Efficacy of second-line chemotherapy after treatment with gemcitabine plus nab-paclitaxel or FOLFIRINOX in patients with metastatic pancreatic cancer.

First-line chemotherapy for patients with metastatic pancreatic cancer (MPC) includes gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX). However, the efficacy of second-line chemotherapy and the role of combination chemotherapy in clinical practice is still unknown. Data was gathered from 14 hospitals in the Kyushu area of Japan from December 2013 to March 2017. The median overall survival (mOS) from second-line treatment was contrasted between patients who received second-line chemotherapy (CT group) and those who received the best supportive care (BSC group). Furthermore, the mOS of combination chemotherapy was compared to mono chemotherapy in the CT group. To control possible bias in the selection of treatment, we performed a propensity score-adjusted analysis. A total of 255 patients received GnP or FFX as first-line chemotherapy. There were 156 in the CT group and 77 in the BSC group of these. The CT group had a significantly longer mOS than the BSC group (5.2 vs. 2.6 months; adjusted hazard ratio (HR) 0.38; 95% CI 0.27-0.54). In the CT group, 89 patients received combination chemotherapy while 67 received mono chemotherapy. The mOS did not differ significantly between the combination and mono chemotherapy groups (5.5 vs. 4.8 months; adjusted HR 0.88; 95% CI 0.58-1.33). Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination chemotherapy conferred no improvement in survival compared to mono chemotherapy.

Prognostic Factors for Distal Bile Duct Carcinoma After Surgery.

BACKGROUND: Distal bile duct carcinoma continues to be one of the most difficult cancers to manage in terms of staging and radical resection. Pancreaticoduodenectomy (PD) with regional lymph node dissection has become the standard treatment of distal bile duct carcinoma. We evaluated treatment outcomes and histological factors in patients with distal bile duct carcinoma. METHODS: Seventy-four cases of resection of carcinoma of the distal bile ducts treated at our department during the period from January 2002 and December 2016 using PD and regional lymph node dissection as the standard surgical procedure were investigated. Survival rates of factors were analyzed using uni- and multivariate analyses. RESULTS: The median survival time was 47.8 months. On univariate analysis, age of 70 years or older, histologically pap, pPanc2,3, pN1, pEM0, v2,3, ly2,3, ne2,3 and postoperative adjuvant chemotherapy were statistically significant factors. On multivariate analysis, histologically pap was identified as a significant independent prognostic factor. The multivariate analysis identified age of 70 years or older, pEM0, ne2,3 and postoperative adjuvant chemotherapy as showing a significant trend towards independent prognostic relevance. CONCLUSION: The good news about resected distal bile duct carcinoma is that the percentage of those who achieved R0 resection has risen to 89.1%. Our multivariate analysis identified age of 70 years or older, pEM0, ne2,3 and postoperative adjuvant chemotherapy as prognostic factors. In order to improve the outcome of treatment, it is necessary to improve preoperative diagnostic imaging of pancreatic invasion and lymph node metastasis, establish the optimal operation range and clarify whether aortic lymph node dissection is needed to control lymph node metastasis, and establish effective regimens of chemotherapy.

Case report: Changes in serum bevacizumab concentration in a hemodialysis patient with unresectable colorectal cancer treated with FOLFIRI plus bevacizumab.

The global incidence of colorectal cancer (CRC) in patients receiving hemodialysis is steadily rising. However, current information on the clinical use of chemotherapy for patients undergoing hemodialysis with CRC is limited. Herein, we describe a clinical course of a 74-year-old patient undergoing hemodialysis with unresectable CRC treated with folinic acid, 5-fluorouracil (5FU), and irinotecan (FOLFIRI) plus bevacizumab whose changes in serum bevacizumab concentration were analyzed. Treatment was initiated with a standard dosage of 5-FU and 80% of the standard dose of irinotecan to avoid any adverse events. However, neutropenia (grade 4) was observed after five treatment cycles, which prompted a dose reduction of 5-FU and irinotecan, after which treatment was safely completed. Progression-free survival of the patient was 7.5 months. Changes in serum bevacizumab concentration were similar to those documented in patients with normal renal function. In addition, no bevacizumab-related adverse events occurred. It was inferred that FOLFIRI plus bevacizumab therapy could be implemented as a safe and efficient treatment for patients undergoing hemodialysis with unresectable CRC. To the best of our knowledge, this is the first report of the analysis of serum bevacizumab concentrations in a patient undergoing hemodialysis with unresectable CRC.

