The new prognostic score for unresectable or recurrent gastric cancer treated with nivolumab: A multi-institutional cohort study.

BACKGROUND: Real-world outcomes of nivolumab treatment for gastric cancer and associated prognostic factors remain unclear; the present study aimed to evaluate both items. METHODS: A total of 278 consecutive patients treated with nivolumab for gastric cancer during 2017-2019 were enrolled in this multi-institutional retrospective cohort study. The impact of laboratory findings, immune-related adverse events (irAEs), and clinicopathological factors on long-term survival was evaluated using the Cox proportional hazards model. RESULTS: The response rate was 11.7% in patients with measurable lesions. The overall and progression-free survival estimates were 6.77 and 2.53 months, respectively. The incidence of irAEs was 30.6% (6.8% for grade ≥3). There were no treatment-related deaths. Multivariate analysis revealed that C-reactive protein level of ≤0.5 mg/dL (hazard ratio = 0.476, P < .001), irAE occurrence (hazard ratio = 0.544, P < .001), albumin level of >3.5 g/dL (hazard ratio = 0.688, P = .045), performance status 0 (hazard ratio = 0.711, P = .028), lymphocyte count >1000/µL (hazard ratio = 0.686, P = .027), and differentiated histological type (hazard ratio = 0.740, P = .046) were independently associated with improved survival. The median survival of patients with four or more good prognostic factors was 18.3 months. CONCLUSION: Nivolumab showed safety and survival benefits in patients with previously treated unresectable or recurrent gastric cancer. Low C-reactive protein level, irAE occurrence, high albumin level, high lymphocyte count, and differentiated histological type may affect outcomes. The presence of four or more good prognostic factors may help identify likely long-term survivors.

[A Case of Brain Metastasis of Gastric Cancer Successfully Treated with Nivolumab].

A 68‒year‒old man was referred to our hospital due to vomiting and light‒headedness. The patient was diagnosed with advanced gastric cancer. Neoadjuvant chemotherapy(S‒1 plus oxaliplatin)was initiated resulting in a partial response(PR) after 5 courses. Total gastrectomy and D1 dissection was performed. The tumor was diagnosed as poorly differentiated adenocarcinoma and the pathological Stage was ypT3, N3b, M1[CY1], ypStage Ⅳ. Ramucirumab plus nab‒paclitaxel was administered due to the appearance of swollen lymph nodes post‒operatively. This treatment maintained PR for 6 courses. However, after an evaluation of progressive disease(PD), nivolumab was initiated as third‒line chemotherapy. After 3 courses, a sudden seizure occurred and a brain metastasis with a diameter of 6 mm was observed. Considering the decrease in CEA level and that the brain metastasis presented as a small lesion, the tumor was inferred to be highly sensitive to nivolumab. We continued nivolumab monotherapy as chemotherapy. Radiotherapy was not performed. Both intra and extra‒cranial metastatic lesions maintained PR for 17 courses. The treatment was changed to irinotecan after evidence of PD was observed. However, after 2 courses(2 years and 3 months from his first visit), the patient died of an unknown cause. To our knowledge, this is the first case of brain metastasis of gastric cancer successfully treated with nivolumab.

What are the important prognostic factors in gastric cancer with positive duodenal margins? A multi-institutional analysis.

PURPOSE: Positive margins are reported in from 4.8 to 9.5% of all gastric cancer surgeries and they have a negative impact on the overall survival. Few cases with positive duodenal margins have been included in previous studies regarding the prognosis. METHODS: This multi-institutional retrospective study included 115 gastric cancer patients with positive duodenal margins following gastrectomy between January 2002 and December 2017. The association between clinicopathological factors and the overall survival was evaluated by univariate and multivariate analyses. RESULTS: The three-year overall survival was 22% and the median survival was 13 months. A multivariate analysis found that distant metastasis, no postoperative chemotherapy, and non-Type 4 disease were significantly associated with a poor survival. Patients without distant metastasis who received postoperative chemotherapy had a 3-year overall survival of 56% and a median survival of 44 months. CONCLUSION: The patients who underwent post-operative chemotherapy showed a significantly better OS compared with those who did not undergo post-operative chemotherapy, regardless of the existence of distant metastasis. Postoperative chemotherapy may, therefore, improve the prognosis of surgically treated gastric cancer patients with positive duodenal margins.

A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01).

