Zinc supplementation for dysgeusia in patients with unresectable pancreatic cancer.

BACKGROUND: Although patients with advanced pancreatic cancer (PC) often experience dysgeusia with zinc deficiency during chemotherapy, data on zinc supplementation for dysgeusia and its effects on nutritional status are scarce. We aimed to examine the efficacy of zinc supplementation in patients with advanced PC. METHODS: Thirty-three patients with unresectable PC who presented with dysgeusia and zinc deficiency during chemotherapy and received zinc acetate hydrate between January 2018 and December 2022 were included. We evaluated the changes in serum zinc levels and the improvement in dysgeusia. Among the 26 patients who received zinc supplementation for 12 weeks, we also compared patient characteristics and changes in serum zinc and albumin levels between patients who showed improvement in dysgeusia (effective group) and those who did not (non-effective group). RESULTS: The serum zinc level increased significantly after zinc supplementation (median: 60 µg/dL at baseline, 99.5 µg/dL at 4 weeks, 101 µg/dL at 8 weeks and 101 µg/dL at 12 weeks). The rate of improvement in dysgeusia increased over time (18.2% at 4 weeks, 33.3% at 8 weeks, and 42.4% at 12 weeks). Comparing the effective group and non-effective group revealed that while the median serum albumin level of the effective group did not change, the non-effective group showed a significant decrease from baseline to 12 weeks (3.2 g/dL to 3.0 g/dL, p = 0.03). CONCLUSION: Zinc supplementation significantly increased serum zinc levels, improving dysgeusia. Zinc supplementation might also contribute to maintaining nutritional status in patients with unresectable PC.

Oil blotting paper for formalin fixation increases endoscopic ultrasound-guided tissue acquisition-collected sample volumes on glass slides.

OBJECTIVES: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is used for pathological diagnosis and obtaining samples for molecular testing, facilitating the initiation of targeted therapies in patients with pancreatic cancer. However, samples obtained via EUS-TA are often insufficient, requiring more efforts to improve sampling adequacy for molecular testing. Therefore, this study investigated the use of oil blotting paper for formalin fixation of samples obtained via EUS-TA. METHODS: This prospective study enrolled 42 patients who underwent EUS-TA for pancreatic cancer between September 2020 and February 2022 at the Osaka International Cancer Institute. After a portion of each sample obtained via EUS-TA was separated for routine histological evaluation, the residual samples were divided into filter paper and oil blotting paper groups for analysis. Accordingly, filter paper and oil blotting paper were used for the formalin fixation process. The total tissue, nuclear, and cytoplasm areas of each sample were quantitatively evaluated using virtual slides, and the specimen volume and histological diagnosis of each sample were evaluated by an expert pathologist. RESULTS: All cases were cytologically diagnosed as adenocarcinoma. The area ratios of the total tissue, nuclear, and cytoplasmic portions were significantly larger in the oil blotting paper group than in the filter paper group. The frequency of cases with large amount of tumor cells was significantly higher in the oil blotting paper group (33.3%) than in the filter paper group (11.9%) (p = 0.035). CONCLUSIONS: Oil blotting paper can increase the sample volume obtained via EUS-TA on glass slides and improve sampling adequacy for molecular testing.

Long-term survival after systemic chemotherapy, chemoradiotherapy, and maintenance therapy for an older adult patient with recurrent pancreatic acinar cell carcinoma.

Pancreatic acinar cell carcinoma (PACC) is a rare cancer with no specific treatment. The treatment and chemotherapy for PACC are selected according to pancreatic ductal adenocarcinoma (PDAC). Herein, we describe a recurrent PACC case of an older adult patient. The patient was treated with systemic chemotherapy, chemoradiotherapy, and maintenance therapy based on the pathologic germline BRCA2 variant, resulting in long-term survival. The pathogenic BRCA variant is detected more frequently in patients with PACC than in those with PDAC. The BRCA variant significantly impacts treatment selection and prognosis; therefore, early genomic analysis is recommended when treating PACC.

Safety and Feasibility of Combining On-Demand Selective Locoregional Treatment with First-Line Atezolizumab Plus Bevacizumab for Patients with Unresectable Hepatocellular Carcinoma.

