Real-world genome profiling in Japanese patients with pancreatic ductal adenocarcinoma focusing on HRD implications.

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges due to its high mortality, making it a critical area of research. This retrospective observational study aimed to analyze real-world data from comprehensive genome profiling (CGP) of Japanese patients with PDAC, mainly focusing on differences in gene detection rates among panels and the implications for homologous recombination deficiency (HRD) status. This study enrolled 2568 patients with PDAC who had undergone CGP between June 2019 and December 2021 using data from the nationwide Center for Cancer Genomics and Advanced Therapeutics database. Two types of CGP assays (tissue and liquid biopsies) were compared and a higher detection rate of genetic abnormalities in tissue specimens was revealed. HRD-related gene alterations were detected in 23% of patients, with BRCA1/2 mutations accounting for 0.9% and 2.9% of patients, respectively. Treatment outcome analysis indicated that patients with BRCA1/2 mutations had a longer time to treatment discontinuation with FOLFIRINOX than gemcitabine plus nab-paclitaxel as first-line therapy (9.3 vs. 5.6 months, p = 0.028). However, no significant differences were observed in the treatment response among the other HRD-related genes. Logistic regression analysis identified younger age and family history of breast, prostate, and ovarian cancers as predictive factors for HRD-related gene alterations. Despite the lack of progression-free survival data and the inability to discriminate between germline and somatic mutations, this study provides valuable insights into the clinical implications of CGP in Japanese patients with PDAC. Further research is warranted to optimize panel selection and elucidate the efficacy of platinum-based therapies depending on the HRD status.

[Safety and Efficacy of Nivolumab plus Ipilimumab Therapy-Our Real World Experience].

In Japan, cancer immunotherapy using immune checkpoint inhibitors(ICIs)has become a new treatment modality in cancer chemotherapy in the 2010s, and is now widely approved for many types of cancer. Today, combination cancer immunotherapy utilizing ICIs is being developed, with many cancer types. The first approved ICI combination in Japan consists of nivolumab, an anti-PD-1 antibody, and ipilimumab, an anti-CTLA-4 antibody. In the combination therapy, ipilimumab is administered at different doses, intervals, and frequencies depending on the cancer type. ICI combination therapy has been reported to be more effective than ICI monotherapy, but also be associated with more severe adverse events. Therefore, optimal dosing strategies for ipilimumab were explored considering both treatment efficacy and adverse event profiles. In the study of 64 cases with multiple cancer, higher efficacy of ICI combined therapy was expected in cases with irAEs, and there were cases with long-lasting efficacy even after early discontinuation of ipilimumab due to irAEs. And the high dose(3 mg/kg)of ipilimumab was suggested to be an independent risk factor for CTCAE Grade 3 or higher for severe irAEs.

[Feasibility of FP Therapy in Outpatient Setting for Inoperable Recurrent Esophageal Cancer].

With the emergence of immune checkpoint inhibitors(ICIs)in recent years, the treatment outcomes for unresectable recurrent esophageal cancer have improved markedly. In 5-FU+cisplatin(FP)first-line therapy, 5-FU administration takes 5 days and generally requires hospitalization. However, frequent hospitalization for treatment is a crucial issue that must be resolved in terms of time investment and optimal use of hospital resources. Here, we evaluated the safety and potential adverse effects of the administration of FP therapy in an outpatient setting. After central venous ports were placed in 5 patients, cisplatin was administered using a short hydration method and 5-FU was infused for 120 hours using an infusion pump. No crucial adverse events or major pump-related problems occurred, suggesting the feasibility of this treatment in an outpatient setting. However, the duration of 5-FU administration via the pump varied more than the expected deviation (10%, 12 hours), indicating that the issues require further consideration.

[A case of sarcomatoid intrahepatic cholangiocarcinoma that was difficult to diagnose].

A 70-year-old man presented to our hospital with fever and abdominal pain. A mass was found in the left lobe of his liver. Three months later, disseminated peritoneal nodules and ascites appeared. Liver biopsy and review laparoscopy did not lead to a diagnosis. Approximately five months later, a pathological autopsy was performed, and a final diagnosis of sarcomatoid intrahepatic cholangiocarcinoma was made. Differentiating sarcomatoid cholangiocarcinoma from sarcomatoid malignant peritoneal mesothelioma was difficult due to the similarity of clinical and pathological findings. Because the two diseases are treated differently, being able to differentiate them is a challenge in the future.

Water-soluble dietary fiber alleviates cancer-induced muscle wasting through changes in gut microenvironment in mice.

