Two autopsied gastric cancer cases of rare drug-induced pneumonia associated with nivolumab plus S-1 and oxaliplatin: a case report.

Background: Drug-induced pneumonia, especially immune-related adverse events, can sometimes be fatal, and it is crucial to seize the signs for early treatment. A clinical trial (ATTRACTION-4) reported no cases of grade 4 or 5 pneumonia or interstitial lung disease associated with nivolumab plus S-1 and oxaliplatin. However, we encountered two cases of fatal pneumonia induced by this regimen. Case Description: The two patients were in their 70s, male and diagnosed gastric cancer with peritoneal dissemination. The patient of case 1 underwent surgery and adjuvant chemotherapy nine years before. The patient of case 2 was diagnosed unresectable 6 months before and chemo naïve. Both patients received nivolumab plus S-1 and oxaliplatin for the dissemination. The onset of both cases occurred after the fifth dose of the regimen, and the responses to corticosteroids were transient and limited. Computed tomography showed bilateral consolidation and ground-glass opacities, seemingly similar to an organizing pneumonia pattern. Acute and organizing stages of diffuse alveolar damage were detected histopathologically. Despite showing notable antitumor effects, both patients had indications of interstitial pneumonitis before admission, such as elevation of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) levels and slight lung opacity or respiratory symptoms approximately 10 days before admission. Conclusions: Patients undergoing nivolumab plus S-1 and oxaliplatin should be closely followed up with imaging, evaluation of symptom including oxygen saturation, and serological marker analysis such as lactate dehydrogenase, CRP, and KL-6. Early detection of pneumonia leads to adequate cessation of chemotherapy and early treatment, and this can prevent severe adverse events.

Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells.

Preoperative Controlling Nutritional Status Score Predicts Mortality after Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: Preoperative nutritional status is reportedly associated with postoperative outcomes in patients with hepatocellular carcinoma. This study aimed to investigate the significance of the controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) as predictors of postoperative outcomes. METHODS: We retrospectively reviewed data from 331 patients who underwent hepatectomy for hepatocellular carcinoma between January 2007 and December 2015. Patients were divided into 2 groups based on their CONUT score and the PNI. We evaluated the effect of the CONUT score and PNI on perioperative outcomes. Multivariate analysis was performed to identify independent predictors of in-hospital mortality after hepatectomy. -Results: The high CONUT group had a significantly higher -incidence of 30-day mortality (p < 0.001), in-hospital mortality (p = 0.002), ascites (p = 0.006), liver failure (p = 0.02), sepsis (p = 0.01), and enteritis (p < 0.001). The low PNI group was also significantly associated with 30-day mortality (p < 0.001), in-hospital mortality (p = 0.003), liver failure (p < 0.001), sepsis (p = 0.02), enteritis (p = 0.02), and hospital stay (p = 0.01). In multivariate analyses, a high CONUT score was an independent predictor of in-hospital mortality after hepatectomy (hazard ratio [HR] 9.41, p = 0.038), but the PNI was not (HR 5.86, p = 0.08). CONCLUSIONS: Preoperative assessment of the CONUT score is helpful for evaluating patients' nutritional status and mortality risk after liver surgery.

The Outcome of Complex Hepato-Pancreato-Biliary Surgery for Elderly Patients: A Propensity Score Matching Analysis.

BACKGROUND/AIMS: Postoperative mortality and morbidity rates after hepato-pancreato-biliary (HPB) surgery remain high, and the number of elderly patients requiring such surgery has been increasing. This study aimed to investigate postoperative outcomes of complex HPB surgery for elderly patients. METHODS: We retrospectively reviewed perioperative data of 721 patients who underwent complex HPB surgery between 2010 and 2015. The patients were divided into 2 groups: elderly (≥75 years) and non-elderly (< 75 years). Surgical outcomes of both groups were compared after propensity score-matching analysis. Subsequently, risk factors for serious postoperative morbidity were identified by multivariate analysis. RESULTS: Before matching, the elderly group (n = 170) had more comorbidities, such as cardiovascular and renal disease, than the non-elderly group (n = 551). Matching yielded elderly (n = 170) and non-elderly groups (n = 170) with similar preoperative backgrounds. The mortality and morbidity rates did not differ significantly between the groups. In multivariate analyses, operative time (OR 1.79; p = 0.005) and blood loss (OR 1.66; p = 0.03) were identified as independent risk factors for serious postoperative morbidity, whereas older age did not have a predictive impact (OR 1.16; p = 0.52). CONCLUSIONS: Although elderly -patients had more comorbidities and higher incidences of postoperative mortality and several complications before matching, their postoperative outcomes were equivalent to those of non-elderly patients after matching.

A novel intestinal rotation method for digestive reconstruction after combined pancreaticoduodenectomy and extended right hemicolectomy: A case report and surgical technique.

INTRODUCTION: Pancreaticoduodenectomy (PD) combined with extended right hemicolectomy (RH) is a challenging procedure for locally advanced malignancies. However, information concerning the reconstruction method of the digestive system is limited. Here, we present a case and surgical technique of a novel intestinal rotation method for digestive reconstruction after PD combined with RH. PRESENTATION OF CASE: A 62-year-old man with locally advanced pancreatic cancer received conversion surgery combined with PD and RH after preoperative chemotherapy. With respect to the reconstruction of the digestive system, the entire intestinal mesentery was rotated 180° forward counterclockwise around the axis of the superior mesenteric artery, and then the reconstruction, according to Child's method, was performed. The patient recovered without problems in gastroenterological functions after the operation. DISCUSSION: With respect to the reconstruction of the digestive system in patients undergoing combined PD and RH, practitioners should pay close attention to twisting of the intestinal mesentery when bringing up the proximal jejunum for pancreatojejunostomy and hepatojejunostomy and the distal ileum for ileocolic anastomosis. This intestinal rotation method enables a smooth and uneventful reconstruction of the digestive system. CONCLUSION: This is the first detailed description of an intestinal rotation method for digestive reconstruction after combined PD and extended RH. The intestinal rotation method can be an alternative and helpful technical option for digestive reconstruction in patients with combined PD and RH.

Left superior pulmonary venous thrombosis complicated with splenic infarction after video-assisted thoracoscopic left upper lobectomy.

A 72-year-old man underwent video-assisted thoracoscopic left upper lobectomy for small cell lung cancer. After 16 days, he experienced epigastric abdominal pain and vomiting, and was taken by ambulance to our hospital. Contrast-enhanced computed tomography (CT) showed a propagation of thrombus in the stump of the left superior pulmonary vein (LSPV) complicated with splenic infarction. The patient received anticoagulation therapy with heparin and warfarin, and further progression of the thrombus or any systemic embolic event was not observed during hospitalization. Here, we report a patient presenting with LSPV thrombosis complicated with splenic infarction after video-assisted thoracoscopic surgery (VATS), and describe several months follow-up CT imaging results after administration of an oral anticoagulation therapy. .