Various locoregional treatments for localized hepatocellular carcinoma (HCC) have been developed. This retrospective study investigated the safety and feasibility of combining on-demand selective locoregional treatment for residual lesions after tumor shrinkage (complete response [CR] oriented) or for solitary or few drug-resistant lesions (progressive disease (PD) salvage) with first-line atezolizumab plus bevacizumab (atezo/bev) for unresectable HCC. Twenty-nine patients with unresectable HCC were included. Fourteen locoregional treatments were performed (CR oriented, 7; PD salvage, 7) in ten patients in the combination-therapy group. All patients in the combination-therapy group successfully achieved a CR or PD salvage status after the planned locoregional treatment. The objective response rate of the combination-therapy group (80.0%) was higher than that of the atezo/bev alone group (21.1%; p = 0.005). Progression-free survival (PFS) and overall survival (OS) were longer in the combination group (medians for PFS and OS not reached) than in the atezo/bev alone group (median PFS, 7.4 months; median OS, 19.8 months) (PFS, p = 0.004; OS, p < 0.001). The albumin-bilirubin score did not change, and no severe complications occurred after locoregional treatment. When performed in a minimally invasive manner, on-demand selective locoregional treatment combined with first-line atezo/bev could be safe and feasible for unresectable HCC.

Portal Vein Aneurysm in a Patient with Cirrhosis Type C Controlled by Direct-Acting Antiviral Treatment.

Introduction: Portal vein aneurysm (PVA) is a rare saccular or fusiform portal vein dilatation. The management and optimal treatment of PVA remain unknown. Case Presentation: A 53-year-old man with hepatitis C virus (HCV) infection was diagnosed with PVA measuring 28 mm in diameter. Under observation, his liver fibrosis progressed, and the PVA diameter gradually increased to 52 mm. The patient was treated with elbasvir-grazoprevir for 12 weeks, and HCV disappeared. After achieving sustained virological response, liver fibrosis improved and the PVA progression ceased. Conclusion: HCV clearance by direct-acting antiviral treatment not only regressed liver fibrosis but may have also restrained the progression of PVA in a patient with cirrhosis type C and PVA.

An age-group analysis on the efficacy of chemotherapy in older adult patients with metastatic biliary tract cancer: a Japanese cancer registry cohort study.

BACKGROUND: The effectiveness of chemotherapy in older adult patients with biliary tract cancer (BTC) remains to be established, despite the fact that the majority of patients diagnosed with BTC tend to be aged ≥ 70 years. In this study, we used three databases to examine the effectiveness of chemotherapy in a large patient population aged ≥ 70 years with metastatic BTC. METHODS: Using a large Japanese database that combined three data sources (Osaka Cancer Registry, Japan's Diagnosis Procedure Combination, the hospital-based cancer registry database), we extracted the data from patients pathologically diagnosed with metastatic BTC, between January 1, 2013, and December 31, 2015, in 30 designated cancer care hospitals (DCCHs). A cohort of patients with comparable backgrounds was identified using propensity score matching. The log-rank test was used to examine how chemotherapy affected overall survival (OS). RESULTS: Among 2,622 registered patients with BTC in 30 DCCHs, 207 older adult patients aged > 70 years with metastatic BTC were selected. Chemotherapy significantly improved the prognosis of older adult patients, according to propensity score matching (chemotherapy, 6.4 months vs. best supportive care, 1.8 months, P value < 0.001). The number of patients receiving chemotherapy tends to decrease with age. Gemcitabine plus cisplatin (GC) and gemcitabine plus S-1 (oral fluoropyrimidine) (GS) combination therapy were frequently performed in the chemotherapy group for patients under 80 years of age (70-74 years, 61.7%; 75-79 years, 62.8%). In contrast, monotherapy including GEM and S-1 was more frequently performed in age groups over 80 years (80-84 years, 56.2%; 85-89 years, 77.7%; ≥90 years, 100%). In the chemotherapy group among older adult patients aged < 85 years, the median OS was significantly longer according to age-group analysis of the 5-year age range following propensity score matching. CONCLUSIONS: In older adult patients with metastatic BTC who received chemotherapy, prolonged survival was observed. Chemotherapy may be a viable option for patients with metastatic BTC who are aged < 85 years.