Cancer cachexia and the associated skeletal muscle wasting are considered poor prognostic factors, although effective treatment has not yet been established. Recent studies have indicated that the pathogenesis of skeletal muscle loss may involve dysbiosis of the gut microbiota and the accompanying chronic inflammation or altered metabolism. In this study, we evaluated the possible effects of modifying the gut microenvironment with partially hydrolyzed guar gum (PHGG), a soluble dietary fiber, on cancer-related muscle wasting and its mechanism using a colon-26 murine cachexia model. Compared with a fiber-free (FF) diet, PHGG contained fiber-rich (FR) diet-attenuated skeletal muscle loss in cachectic mice by suppressing the elevation of the major muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, as well as the autophagy markers LC3 and Bnip3. Although tight-junction markers were partially reduced in both FR and FF diet-fed cachectic mice, the abundance of Bifidobacterium, Akkermansia, and unclassified S24-7 family increased by FR diet, contributing to the retention of the colonic mucus layer. The reinforcement of the gut barrier function resulted in the controlled entry of pathogens into the host system and reduced circulating levels of lipopolysaccharide-binding protein (LBP) and IL-6, which in turn led to the suppression of proteolysis by downregulating the ubiquitin-proteasome system and autophagy pathway. These results suggest that dietary fiber may have the potential to alleviate skeletal muscle loss in cancer cachexia, providing new insights for developing effective strategies in the future.

[A Long‒Term Survival Case of Gastric Cancer with Disseminated Intravascular Coagulation due to Myelocarcinomatosis Treated with S‒1 plus Oxaliplatin Therapy].

We report the case of a 36‒year‒old man who was treated with S‒1 plus oxaliplatin(SOX)therapy for gastric cancer with disseminated intravascular coagulation(DIC). The patient visited our hospital for the treatment of an unresectable type 4 advanced gastric cancer. He had respiratory distress at the first visit. A chest CT scan revealed ground‒glass shadows as well as interstitial and septal thickening diffusely located in both the lungs, which suggested cancerous lymphangiopathy. Moreover, based on blood test results, DIC was diagnosed. After the administration of SOX in combination with recombinant human soluble thrombomodulin, the patient recovered from DIC, and the values of the tumor markers(CEA and CA19‒9) were normalized. After more than 14 months post treatment, the patient has survived without relapse. There are several reports that chemotherapy for gastric cancer is effective for DIC; however, there are no reports on regimens using oxaliplatin. Regimens using this drug may improve the prognosis of gastric cancer complicated by disseminated myelocarcinomatosis and DIC.

[A case of pustular psoriasis preceded by liver dysfunction].

The patient is a female in her thirties. The patient was diagnosed with pustular psoriasis during the treatment course for pneumonia with the appearance of small pustules of the skin and with an increase of serum total bilirubin level. Pustular psoriasis is a designated intractable disease with extremely low prevalence in which the skin of the whole body is flushed with high fever and many sterile pustules occur. This disease has been reported to be accompanied by liver dysfunction. Liver dysfunction appeared 1-2 weeks after the eruption appears in most cases, but this is the rare case in which the liver disorder precedes.

A Case Report of Primary Neuroendocrine Carcinoma of the Anal Canal with Cancer Genome Profiling.

Primary neuroendocrine carcinoma (NEC) of the anal canal is a rare, highly malignant tumor with a poor prognosis. Despite the standard first-line treatment with etoposide or irinotecan combined with cisplatin, effective second-line therapies are lacking. In 2019, Japan approved cancer genome profiling (CGP) tests for solid tumors to enhance genomic understanding. We present the case of a 79-year-old woman with NEC of the anal canal, treated with etoposide, carboplatin, and amrubicin. Post-standard therapy, CGP suggested pemigatinib, a tyrosine kinase inhibitor; however, the patient died before receiving it. This case highlights the potential of personalized medicine to improve outcomes in such cases.

Underwater endoscopic papillectomy for a small neuroendocrine tumor of the ampulla of Vater.

Neuroendocrine tumors (NETs) of the ampulla of Vater are rare. Therefore, there is a lack of comprehensive information regarding their pathogenesis. We herein present the case of a patient with a 5-mm ampullary NET who demonstrated the presence of lymphatic invasion after undergoing endoscopic papillectomy. A 44-year-old woman was referred to our hospital for treatment of a grade 1 NET in the ampulla of Vater. Endoscopic ultrasonography revealed a hypoechoic mass within the submucosal layer without obvious infiltration into the common bile duct or the main pancreatic duct. We performed underwater endoscopic papillectomy (UEP) to remove the tumor with a negative margin. Pathological evaluation of the resected specimen showed a grade 1 NET with a negative margin. However, pancreaticoduodenectomy was subsequently performed because of the risk of lymph node metastasis, which was expected due to the significant number of NET cells infiltrating the endothelium of the lymphatic vessels. No lymph node metastasis or recurrence was observed during the 26-month follow-up period. UEP is a useful method to achieve complete resection for diagnostic and therapeutic purposes. UEP may be a novel option for endoscopic treatment of ampullary NET.

