The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: an exploratory analysis of JCOG1113.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

FOLFIRINOX in advanced pancreatic cancer patients with the double-variant type of UGT1A1 *28 and *6 polymorphism: a multicenter, retrospective study.

BACKGROUND: UGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV. PATIENTS AND METHODS: Advanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV. RESULTS: A total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of ≥ 150 mg/m2 than in those who had received the drug at an initial dose of ≤ 120 mg/m2 (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of ≤ 120 mg/m2 were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV. CONCLUSION: Based on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of ≤ 120 mg/m2.

Prospective study of EUS-guided tissue acquisition with a 20G core biopsy needle with a forward bevel for solid pancreatic mass.

ABSTRACT: There is a growing need for tissue collection for immunostaining and genetic testing. Recently, several fine-needle biopsy needles are commercially available for endoscopic ultrasound-guided tissue acquisition.This prospective historical controlled study evaluates a 20G core biopsy needle with a forward bevel for solid pancreatic masses larger than 15 mm in diameter. The primary endpoint was the accuracy of histological diagnosis. The secondary endpoints included technical success rate, sample adequacy for histology, cytological diagnostic accuracy, and adverse events.Seventy consecutive patients were enrolled between January and October 2017. We achieved technical success in all cases regardless of the puncture sites or the endosonographer's experience. The final diagnoses were neoplasms in 67 patients (95.7%; pancreatic cancer in 65 patients, neuroendocrine neoplasm in 1, and malignant lymphoma in 1) and benign lesions in 3 patients (4.3%; autoimmune pancreatitis in 2 patients and mass-forming pancreatitis in 1). The obtained specimens were adequate for histological evaluation in all cases and the histological accuracy was 91.4% (95% confidence interval, 82.3-96.8%, P < .05) with the sensitivity and specificity of 91.0% and 100%, respectively. The cytological diagnostic accuracy was 95.7% and all patients were accurately diagnosed by combining cytological and histological examinations. As for adverse events, an asymptomatic needle fracture occurred in 1 case (1.4%).This 20G core biopsy needle with a forward bevel showed a high accuracy of histological diagnosis for solid pancreatic masses.

A Multicenter Retrospective Study of Gemcitabine Plus Nab-Paclitaxel for Elderly Patients With Advanced Pancreatic Cancer.

OBJECTIVES: This study aimed to assess the lesser known therapeutic benefit, particularly safety and effectiveness of gemcitabine plus nab-paclitaxel (GnP) treatment in elderly patients with advanced pancreatic cancer. METHODS: We retrospectively enrolled advanced pancreatic cancer patients aged ≥75 years who received GnP as first-line treatment between December 2014 and December 2016. We assessed survival, adverse events, and early treatment discontinuation. RESULTS: The cohort comprised 116 patients (median age, 77 [range, 75-84] years). The overall survival and progression-free survival were 21.8 and 12.1 months in patients with locally advanced cancer and 13.3 and 5.9 months, in patients with metastasis, respectively. The response and disease control rates were 31% and 81%, respectively. Within the first 2 months of treatment, grade 4 hematological and grade 3-4 nonhematological toxicities occurred in 10 and 23 patients, respectively. Early discontinuation due to adverse events occurred in 12 patients; the associated risk factors were age ≥80 years (odds ratio, 9.43) and serum albumin level <3.5 g/dL (odds ratio, 5.12). CONCLUSIONS: In selected patients aged ≥75 years, GnP showed acceptable toxicities and effectiveness. However, patients aged ≥80 years and those with serum albumin levels <3.5 g/dL should be carefully assessed for treatment eligibility.

Improvement of Treatment Outcomes for Metastatic Pancreatic Cancer: A Real-world Data Analysis.