BACKGROUND: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. METHODS: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). RESULTS: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events. CONCLUSIONS: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing. TRIAL REGISTRATION: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347.

Laparoscopic orchidopexy with transabdominal preperitoneal hernia repair in an adult.

We report an adult who underwent laparoscopic orchidopexy and transabdominal preperitoneal hernia repair. The patient was a 53-year-old man who was referred to our hospital for a bulge and pain in his left inguinal area. An abdominal CT scan revealed that the greater omentum was incarcerated in a left inguinal hernia. The patient underwent emergency laparoscopic surgery immediately. After reduction, he was diagnosed with bilateral cryptorchidism and inguinal hernia. After adequate mobilization, pneumoperitoneum was discontinued, and orchidopexy was performed with the Lichtenstein tension-free hernioplasty. One month later, the patient underwent elective laparoscopic orchidopexy with transabdominal preperitoneal hernia repair on his right side. The patient's postoperative course has been uneventful, with no evidence of hernia recurrence to date. This procedure is safe and may be an option for adult patients who desire testis preservation. This may be the first report of laparoscopic hernia repair with orchidopexy.

Gastric volvulus with a large bochdalek hernia in an adult successfully treated with emergency endoscopic reduction followed by elective laparoscopic mesh repair: A case study.

We report a case of gastric volvulus with a large Bochdalek hernia successfully treated with emergency endoscopic reduction followed by elective laparoscopic mesh repair. The patient was a 71-year-old woman with no history of trauma. She was referred to our hospital because of nausea and vomiting after eating. Thoracic and abdominal CT showed gastric volvulus and a large Bochdalek hernia. The patient underwent emergency endoscopic reduction and elective laparoscopic surgery. The defect (10 × 12 cm) was reinforced with a Dual Mesh (expanded polytetrafluoroethylene) and fixed to the diaphragm with nonabsorbable sutures. The postoperative course was uneventful, and no complications or recurrence was found at the 2-year follow-up. The endoscopic reduction and elective laparoscopic procedure was performed successfully and resulted in significant clinical improvement in this case.

Solitary pulmonary metastasis from carcinoma of the papilla of vater.

Pulmonary metastasis from carcinoma of the papilla of Vater is considered to be a late event, and patients can be treated with radiotherapy, chemotherapy, or palliative surgery. However, surgical treatment of an isolated lung metastasis has not been reported. We present a surgical case of solitary pulmonary metastasis from carcinoma of the papilla of Vater. A 51-year-old man underwent pylorus-preserving pancreaticoduodenectomy for Vater carcinoma. During follow-up, chest computed tomography revealed a nodular shadow in the right lung. The pathological examination demonstrated the appearance of the pulmonary tumor resembled that of the previously resected Vater carcinoma, and both tumors showed similar immunostaining properties, leading to the pathological diagnosis of pulmonary metastasis from carcinoma of the papilla of Vater. Isolated pulmonary metastasis from carcinoma of the papilla of Vater is extremely rare, but surgery could be the treatment of choice.

Induction of Foxp3-expressing regulatory T-cells by donor blood transfusion is required for tolerance to rat liver allografts.

BACKGROUND: Donor-specific blood transfusion (DST) prior to solid organ transplantation has been shown to induce long-term allograft survival in the absence of immunosuppressive therapy. Although the mechanisms underlying DST-induced allograft tolerance are not well defined, there is evidence to suggest DST induces one or more populations of antigen-specific regulatory cells that suppress allograft rejection. However, neither the identity nor the regulatory properties of these tolerogenic lymphocytes have been reported. Therefore, the objective of this study was to define the kinetics, phenotype and suppressive function of the regulatory cells induced by DST alone or in combination with liver allograft transplantation (LTx). METHODOLOGY/PRINCIPAL FINDINGS: Tolerance to Dark Agouti (DA; RT1(a)) rat liver allografts was induced by injection (iv) of 1 ml of heparinized DA blood to naïve Lewis (LEW; RT1(l)) rats once per week for 4 weeks prior to LTx. We found that preoperative DST alone generates CD4(+) T-cells that when transferred into naïve LEW recipients are capable of suppressing DA liver allograft rejection and promoting long-term survival of the graft and recipient. However, these DST-generated T-cells did not express the regulatory T-cell (Treg) transcription factor Foxp3 nor did they suppress alloantigen (DA)-induced activation of LEW T-cells in vitro suggesting that these lymphocytes are not fully functional regulatory Tregs. We did observe that DST+LTx (but not DST alone) induced the time-dependent formation of CD4(+)Foxp3(+) Tregs that potently suppressed alloantigen-induced activation of naïve LEW T-cells in vitro and liver allograft rejection in vivo. Finally, we present data demonstrating that virtually all of the Foxp3-expressing Tregs reside within the CD4(+)CD45RC(-) population whereas in which approximately 50% of these Tregs express CD25. CONCLUSIONS/SIGNIFICANCE: We conclude that preoperative DST, in the absence of liver allograft transplantation, induces the formation of CD4(+) T-cells that are not themselves Tregs but give rise directly or indirectly to fully functional CD4(+)CD45RC(-)Foxp3(+)Tregs when transferred into MHC mismatched recipients prior to LTx. These Tregs possess potent suppressive activity and are capable of suppressing acute liver allograft rejection. Understanding the mechanisms by which preoperative DST induces the generation of tolerogenic Tregs in the presence of alloantigens may lead to the development of novel antigen-specific immunological therapies for the treatment of solid organ rejection.

