of stenosis in low third of the right ureter with pronounced uretero-pylo-calicoectasia on the right; there is no fluid in the abdominal cavity. At the MSCT of the thorax no pathological changes were detected. At laboratory inspection of oncomarkers: CA 72-4 31,2 IU, CA 19-9 151,3 IU

Figure 2. MSCT: antrum tumor extends to the bulb of the duodenum.

The clinical diagnosis was formulated as follows: C16.8, cancer of the antrum and body of the stomach, infiltrative-ulcerative form, with spread to the duodenum (type III Borrmann) cT4N1Mx. Taking into account the verified histological tumor lesion of the stomach complicated by decompensated stenosis and recurrent bleeding, in the absence of signs of systemic dissemination of the tumor process and signs of tumor unresectability, a decision was made to conduct an operative intervention in the volume of distal subtotal resection of the stomach with pancreatoduodenectomy according to vital indications.

Within 4 days, the patient underwent preoperative preparation, including parenteral administration of 3-Chamber bags mixtures and sipping with official nutritional mixtures with a total calorie content up to 3,000 kcal/day. Immunonutrition support was provided for enteral and parenteral administration of the Omega-3 fatty acids. In connection with the stricture of the right ureter, an internal ureteral stent was placed on the right.

13.12.2016 the patient was operated under endotracheal anesthesia in combination with epidural anesthesia. At the stage of intraoperative revision, a circular tumor of the antral section, which propagates proximally to the body of the stomach and the subcardia by a small curvature (Figure 3), distally to the bulb and the postbulbar part of duodenum, is revealed invading the serous of the anterior and posterior walls of the stomach. It was found invasion of the tumor along the back wall of the antrum into the head of the pancreas, the mesocolon to the right and left of the middle colonic vessels, into the wall of the transverse colon in the hepatic flexure (Figure 4). In addition, infiltration of the right paracolic space, presence of characteristic foci of dissemination on the visceral peritoneum of ileo-cecal angle and in the projection of the distal part of the inferior mesenteric vein were determined. A macroscopic increase in the lymph nodes of groups 3, 4d, 5, 6, 7, 15 (according to JCGC) was found.

Figure 3. Appearance of the stomach during intraoperative exploration.

Figure 4. Local prevalence of the tumor process.

Taking into account the data of the operational finding, the volume of the operation was extended to gastrectomy, pancreatoduodenectomy, extended right colectomy with regional lymphadenectomy D2. During the resection stage, the esophagus was crossed 3 cm above the cardia, the jejunum – 10 cm distal to Treitz ligamentum; the pancreas was crossed along the border of the neck and body to the left of the superior mesenteric vein ; the ileum was crossed 20 cm proximal to the ileocolic angle, the colon – 8 cm distal to the splenic flexure; the c holedoch was crossed 0.5 cm distal to the confluence of the cystic duct; ilio-colon and middle colonic artery are ligated at the point of departure from the superior mesenteric artery, veins of the same name – at the point of confluence in the superior mesenteric vein. The inferior mesenteric vein after the test compression was crossed 4 cm from the point of confluence into the splenic vein. Regional lymphadenectomy with removal of lymph nodes of groups 1-12, 13, 14v, 15, 16b1, 17, 18 (according to JGCA classification) was performed (Figure 5). The resected tissues were removed by a single block (Figure 9). Dissection of tissues during the resection stage was carried out using ultrasound dissection and bipolar coagulation. Urgent histological examination showed no tumor growth at the margins of resection.

Figure 5. Resection stage of the surgery is completed.

The reconstructive stage of the surgery was performed with the formation of alimentary and biliopancreatic (70 cm) loops of small bowel according to Roux mode (Figure 6). On the alimentary loop, an “end-to-end” esophagogo-enteroanastomosis was formed with the circular stapler (28 mm), ileo-descendoanastomosis “side by side” was formed with the stapler device (60mm) (Figure 7). The alimentary and biliopancreatic loops were connected by “side-to-side” Rouxe-en-Y-anastomosis with the stapler device (60mm), distal to esophago-enteroanastomosis by 45 cm. On the biliopancreatic loop, the “end-to-end” pancreato-enteroanastomosis was formed by single sutures Maxon 3/0 according to J.L. Cameron mode (invagination of the edge of the pancreas into the lumen of the small intestine) . This method of formation of pancreato-enteroanastomosis anastomosis was chosen because of the small diameter of the main pancreatic duct (up to 1.5 mm), the absence of fibrosis of the parenchyma and the unexpressed pancreatic capsule. At 20 cm distal to this anastomosis, cholecysto-enteroanastomosis was formed with a single continuous Biosyn 3/0 suture. In addition, on the biliopancreatic loop, the interintestinal (Braun’s) anastomosis was formed “side by side” with the stapler device (60mm) (Figure 8). A transnasal nourishing probe was conducted into the alimentary loop beyond the esophago-enteroanastomosis and Roux-en-Y-anastomosis. Surgery was completed by draining the subhepatic, left subdiaphragmatic space, the pelvic cavity and the pancreato-enteroanastomosis zone. The duration of the surgery was 7 hours and 30 minutes. The total volume of intraoperative blood loss, taking into account the remote tissues – up to 1 liter. Transfusion of one unit of RBC and three units of plasma was performed intraoperatively.