BACKGROUND/AIM: FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel therapy have recently been introduced for the treatment of metastatic pancreatic cancer. Herein, overall treatment outcomes of metastatic pancreatic cancer after introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel therapy were evaluated, in daily practice. PATIENTS AND METHODS: Metastatic pancreatic cancer patients (n=321) who started systemic chemotherapy between January 2011 and December 2016 were included and were divided into two groups: group A (2011-2013) and group B (2014-2016). Treatment outcomes were evaluated retrospectively. RESULTS: Patient characteristics were similar between the two groups except for the rates of distant lymph node metastasis and peritoneal metastasis. The preferred regimens in groups A and B were gemcitabine monotherapy and gemcitabine plus nab-paclitaxel therapy, respectively. The response rates, median progression-free survival, and median overall survival of groups A and B were 7.8% and 28.4% (p<0.01), 3.1 months and 5.4 months (p<0.01), and 6.7 months and 10.2 months (p<0.01), respectively. CONCLUSION: Overall treatment outcomes for metastatic pancreatic cancer were significantly improved after introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel combination therapy in daily practice.

Enteral stent placement for malignant afferent loop obstruction by the through-the-scope technique using a short-type single-balloon enteroscope.

Background and study aims A short-type single-balloon enteroscope with a 3.2-mm working channel makes it possible to insert an enteral stent by the through-the-scope technique in patients with malignant afferent loop obstruction. Here, we report five cases of malignant afferent loop obstruction treated with endoscopic enteral stenting. We also propose a new classification for three types of malignant afferent loop obstruction. Type 1: The obstruction site is located distal to the papilla or the bilioenteric anastomosis. Type 2: The obstruction site is located at the papilla or the bilioenteric anastomosis. Type 3: The obstruction site is located between the bilioenteric and pancreaticoenteric anastomosis. The patients with type 1 and 3 were simply treated by inserting an enteral stent endoscopically. The patient with type 2 was treated with an endoscopic enteral stent for malignant afferent loop obstruction and with percutaneous transhepatic biliary stenting for malignant biliary obstruction. Although double stenting for type 2 remains a difficult endoscopic procedure, the endoscopic approach has become the standard approach for malignant afferent loop obstruction.

Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma.

We conducted a multicenter retrospective analysis to evaluate the efficacy of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We enrolled 36 patients with pathologically proven, unresectable combined hepatocellular and cholangiocarcinoma treated with systemic chemotherapy. The log-rank test determined the significance of each prognostic factor. Elevated alpha-fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19-9 levels were observed in 58.3%, 16.7% and 38.9% of patients, respectively. First-line chemotherapy included platinum-containing regimens consisting of gemcitabine/cisplatin (n = 12) and fluorouracil/cisplatin (n = 11), sorafenib (n = 5) and others (n = 8). The median overall and progression-free survival times were 8.9 and 2.8 months, respectively, with an overall response rate of 5.6%. Prognostic factors associated with negative outcomes included poor performance status, no prior primary tumor resection, a Child-Pugh class of B, and elevated carcinoembryonic antigen levels with a hazard ratio of 2.25, 2.48, 3.25 and 2.84 by univariate analysis, respectively. The median overall survival times of the gemcitabine/cisplatin, fluorouracil/cisplatin, sorafenib and other groups were 11.9, 10.2, 3.5 and 8.1 months, respectively. Multivariate analysis revealed that the overall survival of patients within the sorafenib monotherapy group was poor compared with platinum-containing regimens (HR: 15.83 [95% CI: 2.25-111.43], P = .006). All 7 patients in the sorafenib group had progressive disease, including 2 patients with second-line therapy. In conclusion, the platinum-containing regimens such as gemcitabine/cisplatin were associated with more favorable outcomes than sorafenib monotherapy for unresectable combined hepatocellular and cholangiocarcinoma.

Prognostic value of neutrophil-lymphocyte ratio and level of C-reactive protein in a large cohort of pancreatic cancer patients: a retrospective study in a single institute in Japan.