Parallel administration of nanoliposomal irinotecan and levo-leucovorin for pancreatic cancer.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/levo-leucovorin (Levo-LV) was approved for unresectable pancreatic cancer (UR-PC) in March 2020 in Japan. Levo-LV is administered by intravenous infusion over 120 min following 90 min intravenous infusion of nal-IRI (conventional method), causing a significant burden on both patients and the outpatient chemotherapy room owing to the prolonged administration time. Thus, from July 2021, we introduced the simultaneous intravenous administration of nal-IRI and Levo-LV (parallel method) with the approval of the institutional regimen committee. METHODS: We retrospectively reviewed the data of 69 patients with UR-PC who received nal-IRI plus 5-FU/Levo-LV at our hospital between June 2020 and October 2021. We examined the safety of the parallel method and compared the treatment outcomes and administration times between the two methods. RESULTS: The median age was 66 years (54%, male). Disease statuses were locally advanced, metastatic, and postoperative recurrence after pancreatectomy in 7, 50, and 12 patients, respectively. Nal-IRI plus 5-FU/Levo-LV treatment was second and third-line or later in 35 and 34 patients, respectively. No intravenous line problems were observed during the parallel administration of nal-IRI and Levo-LV. Although there were no significant differences in response rates and adverse events between the two methods, the administration time was significantly shorter in the parallel method than in the conventional method. CONCLUSION: The parallel administration of nal-IRI and Levo-LV is clinically safe and not inferior in efficacy. Moreover, parallel administration may offer convenience to patients and healthcare workers by reducing administration time.

Hospital volume and prognosis of patients with metastatic pancreatic cancer: A study using the Osaka Cancer Registry.

PURPOSE: Pancreatic cancer (PC) has one of the worst prognoses among all solid cancers. Hospital volume has been shown to be significantly associated with outcomes in patients with PC undergoing surgery. Nonetheless, the association between hospital volume and prognosis in patients with metastatic PC remains unclear. This study aimed to examine the association between hospital volume and prognosis in patients with metastatic PC using large-scale population-based cancer registry data. METHODS: This retrospective observational study was conducted using data from the Osaka Cancer Registry database. Data of patients with metastatic PC over 10 years (2009-2018) were obtained. Hospitals were categorized into high-volume hospitals (HVHs; ≥ 240 patients diagnosed with PC for 10 years), middle-volume hospitals (MVHs; 120-239 patients diagnosed with PC for 10 years), and low-volume hospitals (LVHs; < 120 patients diagnosed with PC for 10 years). Multivariate analysis was performed to identify factors associated with overall survival (OS). RESULTS: The analysis included 8,929 patients with metastatic PC. Median OS was significantly more favorable in HVHs than in MVHs and LVHs. Multivariate analysis adjusted for hospital volume, age, primary tumor site, year of diagnosis, chemotherapy, and radiotherapy revealed that hospital volume was an independent factor associated with OS (HVHs vs. MVHs: hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.16; P = 0.003, HVHs vs. LVHs: HR, 1.20; 95% CI, 1.13-1.27; P < 0.001). CONCLUSION: Hospital volume is an independent prognostic factor in patients with metastatic PC, suggesting an association between hospital volume and treatment outcomes.

Sensitivity of cytology in liver tumor biopsy and its significance in the prompt clinical diagnosis of non-hepatocellular carcinoma.

BACKGROUND: Cytology is a fast and simple modality for identifying malignancies and tumor histology. In this study, we analyzed the sensitivity of cytology for liver tumor biopsy and evaluated its potential for prompt clinical diagnosis. METHODS: This retrospective study included patients who had concurrently undergone conventional cytology, on-site cytology, and histopathology for ultrasound-guided liver tumor biopsies. In the case of malignant tumors, malignancy was first diagnosed, then preliminary clinical diagnosis was established using histology based on cytology and clinical information, followed by histopathological diagnosis. Sensitivity of malignancy detection was evaluated by comparison with histopathological diagnosis. RESULTS: Of the 191 tumors, 164 (85.9%) were malignant. The sensitivity of conventional cytology for malignancy detection was 97.6%. The sensitivity of non-hepatocellular carcinoma (non-HCC) (99.3%) detection was higher than that of the HCCs (87.5%; p = 0.001). The sensitivity of on-site cytology for malignancy detection was as high as that of conventional cytology. Similar to conventional cytology, the sensitivity of on-site cytology for non-HCC detection (99.3%) was higher than that for HCCs (79.2%; p < 0.001). In most cases of non-HCC tumors (126/140, 90.0%), accurate preliminary clinical diagnoses were obtained by combining on-site cytology with clinical information. CONCLUSION: Cytology of liver tumor biopsy has high sensitivity for malignancy, especially in non-HCC tumors. On-site cytology can contribute to the prompt clinical diagnosis of non-HCC tumors when combined with clinical information. This approach may be a reassuring modality for patients with severely advanced cancers requiring prompt clinical diagnosis and quick initiation of treatment owing to their deteriorating health.