Hyperlipidemia as a risk factor for Trousseau syndrome-related cerebral infarction in patients with advanced gastrointestinal cancer.

Trousseau syndrome-related cerebral infarction rarely occurs during chemotherapy in patients with gastrointestinal (GI) cancer, and its clinical features remain unclear. The present study aimed to examine the clinical features of Trousseau syndrome-related cerebral infarction developed during chemotherapy for GI cancer. The present retrospective cohort study consecutively enrolled 878 patients with unresectable GI cancer who received chemotherapy at the Multidisciplinary Treatment Cancer Center, Kurume University Hospital (Kurume, Japan) between April 2014 and March 2020. Patients with colorectal cancer (n=308) were the most common, followed by those with pancreatic (n=242), gastric (n=222) and biliary tract (n=59) cancer, neuroendocrine tumors (n=34) and duodenal cancer (n=11). Among the 878 patients, Trousseau syndrome-related cerebral infarction occurred in 8 (0.9%) patients with a median age of 70.5 years (range, 58-75 years), and 50% of the patients were male (4/8). In total, 3 patients had gastric cancer, 3 had pancreatic cancer and 2 had biliary tract cancer. A greater percentage of patients with Trousseau syndrome-related cerebral infarction had hyperlipidemia (38.0%) than those without (8.2%; P=0.005). Hyperlipidemia was a risk factor for occurrence of Trousseau syndrome-related cerebral infarction with an odds ratio of 7.009 (95% confidence interval, 1.785-27.513). Trousseau syndrome-related cerebral infarction developed during GI chemotherapy was rare and hyperlipidemia may predict its onset.

Nationwide epidemiological survey of immunoglobulin G4-related disease with malignancy in Japan.

BACKGROUND AND AIM: To clarify the clinicoepidemiological characteristics of immunoglobulin G4 (IgG4)-related disease (IgG4-RD) with malignancy, a nationwide epidemiological survey was conducted. METHODS: Immunoglobulin G4-related disease patients with malignancy who had visited selected hospitals in Japan were surveyed. The study consisted of two stages: the number of IgG4-RD patients with malignancy was estimated by the first questionnaire and their clinicoepidemiological characteristics were assessed by the second questionnaire. RESULTS: The frequencies of autoimmune pancreatitis (AIP), IgG4-related sialadenitis, IgG4-related eye disease, IgG4-related kidney disease, and IgG4-related retroperitoneal fibrosis were 44.7%, 20.8%, 14.0%, 5.16%, and 5.12%, respectively. The overall prevalence of malignant disease in IgG4-RD cases was estimated to be 10 900 per 100 000 cases, which was significantly higher than that of malignant disease in the general population. The prevalence of malignant lymphoma in IgG4-RD cases was the highest and was estimated to be 1985 per 100 000 cases. IgG4-related kidney disease had the highest frequency of malignant disease (17.1%). In data from 200 patients, 61 (30.5%) cases of cancer were found 2 years or more before the IgG4-RD diagnosis, 92 cases (46%) during the 1 year preceding or following IgG4-RD diagnosis, and 62 cases of cancer (31%) 2 or more years following IgG4-RD diagnosis. CONCLUSIONS: The nationwide survey for IgG4-RD with malignancy in Japan showed that IgG4-RD may be related with malignant diseases.