OBJECTIVE: Recent studies suggest that systemic inflammatory response is closely associated with cancer patient prognosis. Although several inflammatory prognostic markers have been proposed, the data to support their validity are lacking in large Japanese cohorts. METHODS: This is a retrospective study to examine the prognostic value of inflammatory markers, such as C-reactive protein, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and modified Glasgow prognostic scale, in pancreatic cancer. Selection criteria were admittance to hospital between January 2008 and December 2012, histologically confirmed adenocarcinoma, diagnosis of invasive ductal pancreatic cancer compatible by computed tomography imaging, and followed-up until death or for 180 days or longer. The primary end point was overall survival, which was measured from the day of histological diagnosis. RESULTS: There were 440 patients who met the selection criteria. Of the 440 cases, 200 (45.5%) received curative resection (166 Stage I/II and 34 Stage III patients), 237 (53.9%) received chemotherapy (4 Stage I/II, 92 Stage III and 141 Stage IV patients), and the remaining 3 received palliative care. Univariate and multivariate regression analyses revealed that advanced computed tomography stage, high level of C-reactive protein (0.45 mg/dl or greater), neutrophil-lymphocyte ratio (2.0 or greater) and CA19-9 level (1000 U/ml or greater) were significantly associated with worse prognosis. CONCLUSIONS: We verified the results of previous studies, and showed that neutrophil-lymphocyte ratio and C-reactive protein also had prognostic value in a large Japanese PC cohort.

[FOLFIRINOX-induced hyperammonemic encephalopathy in a patient with pancreatic cancer].

Hyperammonemic encephalopathy is a rare adverse event of chemotherapies based on high-dose 5-fluorouracil. We present a woman in her 70s with metastatic pancreatic adenocarcinoma who underwent FOLFIRINOX therapy. She developed acute onset disturbance of consciousness after completing the first 5-fluorouracil infusion cycle (2400 mg/m(2)/46h). We suspected hyperammonemic encephalopathy induced by 5-fluorouracil and administered branched-chain amino acids solutions and she recovered within a few hours of treatment. Brain computed tomography and magnetic resonance imaging revealed no abnormal findings. She subsequently received chemotherapy with gemcitabine and developed no further hyperammonemia. To the best of our knowledge, this is the first report of FOLFIRINOX-induced hyperammonemic encephalopathy in a patient with pancreatic cancer.

[Neuroendocrine gallbladder cancer treated with cisplatin plus irinotecan - a case report].

A 52-year-old woman was referred to our hospital because of upper abdominal pain. A computed tomography(CT)scan revealed bulky gallbladder and liver tumors. We reached a tentative diagnosis of invasive adenocarcinoma of the gallbladder and performed needle biopsy of the tumor. Biopsied specimens showed the proliferation of small round to oval cells with scanty cytoplasm and high rates of mitosis. Immunohistochemical examination showed that many tumor cells were positive for chromogranin A, synaptophysin, and CD56. Our final diagnosis was neuroendocrine carcinoma of the gallbladder with multiple liver metastases. The patient received cisplatin plus irinotecan chemotherapy. Remarkable shrinkage was observed after 3 cycles of chemotherapy, and a good response continued for more than 6 months. Gallbladder cancer patients generally have a poor response to chemotherapy, so we should be aware of the histopathological diagnosis of the cancer before starting treatment.

Lack of associations between genetic polymorphisms in GSTM1, GSTT1 and GSTP1 and pancreatic cancer risk: a multi-institutional case-control study in Japan.

BACKGROUND: We aimed to evaluate the role of genetic polymorphisms in tobacco carcinogen-metabolizing genes and their interactions with smoking in a hospital-based case-control study of Japanese subjects. MATERIALS AND METHODS: We examine the associations of pancreatic cancer risk with genetic polymorphisms in GSTM1, GSTT1 and GSTP1, phase II enzymes that catalyze the conjugation of toxic and carcinogenic electrophilic molecules. The study population consisted of 360 patients and 400 control subjects, who were recruited from several medical facilities in Japan. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotypes and pancreatic cancer risk. RESULTS: Among the control subjects, the prevalence of the GSTM1-null genotype and the GSTT1-null genotype was approximately 56% and 48%, respectively. Cases and controls were comparable in terms of GSTM1 and GSTT1 genotype distributions. Neither of the deleted polymorphisms in GSTM1 and GSTT1 was associated with the risk of pancreatic cancer, with an age- and sex-adjusted OR of 0.99 (95%CI: 0.74-1.32) for the GSTM1-null genotype, and 0.98 (95%CI: 0.73-1.31) for the GSTT1-null genotype. The OR was 0.97 (95%CI: 0.64-1.47) for individuals with the GSTM1 and GSTT1-null genotypes compared with those with the GSTM1 and GSTT1- present genotypes. No synergistic effects of smoking or GST genotypes were observed. CONCLUSIONS: Our results indicate no overall association between the GSTM1 and GSTT1 deletion polymorphisms and pancreatic cancer risk in the Japanese subjects in our study.