Role of reactive metabolites of oxygen and nitrogen in partial liver transplantation: lessons learned from reduced-size liver ischaemia and reperfusion injury.

1. Hepatic resection with concomitant periods of ischaemia and reperfusion (I/R) is required to perform reduced-size liver (RSL) transplantation procedures, such as living donor or split liver transplantation. Although a great deal of progress has been made using these types of surgical procedures, a significant number of patients develop tissue injury from these procedures, ultimately resulting in graft failure. 2. Because of this, there is a real need to understand the different mechanisms responsible for the tissue injury induced by I/R of RSL transplantation (RSL + I/R), with the ultimate goal to develop new and improved therapeutic agents that may limit the tissue damage incurred during RSL transplantation. 3. The present paper reviews the recent studies that have been performed examining the role of reactive metabolites of oxygen and nitrogen in a mouse model of RSL + I/R. In addition, we present data demonstrating how the pathophysiological mechanisms identified in this model compare with those observed in a model of RSL transplantation in rats.

Divergent roles of superoxide and nitric oxide in reduced-size liver ischemia and reperfusion injury: Implications for partial liver transplantation.

Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) are required to perform partial liver transplantation procedures such as split liver or living donor transplantation. Although great progress has been made using these types of surgeries, there remains substantial risk to both donors and recipients, with a significant number of patients developing liver injury and failure during the course these operations. Therefore, there is need to investigate the different mechanisms responsible for the tissue injury induced by ischemia and reperfusion of a reduced-size liver (RSL+I/R) with the ultimate objective of developing new therapeutic agents that may limit hepatocellular damage induced during partial liver transplantation. This review summarizes recent studies that have been performed in a mouse model of RSL+I/R. In addition, we present data demonstrating how the pathophysiological mechanisms identified in this model compare to those observed in a rat model of RSL transplantation.

Platelet recruitment in the murine hepatic microvasculature during experimental sepsis: role of neutrophils.

OBJECTIVES: Sepsis is a major clinical problem that often results in the dysfunction or failure of multiple organs, including the liver. While inflammatory cell activation has been implicated as an early critical event in sepsis-induced liver dysfunction, there is growing evidence for the involvement of activated platelets in this pathologic process. METHODS: Intravital microscopy was used in this study to assess the magnitude and time course of platelet adhesion in the liver microcirculation during experimental sepsis and to determine whether the platelet accumulation is linked to leukocyte infiltration. The adhesion of platelets and leukocytes in terminal hepatic venules (THV) and sinusoids was quantified at 2, 4, and 6 h after abdominal sepsis induced by cecal ligation and puncture (CLP). RESULTS: While the rolling and firm adhesion of platelets and leukocytes in THV were not altered in the first 2 h after CLP, platelet recruitment was observed at 4 h and further elevated at 6 h after CLP. Leukocyte adhesion in THV exhibited a similar time course. A similar accumulation of blood cells in sinusoids was noted after CLP. This was accompanied by an increased number of nonperfused sinusoids. CLP-induced leukocyte and platelet recruitment in THV and sinusoids was attenuated in mice rendered neutropenic with anti-neutrophil serum. CONCLUSION: These findings indicate that sepsis is associated with a neutrophil-dependent recruitment of platelets in the liver microcirculation that impairs sinusoidal perfusion and may contribute to the liver dysfunction associated with sepsis.