Figure 6. The general plan of the reconstructive stage of the surgery: 1 – alimentary loop of the small bowel, 2 – biliopancreatic loop of the small bowel.

Figure 7. The beginning of the reconstructive stage of the surgery: 1 – alimentary loop of the small bowel, 2 – biliopancreatic loop of the small bowel before the formation of anastomoses, 3 – esophagoeteroanastomosis.

Figure 8. Figure 8. Biliopancreatic loop of small bowel: 1 – invaginated pancreatoenteroanastomosis according to J.L. Cameron, 2 – cholecystoenteroanastomosis, 3 – interintestinal anastomosis according to Braun.

Thus, the patient underwent surgical treatment in the following volume: total gastrectomy, pancreatoduodenectomy, expanded right colectomy, D2+ lymphadenectomy (Figure 9).

Figure 9. Surgical specimen: 1 – caecum, 2 – ascending colon, 3 – transverse colon, 4 – the left splenic flexure, 5 – stomach, 6 – duodenum, 7 – head and neck of the pancreas.

In the first 48 hours of the postoperative period the patient was observed in the ICU. Self-breathing was restored in one hour after the end of the surgery. Six hours after the end of the surgery infusion of semi-elemental mixtures into the nutritive probe, parenteral nutritional support with a “three in one” mixture was started. After 24 hours from the end of the surgery the patient was switched to a probe feed with a standard enteral mixture. The feeding probe was removed 36 hours after the end of the operation. Later the patient received standard postoperative therapy according “fast track” protocol: prolonged epidural anesthesia and NSAID without opioids, combined parenteral-enteral support with the siping of high-calorie mixtures, immunonutrition support with the Omega-3 fatty acids, antibacterial prophylaxy, octreotide infusion 0.025 mg / h, thromboprophylaxis. From the second day after surgery began the physical activation of the patient (sitting in bed, lifting to the feet). Auscultatory peristalsis began to be determined 18 hours after the end of the surgery, stool – on the 3rd day of the postoperative period.

From the third day of the postoperative period, rehabilitation was performed under the conditions of the abdominal surgery department. The diet was extended by oral intake of fermented milk products, broths. During 3-6 days there was a multiple liquid stool, periodic spastic pains in the abdomen, and phenomena of flatulence. However, already by the 7 days of the postoperative period, these phenomena were leveled, the stool returned to normal, once a day. Separated by drainage, starting from 1 day postoperative period, was serous, amounting to a total of 100 ml per day and limited to 6 days postoperative period to 50 ml. Drainages from the small pelvis and the left sub-diaphragmatic space were removed on the 4th day of the postoperative period, drainage from the subhepatic space – on day 6. On the 7th day of the postoperative period, a clear colorless discharge from the drainage set in the region of pancreato-enteroanastomosis in the amount of up to 50-100 ml per day (amylase 9100 IU) was noted. With control ultrasound of the abdominal cavity on the 1^st, 3rd, 6th, 9th and 13th day of the postoperative period there were no accumulations of fluid in the abdominal cavity and in the retroperitoneal space. The patient completely switched to taking the standart diet on the 9^th day after surgery.

In laboratory indicators moderate anemia (Hb up to 95 g/l), leukocytosis (WBC up to 13.4), hyperamilazemia up to 340 IU, hypoproteinemia (total protein up to 47 g/l) for 1-4 days of the postoperative period were noted. Episodes of hyperthermia for the entire period of postoperative observation were not noted. On the 12th day of the postoperative period, Hb 103 g / l, WBC – 7.7, a-amylase – 76 IU, total protein – 66 g / l. The surgical wound healed by primary tension.

In consideration of absence of infectious complications, the relative normalization of the function of the digestive tract, but the remaining rate of pancreatic juice in the 50-70 ml / day, it was decided to discharge the patient from the hospital for outpatient monitoring with functioning drainage on the 12-day postoperative period. When follow-up examined on the 14th day after discharge, it was found that there was no liquid by drainage. The drainage was removed.