Genomic profile and clinical features of MSI-H and TMB-high pancreatic cancers: real-world data from C-CAT database.

BACKGROUND: Microsatellite instability high (MSI-H) and tumor mutational burden high (TMB-high) pancreatic cancer are rare, and information is lacking. Based on the C-CAT database, we analyzed the clinical and genomic characteristics of patients with these subtypes. METHODS: We retrospectively reviewed data on 2206 patients with unresectable pancreatic adenocarcinoma enrolled in C-CAT between July 2019 and January 2022. The clinical features, proportion of genomic variants classified as oncogenic/pathogenic in C-CAT, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) of chemotherapy as first-line treatment were evaluated. RESULTS: Numbers of patients with MSI-H and TMB-high were 7 (0.3%) and 39 (1.8%), respectively. All MSI-H patients were TMB-high. MSI-H and TMB-high patients harbored more mismatch repair genes, such as MSH2, homologous recombination-related genes, such as ATR and BRCA2, and other genes including BRAF, KMT2D, and SMARCA4. None of the 6 MSI-H patients who received chemotherapy achieved a clinical response, including 4 patients treated with gemcitabine plus nab-paclitaxel (GnP) therapy, whose DCR was significantly lower than that of microsatellite stable (MSS) patients (0 vs. 67.0%, respectively, p = 0.01). Among the TMB-high and TMB-low groups, no significant differences were shown in ORR, DCR (17.1 vs. 23.1% and 57.1 vs. 63.1%, respectively), or median TTF (25.9 vs. 28.0 weeks, respectively) of overall first-line chemotherapy. CONCLUSIONS: MSI-H and TMB-high pancreatic cancers showed some distinct genomic and clinical features from our real-world data. These results suggest the importance of adapting optimal treatment strategies according to the genomic alterations.

Prevalence of carbapenem-resistant Enterobacterales with bla IMP-6 predominance in hospitals from 2018 to 2021 in Nara, Japan.

Objectives: Despite the global health risk of carbapenem-resistant Enterobacterales (CRE), especially carbapenemase-producing Enterobacterales (CPE), Japan reports a significantly low frequency of CRE with a predominance of IMP-type carbapenemases. This study aimed to investigate the prevalence and characteristics of CRE isolated from hospitals in the city of Nara, Japan. Methods: We obtained 171 CRE isolates from 16 791 Enterobacterales isolated at 23 hospitals in Nara between January 2018 and December 2021. Isolates of CPE were characterized through antimicrobial susceptibility testing, the carbapenem inactivation method, PCR and DNA sequencing. Genotypic diversity of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae was determined via MLST and PFGE. Results: The prevalence of CRE between 2018 and 2021 was 1.02%, gradually decreasing from 1.13% to 0.74%. Ninety-nine isolates were identified as CPE, representing six species. Ninety-seven CPE isolates harboured bla IMP-6, while the remaining two carried either bla IMP-1 or bla IMP-19. Genotype analysis identified ST131 as the dominant genotype for E. coli, but none for K. pneumoniae. PFGE results suggested clonal spread of CPE in Hospital A, where CRE was isolated in high numbers (n = 44). Conclusions: In this study, CRE prevalence was marginally higher than previously reported in Japan, but still low in frequency. A predominance of Enterobacterales harbouring bla IMP-6 was confirmed in Nara. The spread of CPE at Hospital A suggested the possibility of a nosocomial outbreak due to bla IMP-6 transmission via plasmids or clonal spread. Continued monitoring is crucial for effective management of CRE prevalence in the region.

Genomic landscape and clinical features of rare subtypes of pancreatic cancer: analysis with the national database of Japan.