Efficacy of contrast-enhanced ultrasonography in radiofrequency ablation for hepatocellular carcinoma.

OBJECTIVE: Local recurrence after radiofrequency ablation (RFA) is a major problem that needs to resolved to increase the survival rate of hepatocellular carcinoma (HCC). CE-US with Sonazoid(®), the second-generation contrast media, can detect smaller HCC lesions and the detection rate of ultrasonically unrecognized hypervascular HCC was improved by CE-US. The aim of the present study was to evaluate the role of CE-US with Sonazoid(®) in improving radicality and reducing local recurrence after RFA for HCC. PATIENTS AND METHODS: A total of 102 nodules treated by RFA at our hospital from January 2006 to October 2009 were enrolled: 31 nodules were treated without CE-US, since CE-US was not yet available (Group A), and 71 nodules were treated with a combination of RFA and CE-US with Sonazoid(®) (Group B). RESULTS: The clinical characteristics (sex, virus marker, Child-Pugh grade, with or without transcatheter arterial infusion chemotherapy with lipiodol, and T factor) did not differ significantly between group A and group B. Mean age was significantly older and tumor size was significantly larger in group B. Group B had significantly better radicality compared with group A. The non-local recurrence rate was significantly higher in group B as compared with group A. CONCLUSION: CE-US with Sonazoid(®) greatly helps to improve RFA efficacy in HCC treatment. We suggest that the ability of CE-US with Sonazoid(®) to detect an accurate area of HCC before RFA and to immediately detect a residual tumor during RFA might contribute to an increase of the radicality and reduction of local recurrence after RFA.

Skull metastasis from hepatocellular carcinoma with chronic hepatitis B.

A 56-year-old male visited our hospital for evaluation of an occipital mass. Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver. Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae. Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A. Our diagnosis was hepatocellular carcinoma (HCC) with skull and vertebrae metastases on chronic hepatitis B. He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC. But he developed acute respiratory failure because of aspiration pneumonia, congestion and oedema with haemorrhage of the lungs and died. Dissection showed HCC with multiple bone metastases. The liver tumor was categorized as well-differentiated HCC, Edmondson classification I, trabecular type and pseudoglandular type. In the liver mild infiltration of lymphocytes was seen in Glisson's capsules which were significantly enlarged with well preserved limiting plates. Piecemeal necrosis was not obvious. No fibrosis was noted. An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone. The lesion was osteolytic and showed invasion into the dura mater. Neither the subdural cavity nor the brain showed involvement from the metastatic tumor. However, skull metastasis from HCC is very rare and it affects the patient's prognosis and the quality of life. Therefore, it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.

Mao (Ephedra sinica Stapf) protects against D-galactosamine and lipopolysaccharide-induced hepatic failure.

Mao is one component of various traditional herbal medicines. We examined the effects of Mao on an acute liver failure model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). The lethality of mice administrated Mao with GalN/LPS was significantly decreased compared with that in mice without Mao. Hepatic apoptosis and inflammatory cell infiltration were slight in Mao-treated mice. Serum alanine aminotransferase (ALT) and total bilirubin (T.Bil) activity, tumor necrosis factor alpha (TNF-alpha) levels and caspase 8, 9, and 3 activity in the liver were significantly lower in mice administrated Mao. But, Serum interleukin-6 (IL-6), IL-10 levels and signal transducers and activators of transcription 3 (STAT3) activity in the liver were significantly higher in mice administrated Mao. To investigate the effect of STAT3, we used AG490, which selectively inhibits the activation of Janus kinase (JAK) family tyrosine kinase and inhibits the constitutive activation of STAT3. There was significant aggravation in hepatic apoptosis treated with Mao and AG490 compared with Mao alone. In conclusions, Mao significantly suppressed hepatic apoptosis by inhibition of TNF-alpha production and caspase activity. Furthermore, it is also suggested that Mao, which activates STAT3 induced by IL-6, may be a useful therapeutic tool for fulminant hepatic failure.