Histological study of the surgical specimen (stomach with omentum major and minor, duodenum, proximal part of small bowel, head and neck of pancreas, distal part of ileum, caecum, ascending colon with paracolic fat, transverse colon with mesocolon, left splenic flexure) : the circular tumor infiltration in the antrum and the body of the stomach is determined, spreading along the small curvature to the subcardia, passing to the duodenum, the ulceration of the tumor in the antrum (type III Borrmann), with signs of bleeding; in the wall of the stomach – the growth of a tumor having the structure of a low-grade adenocarcinoma with the presence of signet-ring cells; the tumor grows into the submucosal and muscular layers, into the subserous and serous layer, grows into a small omentum, the transverse colon and mesocolon, grows along the fibrous layers in the thickness of the fatty tissue; a large number of tumor cells is determined in perineural spaces, lymphatic vessels and veins; elements of the tumor are found in the tissue of the head of the pancreas, the muscular and submucosal layer of the caecum and the appendix, the wall of the duodenum, mesocolon, paracolic fiber. Tumor metastases were detected in 7 of the 38 lymph nodes examined. In the margins of resection (stomach, pancreas, jejunum, ileum, colon, mesocolon) tumor growth was not detected (PM 0, DM 0), radical surgery – R0. Pathomorphologic diagnosis: C16.8, advanced stomach cancer (type III Borrmann) with spread to the duodenum, pancreas head, transverse colon, mesocolon, right paracolon, metastasis of the visceral peritoneum of the caecum pT4b ly3 v3 N3 M1 P1 CYX H0. Immunohistochemical examination with antibodies to Her2 / neu (Pathway 4B5 Roche-Ventana): Her2 / neu – 0.

Starting with the fifth week of the postoperative period, the patient was subjected to adjuvant chemotherapy according to the EOX scheme (oxorubicin, oxaliplatin, capecitabine). A total of 6 courses of chemotherapy with stimulation filgrastim. In August 2017, a control PET CT was performed. A slight diffuse increased accumulation of difluoroglucose in the parietal peritoneum of the epigastric region is determined. At the control laboratory examination: indicators of clinical and biochemical blood tests within reference values, CA 72-4 5, 6 IU, CA 19-9 32,3 IU. Patient was assigned continued reception of capecitabine in mono regimen.

Currently in September 2017, the patient leads a normal lifestyle, has a regular diet without dyspepsia, regains her usual body weight and works by her profession.

Conclusion

Concluding the description of the above clinical case, we consider it necessary to give a number of comments. Undoubtedly, the surgical treatment of the patient is non-standard and rarely performed operations. This operation should be attributed to the category of desperation operations dictated by a perfectly understandable motivation to save or at least prolong the patient’s life in the presence of not only formal indications in the form of decompensated stenosis and recurrent bleeding from the tumor, but also motivation caused by a variety of social factors. During the surgery, having determined the prevalence of the tumor, we were perfectly aware of the illusory nature of our hopes for performing absolutely radical surgery. And at the same time, the decision to limit the surgery only by bypass formation, depriving the patient of any chance of life for more than 2-3 months was collectively found unacceptable. Moreover, taking into account the high risk of intra- and postoperative complications, we nevertheless counted on a favorable outcome of the surgery, taking into account a number of apparently positive factors, namely: young age and satisfactory physical condition of the patient, absence of signs of subclinical organ failure and significant violations of homeostasis. When performing surgery for a tumor of this prevalence, we certainly hoped for the possibility of modern adjuvant chemotherapy options. The early postoperative period and nine months of patient monitoring showed that our hopes were not unfounded.

We have presented only a single clinical observation of multivisceral resection in locally advanced stomach cancer, but we believe that it can be useful both for continuing the discussion about the necessity and possibility of operations of this size, and for making a decision that is extremely difficult from a medical and human perspective, in a concrete clinical situation.

References

1. Xin-Bao Wang, Li-Tao Yang, Ze-Wei Zhang (2008) Pancreaticoduodenectomy for advanced gastric cancer with pancreaticoduodenal region involvement. World J Gastroenterol 14: 3425–3429.
2. Roberts P, Seevaratnam R, Cardoso R, Law C, Helyer L, et al. (2012) Systematic review of pancreaticoduodenectomy for locally advanced gastric cancer. Gastric Cancer 15 Suppl 1: S108–115. [crossref]
3. Kit OI, Kasatkin VF, Maksimov AY, Trifanov VS (2005) Gastrectomy in combination with pancreatoduodenal resection for gastric cancer. Oncosurgery Vol.5: 1.
4. Combined operations for stomach cancer. Ed. V.F. Kasatkin
5. Otsuji E, Yamaguchi T, et al. Total gastrectomy with simultaneous pancreaticosplenectomy or splenectomy in patients with advanced gastic carcinoma. Br J Cancer 79: 1789–1793.
6. Zhang M, Zhang H, Ma Y, Zhu G, Xue Y. Prognosis and surgical treatment of gastric cancer invading adjacent organs. ANZ J Surg 80: 510–4.
7. Ozer I, Bostanci EB, Orug T, Ozogul YB, Ulas M, Ercan M, et al. (2017) Surgical outcomes and survival after multiorgan resection for locally advanced gastric cancer. Am J Surg 198: 25–30.

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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)

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).

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).

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).

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).

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]

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

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.

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.

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.

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.

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].

Figure 5.

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.

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.