BACKGROUND: Special subtypes of pancreatic cancer, such as acinar cell carcinoma (ACC), adenosquamous carcinoma (ASC), and anaplastic carcinoma of the pancreas (ACP), are rare, and so data on them are limited. Using the C-CAT database, we analyzed clinical and genomic characteristics of patients with these and evaluated differences on comparison with pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: We retrospectively reviewed data on 2691 patients with unresectable pancreatic cancer: ACC, ASC, ACP, and PDAC, entered into C-CAT from June 2019 to December 2021. The clinical features, MSI/TMB status, genomic alterations, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) on receiving FOLFIRINOX (FFX) or GEM + nab-PTX (GnP) therapy as first-line treatment were evaluated. RESULTS: Numbers of patients with ACC, ASC, ACP, and PDAC were 44 (1.6%), 54 (2.0%), 25 (0.9%), and 2,568 (95.4%), respectively. KRAS and TP53 mutations were prevalent in ASC, ACP, and PDAC (90.7/85.2, 76.0/68.0, and 85.1/69.1%, respectively), while their rates were both significantly lower in ACC (13.6/15.9%, respectively). Conversely, the rate of homologous recombination-related (HRR) genes, including ATM and BRCA1/2, was significantly higher in ACC (11.4/15.9%) than PDAC (2.5/3.7%). In ASC and ACP, no significant differences in ORR, DCR, or TTF between FFX and GnP were noted, while ACC patients showed a trend toward higher ORR with FFX than GnP (61.5 vs. 23.5%, p = 0.06) and significantly more favorable TTF (median 42.3 vs. 21.0 weeks, respectively, p = 0.004). CONCLUSIONS: ACC clearly harbors different genomics compared with PDAC, possibly accounting for differences in treatment efficacy.

A case of pancreatic walled-off necrosis successfully treated with endoscopic ultrasonography-guided drainage using Hot AXIOS System in a patient with severe hemophilia A.

BACKGROUND: Hemophilia A causes a bleeding tendency due to the congenital absence of coagulation factor VIII or the production of antibodies against it. It is challenging to perform invasive procedures in patients with hemophilia A. Walled-off necrosis (WON) is a serious complication of acute pancreatitis. Recently, a new metallic stent has been used to drain WON. CLINICAL COURSE: We treated a 32-year-old man who developed WON due to acute pancreatitis and has severe congenital hemophilia A. Since conservative treatment was ineffective, he underwent endoscopic ultrasonography (EUS)-guided transgastric WON drainage using a new metallic stent Hot AXIOS System. The procedure was successful without any severe hemorrhagic complications. Before and after the procedure, his clotting factors were strictly monitored by a hemophilia specialist. CONCLUSION: EUS-guided pancreatic cyst drainage can be an effective option for WON in patients with severe congenital hemophilia, under adequate management.

Proton Pump Inhibitors Enhance the Antitumor Effect of Chemotherapy for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Vacuolar ATPase (V-ATPase) is involved in cancer development. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been reported to enhance the effectiveness of chemotherapy in certain cancers. This study aimed to evaluate the effect of PPIs on chemotherapy for esophageal cancer. METHODS: To investigate the effects of PPIs on esophageal cancer cells, human KYSE50 and 70 cells were plated and 3 PPIs (lansoprazole, esomeprazole, vonoprazan) were added at various concentrations with 5-Fluorouracil (5-FU) to the corresponding cells for a cell viability assay. To investigate the effects of PPI treatment on patients undergoing 5-FU-based therapy in the clinical setting, we retrospectively analyzed the clinical outcomes and chemotherapy-related adverse events in 40 esophageal cancer patients who received 5-FU chemotherapy in our hospital between May 2013 and April 2017. RESULTS: In the viability assays, all PPIs significantly enhanced the cytotoxic effect of 5-FU on the two esophageal cancer cell lines. In the clinical study, PPI-treated patients showed better overall survival (OS) than patients managed without PPI treatment. A multivariate analysis revealed that PPI treatment was independently associated with OS (p = 0.009, HR, 0.33; 95% CI, 0.12-0.76). CONCLUSIONS: PPI treatment may safely enhance chemosensitivity in esophageal cancer patients.

Granulocyte and Monocyte Adsorptive Apheresis for Ulcerative Colitis in a Patient with Low Bone Mineral Density Due to Fanconi-Bickel Syndrome.

Systemic steroid is required for the exacerbation of ulcerative colitis (UC), although its administration should be avoided in patients with a low bone mineral density (BMD) exacerbated by side effects of steroids. We herein report the successful induction of remission in an UC case with a low BMD due to Fanconi-Bickel syndrome-or glycogen storage disease type XI-using granulocyte and monocyte adsorptive apheresis (GMA). For a 43-year-old woman with a BMD of 50% the young adult mean, GMA was performed 2 times a week for a total of 10 times. GMA might be a steroid-free treatment option for UC patients with a low BMD.