A case of multiple myeloma with pancreatic involvement diagnosed via endoscopic ultrasound-guided fine needle aspiration.

This report highlights the importance of considering multiple myeloma in the differential diagnosis of a pancreatic tumor with bone lesions. sampling not only from the pancreatic lesion but also from bone lesions may reach an accurate diagnosis.

Utility of Comprehensive Genomic Profiling Tests for Patients with Incurable Pancreatic Cancer in Clinical Practice.

Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests in a Japanese cancer referral center from November 2019 to August 2021. We evaluated the results of CGP tests, treatments based on CGP tests, and survival time. Eight cases (6.9%) were diagnosed as tumor mutation burden-high (TMB-H) and/or microsatellite instability-high (MSI-H). The gene mutation rates of KRAS/TP53/CDKN2A/SMAD4 were 93.0/83.0/53.0/25.2%, respectively. Twenty-five patients (21.7%) had homologous recombination deficiency (HRD)-related genetic mutations. Four patients (3.5%) having TMB-H and/or MSI-H were treated with pembrolizumab, and only two patients (1.7%) participated in the clinical trials. Patient characteristics were not significantly different between patients with and without HRD-related gene mutations. The median OS was significantly longer in the HRD (+) group than in the HRD (-) group (749 days vs. 519 days, p = 0.047). In multivariate analysis, HRD-related gene mutation was an independent prognostic factor associated with favorable OS. CGP tests for patients with IPC have the potential utility of detecting HRD-related gene mutations as prognostic factors as well as a therapeutic search.

Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study.

Background and Aim: To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods: We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results: The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions: According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.

Usefulness of on-site cytology of liver tumor biopsy in specimen sampling for cancer genomic profiling test.

AIM: Appropriate sample selection with a tumor fraction ≥20% without necrosis contamination is required for successful cancer genomic profiling (CGP). Rapid on-site evaluation (ROSE) is performed to assess adequate sampling. METHOD: This retrospective study included 54 patients who underwent CGP using liver tumor biopsy specimen with ROSE. RESULT: The sampling success rate (98.1%) was higher than the previously reported 77.5%-88.9%. ROSE was performed once in 51 patients and twice in three patients; for those undergoing ROSE twice, the first ROSE was negative for malignancy, or showed few tumor cells with necrotic cell contamination, while the second ROSE obtained from another location showed abundant malignant cells. In these patients, the CGP was successful using the second specimen, though the first sample did not meet the required criteria for CGP test. CONCLUSION: Performing ROSE during liver tumor biopsy may be useful for CGP test sampling because ROSE prevents sampling errors and contributes to adequate sampling.

Establishment of preanalytical conditions for microRNA profile analysis of clinical plasma samples.

The relationship between the expression of microRNAs (miRNAs) in blood and a variety of diseases has been investigated. MiRNA-based liquid biopsy has attracted much attention, and cancer-specific miRNAs have been reported. However, the results of analyses of the expression of these miRNAs vary among studies. The reproduction of results regarding miRNA expression levels could be difficult if there are differences in the data acquisition process. Previous studies have shown that the anticoagulant type used during plasma preparation and sample storage conditions could contribute to differences in measured miRNA levels. Thus, the impact of these preanalytical conditions on comprehensive miRNA expression profiles was examined. First, the miRNA expression profiles of samples obtained from healthy volunteers were analyzed using next-generation sequencing. Based on an analysis of the library concentration, human genome identification rate, ratio of unique sequences and expression profiles, the optimal preanalytical conditions for obtaining highly reproducible miRNA expression profiles were established. The optimal preanalytical conditions were as follows: ethylenediaminetetraacetic acid (EDTA) as the anticoagulant, whole-blood storage at room temperature within 6 hours, and plasma storage at 4°C or -20°C within 30 days. Next, plasma samples were collected from 60 cancer patients (3 facilities × 20 patients/facility), and miRNA expression profiles were analyzed. There were no significant differences in measurements except in the expression of erythrocyte-derived hsa-miR-451a. However, the variation in hsa-miR-451a levels was smaller among facilities than among individuals. This finding suggests that samples obtained from the same facility could show significantly different degrees of hemolysis across individuals. We found that the standardization of anticoagulant use and storage conditions contributed to reducing the variation in sample quality across facilities. The findings from this study could be useful in developing protocols for collecting samples from multiple facilities for cancer screening tests.

Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy.

Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy.

Feasibility of immunotherapy in cancer patients with persistent or past hepatitis B or C virus infection.

Background and Aim: Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events in the liver. The risk of exacerbating liver injury is of concern in patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), as immunotherapy can damage liver function because of the immune response against viral antigens. We assessed the feasibility of immunotherapy in HBV- or HCV-infected patients. Methods: This retrospective study included 266 patients with persistent or past HBV infection, 26 patients seropositive for anti-HCV, and 820 patients with negative viral markers for HBV and HCV, who were treated with ICIs. ICI-induced liver injury and changes in virological markers were analyzed. Results: The occurrence rates of ICI-induced liver injury in the HBsAg-positive, anti-HBc-positive/anti-HBs-positive, and anti-HBc-positive/anti-HBs-negative groups were 12.5, 21.6, and 19.1%, respectively, which were comparable with those of the negative for HBV- and HCV-related markers group (20.9%). The frequency of any grade ICI-induced liver injury was different among the HCV RNA-positive (3/5; 60.0%), anti-HCV-positive/HCV RNA-negative (2/21; 9.5%), and negative for HBV- and HCV-related markers (171/820; 20.9%) groups (P = 0.045), with no significant difference in grade ≥2 ICI-induced liver injury. In patients with persistent infection, neither serum HBV DNA, HBsAg, nor HCV RNA level changed significantly during ICI treatment. One of five treatment-naïve HCV-infected patients required interruption of ICI treatment due to virus-related liver injury. Conclusion: Immunotherapy is feasible for most cancer patients with chronic HBV or HCV infection; however, liver function and virological markers should be carefully monitored in treatment-naïve patients, especially those with HCV infection, during ICI treatment.

5-Fluorouracil/L-Leucovorin Plus Oxaliplatin (FOLFOX) Regimen as Salvage Chemotherapy for Patients with Unresectable Pancreatic Cancer Receiving Gemcitabine and Nab-Paclitaxel and 5-Fluorouracil/L-Leucovorin Plus Nanoliposomal Irinotecan: Preliminary Results from Clinical Practice.

Salvage chemotherapy for patients with unresectable pancreatic cancer (UR-PC) who have been treated with gemcitabine and nab-paclitaxel (GnP), and 5-fluorouracil (5-FU)/l-leucovorin (LV) plus nanoliposomal irinotecan (nal-IRI), has not been fully established. We retrospectively reviewed data from 17 patients with UR-PC who initiated 5-FU/l-LV plus oxaliplatin (FOLFOX) as salvage chemotherapy at our hospital between June 2020 and August 2021, after treatment with GnP and 5-FU/LV plus nal-IRI. The primary endpoint was tumor response. The secondary endpoints were progression-free survival (PFS) and adverse events (AEs). The response and disease control rates were 5.9% (1/17) and 17.6% (3/17), respectively. The median PFS was 1.8 months (range: 0.4-5.2 months). Eight patients (47.1%) experienced grade 3 nonhematologic AEs, while none experienced grade 3 hematologic AEs. Two patients with controlled disease had homologous recombination deficiency (HRD)-associated gene mutations in cancer panel testing. The FOLFOX regimen benefit for UR-PC patients treated with GnP and 5-FU/LV plus nal-IRI may be limited to patients with HRD-associated gene mutations.

A case of refractory tumor bleeding from an ampullary adenocarcinoma: Compression hemostasis with a self-expandable metallic stent.

Although patients with ampullary cancers frequently experience obstructive jaundice and tumor bleeding, there have been few reports on efficient management of refractory hemorrhage after conservative treatment. In this report, we describe a case of refractory bleeding from a 15-mm ampullary adenocarcinoma. A Japanese woman in her 60s was urgently hospitalized for cholangitis, pancreatitis, and sepsis treatment. Investigation with a side-viewing duodenoscope revealed an ulcerated ampullary adenocarcinoma. After the patient underwent anticoagulation therapy for pulmonary thromboembolism, the tumor bleeding gradually increased, resulting in severe anemia. Because the anemia did not improve with fasting or discontinuation of the anticoagulation therapy, the patient underwent repeated red blood cell transfusions. As no hemobilia was observed in the bile juice aspirated during endoscopic retrograde cholangiography, we supposed that the bleeding originated from the ulcerative cancer surface. We did not perform thermal therapy because we considered that it would worsen the bleeding. Abdominal angiography showed no pseudoaneurysms or extravasation. Ultimately, we performed transpapillary placement of a fully covered self-expandable metallic stent (SEMS) with an anchoring double pigtail plastic stent that resulted in successful hemostasis. In this case, the mechanism of hemostasis was not presumably explained by direct compression of the bleeding point but by indirect compression. When tumor volume is small, the radial force of the SEMS may cause compression of the tumor volume, leading to shrinkage of the bleeding blood vessels. In conclusion, covered SEMS placement could be an efficient treatment for refractory ampullary cancer bleeding, even from an ulcerated cancer surface.