Vascular/perivascular inflammation in IgG4-related disease.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is characterized by the infiltration of IgG4-positive plasma cells and fibrosclerotic inflammation in multiple organs. Although vascular complications are present in some patients with IgG4-RD, vascular and/or perivascular inflammatory activity compared to control subjects remains unknown. This study sought to investigate vascular/perivascular inflammation in IgG4-RD patients compared to control subjects using 18F-fluorodeoxyglucose-positron emission tomography combined with computed tomography (FDG-PET/CT). METHODS: We examined 37 consecutive patients diagnosed as IgG4-RD (29 males, mean age of 64.3 ± 8.3 years old), who underwent FDG-PET/CT. Thirty-seven age- and gender-matched subjects without IgG4-RD were employed as controls. Vascular/perivascular inflammation was quantified by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR). RESULTS: All IgG4-RD patients presented with multiple region involvements. Twelve (32.4%) of the IgG4-RD patients had vascular complications, all of which appeared in the abdominal aorta. IgG4-RD patients had significantly higher TBR values in the descending aorta, abdominal aorta, and common iliac artery than control subjects. Also, IgG4-RD patients with vascular complication exhibited higher TBR values in the infra-renal aorta and common iliac artery than those without vascular complication. CONCLUSIONS: We found that vascular FDG activity is significantly elevated in IgG4-RD patients regardless of vascular complication than control subjects. FDG-PET/CT is a useful modality for assessing vascular/perivascular inflammation, which may contribute vascular complication in IgG4-RD patients.

A phase II study of gemcitabine plus nab-paclitaxel as first-line therapy for locally advanced pancreatic cancer.

ABSTRACT: Gemcitabine plus nab-paclitaxel (GnP) is widely used in clinical practice, despite a lack of prospective data to validate its efficacy in locally advanced pancreatic cancer (LAPC). We conducted a phase II study of GnP for LAPC to assess its efficacy and safety.We performed a single-arm, single-institution study with GnP in 24 patients with LAPC. The treatment protocol included successive administration of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2). The primary endpoint was the tumor overall response rate (ORR), and secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events (AEs).The median PFS was 11.0 months, median OS was 21.2 months, ORR was 62.5%, and 37.5% of the patients had stable disease. Four (16.7%) of the patients were converted to surgical resection; 3 of these achieved R0 resection. Grade 3 to 4 AEs included hematological (neutropenia, 64%; thrombocytopenia, 12%), nonhematological (cholangitis, 16%), and sensory neuropathy (4%). These AEs were manageable and tolerable.The GnP treatment in patients with LAPC showed favorable tumor shrinkage, good toxicity profile, and enabled conversion to surgical resection in a subset of patients; therefore, GnP is an option for first-line chemotherapy in patients with LAPC.

Profiles Combining Muscle Atrophy and Neutrophil-to-Lymphocyte Ratio Are Associated with Prognosis of Patients with Stage IV Gastric Cancer.

We aimed to investigate the impact of muscle atrophy and the neutrophil-to-lymphocyte ratio (NLR), a sub-clinical biomarker of inflammation and nutrition, on the prognosis of patients with unresectable advanced gastric cancer. We retrospectively enrolled 109 patients with stage IV gastric cancer (median age 69 years; female/male 22%/78%; median observational period 261 days). Independent factors and profiles for overall survival (OS) were determined by Cox regression analysis and decision-tree analysis, respectively. OS was calculated using the Kaplan-Meier method. The prevalence of muscle atrophy was 82.6% and the median NLR was 3.15. In Cox regression analysis, none of factors were identified as an independent factor for survival. The decision-tree analysis revealed that the most favorable prognostic profile was non-muscle atrophy (OS rate 36.8%). The most unfavorable prognostic profile was the combination of muscle atrophy and high NLR (OS rate 19.6%). The OS rate was significantly lower in patients with muscle atrophy and high NLR than in patients with non-muscle atrophy (1-year survival rate 28.5% vs. 54.7%; log-rank test p = 0.0014). In conclusion, "muscle atrophy and high NLR" was a prognostic profile for patients with stage IV gastric cancer. Thus, the assessment of muscle mass, subclinical inflammation, and malnutrition may be important for the management of patients with stage IV gastric cancer.

[A case of hemobilia due to the rupture of pancreaticoduodenal artery aneurysm with choledocholithiasis].

A 79-year-old male patient had a huge choledocholithiasis that was difficult to remove and underwent endoscopic retrograde biliary drainage. He complained of hematemesis upon admission to our hospital. Endoscopic retrograde cholangiography showed bleeding from the papilla of Vater and revealed an upper filling defect with a large stone in the common bile duct. Furthermore, computed tomography detected an aneurysm close to the stone. Considering the occurrence of a ruptured pancreaticoduodenal artery aneurysm, we diagnosed this condition as hemobilia. Through angiography, we also detected a saccular aneurysm in the posterior superior pancreaticoduodenal artery (PSPDA);subsequently, selective transcatheter arterial embolization (TAE) was performed. However, bleeding persisted after TAE;therefore, we performed second-time embolization for other PSPDA branches. Consequently, hemostasis was achieved. To date, bleeding has not reoccurred. The pancreaticoduodenal artery constitutes a complex arcade;hence, cases of extremely difficult hemostasis by embolization have been reported. Herein, we have presented a life-saving case of choledocholithiasis treated with TAE for biliary bleeding from a PSPDA aneurysm rupture.

Significance of neoadjuvant chemoradiotherapy for borderline resectable pancreatic head cancer: Pathological local invasion and microvessel invasion analysis.

Borderline resectable pancreatic head cancer (BR-PHC) has low resectability due to vascular invasion. Although the clinical effects of neoadjuvant chemoradiotherapy (NAC-RT) for BR-PHC have been examined, few studies have reported its pathological aspects. The present study retrospectively investigated the effect of NAC-RT on the histological features of BR-PHC. A total of 29 patients with BR-PHC who underwent NAC-RT, and 55 controls with resectable PHC, who underwent pancreaticoduodenectomy at the Kurume University Hospital. Tumor staging, lymphovascular invasion (LVI), and microvessel invasion (MVI) were evaluated. The median tumor size in the NAC-RT group was 2.0 cm, and it was smaller than that of the control group (P=0.006). The rates of lymph node metastasis, LVI, and MVI were significantly lower in the NAC-RT group (P<0.001, 0.002, and 0.015, respectively). Overall survival in the NAC-RT group was comparable to that in the control group, although patients with BR-PHC generally had a poorer prognosis than those with resectable PHC. Patients in the NAC-RT group without portal vein invasion (PVI) had a significantly better prognosis than those with PVI in the control group (P=0.002). NAC-RT may be beneficial for patients with BR-PHC by inhibiting local invasion and metastasis as prognosis following resection could be equivalent to that of patients with conventional ductal adenocarcinoma.

[A Case of Chemotherapy-Induced Hyperammonemic Encephalopathy in a Patient with Metastatic Colon Cancer].

A 70-year-old man was diagnosed with colon cancer with multiple liver metastases.He was administered modified FOLFOX6 plus panitumumab as first-line chemotherapy.He showed consciousness disturbance on the 3rd day during the 8 cycle and was hospitalized urgently.We diagnosed him with 5-FU-induced hyperammonemia.Administration of branchedchain amino acid preparation improved his consciousness disturbance.After changing the regimen of chemotherapy to another one containing oral fluoropyrimidine, the recurrence of hyperammonemic encephalopathy was not found.

Glycosylation of ascites-derived exosomal CD133: a potential prognostic biomarker in patients with advanced pancreatic cancer.

Cancer cells surviving in ascites exhibit cancer stem cell (CSC)-like features. This study analyzed the expression of the CSC marker CD133 in the ascites-derived exosomes obtained from patients with unresectable pancreatic cancer. In addition, inverse correlation of CD133 expression with prognosis was examined. Of the 133 consecutive patients, 19 patients were enrolled in the study. Exosomes derived from the malignant ascites demonstrated higher density and wider variation in size than those from non-malignant ascites. Western blot revealed enhanced expression of CD133 in exosomes obtained from patients with pancreatic cancer compared to those obtained from patients with gastric cancer or liver cirrhosis. A xenograft mouse model with malignant ascites was established by intraperitoneal inoculation of human pancreatic cancer cells in nude mice. Results obtained from the human study were reproduced in the mouse model. Statistically significant equilateral correlation was identified between the band intensity of CD133 in western blot and overall survival of patients. Lectin microarray analyses revealed glycosylation of CD133 by sialic acids as the major glycosylation among diverse others responsible for the glycosylation of exosomal CD133. These findings suggest that highly glycosylated CD133 in ascites-derived exosomes as a potential biomarker for better prognosis of patients with advanced pancreatic cancer.