Early detection of venous thromboembolism after the initiation of chemotherapy predicts a poor prognosis in patients with unresectable metastatic pancreatic cancer who underwent first-line chemotherapy with gemcitabine plus nab-paclitaxel.

BACKGROUND: Pancreatic cancer is associated with a high thromboembolism risk. We investigated the significance of early venous thromboembolism (VTE) detection in patients with unresectable metastatic pancreatic cancer (UR-MPC) who received first-line chemotherapy with gemcitabine plus nab-paclitaxel (GnP). METHODS: This single-center retrospective study enrolled 174 patients with UR-MPC who underwent GnP as a first-line chemotherapy from April 2017 to March 2020. The early detection of VTE (deep venous thrombosis and pulmonary thromboembolism) was defined as diagnosis by the first follow-up CT scan after the initiation of chemotherapy. We compared the patients with early detection of VTE (VTE (+) group) with the others (VTE (-) group). We examined overall survival (OS), progress free survival (PFS), severe adverse events, and predictors associated with OS using the Cox proportional hazards model. RESULTS: Early detection of VTE was observed in 17 patients (9.8%). Thirteen patients were diagnosed with VTE at treatment initiation, and four patients were diagnosed after treatment initiation. The median time to diagnosis after treatment initiation was 55 days (range: 31-71 days). Only 3 patients were symptomatic. The VTE (+) group exhibited worse OS and PFS than the VTE (-) group (OS: 259 days vs. 400 days, P < 0.001; PFS: 120 days vs. 162 days, P = 0.008). The frequency of grade 3-4 adverse events was not significantly different. Although the performance status was poorer in the VTE (+) group, VTE was identified as a statistically significant independent predictor for OS in multivariate analyses (HR, 1.87; 95% CI, 1.02-3.44; P = 0.041). CONCLUSIONS: Early VTE detection is a predictor of a poor prognosis in UR-MPC patients who receive GnP as first-line chemotherapy, suggesting that screening VTE for patients with UR-MPC is crucial, even if patients are asymptomatic.

Capsid Allosteric Modulators Enhance the Innate Immune Response in Hepatitis B Virus-Infected Hepatocytes During Interferon Administration.

Capsid allosteric modulators (CAMs) inhibit the encapsidation of hepatitis B virus (HBV) pregenomic RNA (pgRNA), which contains a pathogen-associated molecular pattern motif. However, the effect of CAMs on the innate immune response of HBV-infected hepatocytes remains unclear, and we examined this effect in this study. Administration of a CAM compound, BAY41-4109 (BAY41), to HBV-infected primary human hepatocytes (PHHs) did not change the total cytoplasmic pgRNA levels but significantly reduced intracapsid pgRNA levels, suggesting that BAY41 increased extracapsid pgRNA levels in the cytoplasm. BAY41 alone did not change the intracellular interferon (IFN)-stimulated gene (ISG) expression levels. However, BAY41 enhanced antiviral ISG induction by IFN-α in HBV-infected PHHs but did not change ISG induction by IFN-α in uninfected PHHs. Compared with BAY41 or IFN-α alone, coadministration of BAY41 and IFN-α significantly suppressed extracellular HBV-DNA levels. HBV-infected human liver-chimeric mice were treated with vehicle, BAY41, pegylated IFN-α (pegIFN-α), or BAY41 and pegIFN-α together. Compared with the vehicle control, pegIFN-α highly up-regulated intrahepatic ISG expression levels, but BAY41 alone did not change these levels. The combination of BAY41 and pegIFN-α further enhanced intrahepatic antiviral ISG expression, which was up-regulated by pegIFNα. The serum HBV-DNA levels in mice treated with the combination of BAY41 and pegIFN-α were the lowest observed in all the groups. Conclusion: CAMs enhance the host IFN response when combined with exogenous IFN-α, likely due to increased cytoplasmic extracapsid pgRNA.