A case of pancreatic neuroendocrine tumor with multiple cystic components of various sizes.

The patient was a 51-year-old woman who, while undergoing a thorough health checkup, was found to have a tumor (measuring 60 mm in diameter) in the tail of the pancreas by abdominal ultrasonography. Contrast-enhanced computed tomography revealed delayed contrast enhancement; the tumor also contained numerous low-absorption areas showing poor contrast enhancement. On magnetic resonance imaging, the tumor was visualized as having high signal intensity areas inside the tumor on T2-weighted images. Positron emission tomography revealed an abnormal accumulation in the area corresponding to the tumor. Endoscopic ultrasonography (EUS) revealed a relatively hyperechoic solid area, with a number of echo-free areas of various sizes that assumed a honeycomb appearance. EUS-guided fine needle aspiration was carried out targeting the solid area within the tumor, which led to a diagnosis of pancreatic neuroendocrine tumor (PNET). Histopathological examination of the resected specimen revealed that the tumor was composed of numerous cysts of various sizes and solid components. The cysts contained no evidence of necrosis or bleeding. Immunohistochemically, the cystic as well as solid components were CD56 (+), synaptophysin (+) and chromogranin A (+) with MIB1 labeling index of 5%. On the basis of these findings, the final diagnosis was PNET (G2).

mFOLFOX6 Chemotherapy after Resection of Anal Canal Mucinous Adenocarcinoma.

Because of their rarity, there are no clear guidelines for the treatment of anal carcinomas; such tumors are normally subjected to the same modalities as recommended for rectal cancer. We report a patient with anal canal mucinous adenocarcinoma, with metastases in the pararectal and right inguinal lymph nodes, who was treated with abdominoperineal resection followed by mFOLFOX6 chemotherapy for 6 months (12 cycles). The patient has remained recurrence-free thus far, approximately 2 years since the surgery. As the optimal treatments for anal carcinomas have not been fully elucidated, we present this case to highlight a possible course of action for such patients that appears to be effective and promising.

Successful Treatment of Metastatic Anal Canal Adenocarcinoma with mFOLFOX6 + Bevacizumab.

Anal canal adenocarcinoma is a relatively rare malignancy without established diagnostic and treatment criteria. Case reports of chemotherapy for anal canal adenocarcinoma with distant metastasis are limited, and there is no convincing evidence for treatment effectiveness. A 62-year-old man complained of difficulty in defecation, anal pain, and bleeding during bowel movement. He was diagnosed with moderately differentiated primary anal canal adenocarcinoma. A computed tomography scan revealed multiple metastases in the lung and liver. The patient was treated with abdominoperineal resection to control local tumor growth and then with chemotherapy consisting of mFOLFOX6 + bevacizumab. Because he had an activating KRAS mutation, anti-EGFR therapy was not considered. A reduction in the size of lung and liver metastases was observed after 4 courses of mFOLFOX6 + bevacizumab, and after 22 courses, maximum reduction in the metastatic lesions was achieved. The patient demonstrated tolerable levels of oxaliplatin-related peripheral neurotoxicity (grades 1-2) and was considered as having partial response to treatment. He is currently at the partial response state for 1 year. We plan to continue the treatment unless the patient develops progressive disease or intolerable adverse reactions. This case demonstrates that anal canal adenocarcinoma with distant metastases could be successfully treated with mFOLFOX6 + bevacizumab therapy according to the guidelines for rectal carcinoma. However, as anal canal carcinoma has multiple histological subtypes, it is important to establish subtype-specific treatment strategies.