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Pancreatic cancer frequently involves cancer‐associated thromboembolism, which is strongly associated with poor prognosis. Tissue factor, a blood coagulation factor largely produced in cancer patients as a component of extracellular vesicles, plays a key role in the incidence of cancer‐associated thromboembolism in patients with pancreatic cancer. However, no prospective studies have been published on the relationship between tissue factor and cancer‐associated thromboembolism or patient clinical characteristics, including recent chemotherapy regimens. Thus, we aimed to address this in a Japanese cohort of 197 patients and 41 healthy volunteers. Plasma tissue factor levels were measured by ELISAs preevaluated by tissue factor specificity. Multivariable analysis was used to identify independent predictors of cancer‐associated thromboembolism. We found that the cancer‐associated thromboembolism rate in the patient cohort was 6.6% (4.6%, venous thromboembolism; 2.0%, arterial thromboembolism). Tissue factor levels of 100 pg/mL or higher at patient registration were predictive of cancer‐associated thromboembolism, with positive and negative predictive values of 23.1% and 94.6%, respectively. Multivariable analysis showed that plasma tissue factor levels were an independent predictive factor for cancer‐associated thromboembolism, with a risk ratio of 5.54 (95% confidence interval, 1.02‐30.09). Unlike in healthy volunteers and patients without cancer‐associated thromboembolism, tissue factor levels were highly correlated with extracellular vesicles’ procoagulant activity in patients developing cancer‐associated thromboembolism. Taken together, our data show that the tissue factor levels at patient registration were a predictive factor for cancer‐associated thromboembolism in this cohort of patients with pancreatic cancer. Tissue factor levels were highly correlated with extracellular vesicles’ procoagulant activity in patients with pancreatic cancer who developed cancer‐associated thromboembolism. Tissue factor levels before the start of systemic chemotherapy were a predictive factor of cancer‐associated thromboembolism in a Japanese cohort of patients with pancreatic cancer.

Background Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP). Methods This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP. Discussion If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy. Trial registration This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].

Background Malignant gastric outlet obstruction (MGOO) occasionally occurs due to pancreaticobiliary cancer. Endoscopic duodenal stenting (DS) is a common treatment for MGOO. However, it has been reported that DS does not have sufficient patency time for it to be used in patients who have a potentially increased lifespan. Nowadays, systemic chemotherapy for pancreaticobiliary cancer has developed, and its anti-tumour effect would make time to stent dysfunction longer. Therefore, we retrospectively evaluated the association between objective response to systemic chemotherapy, followed by DS and time to stent dysfunction in patients with advanced pancreaticobiliary cancer. Methods This retrospective study included 109 patients with advanced pancreaticobiliary cancer who received systemic chemotherapy after DS. Patients who showed complete or partial response were defined as responders. The rest were defined as non-responders. Time to stent dysfunction was compared between responders and non-responders using the landmark analysis at 2 months after DS. Death without recurrence of MGOO was considered as a competing risk for time to stent dysfunction. Results Combination and monotherapy regimens were adopted for 46 and 63 patients, respectively. Median progression-free survival and overall survival were 3.2 months (95% confidence interval [CI], 2.4–4.0) and 6.0 months (95% CI, 4.6–7.3). Objective response was observed in 21 patients (19.3%). Median time to stent dysfunction was 12.5 months (95% CI, 8.4–16.5) in the entire cohort. In 89 patients, responders had a lower cumulative incidence of stent dysfunction than non-responders: 9.5 and 19.1% at 6 months, and 19.0 and 27.9% at 1-year, respectively. There was difference of time to stent dysfunction between responders and non-responders among patients who received combination regimen as the first-line treatment with p -value of 0.009: cumulative incidence was 0 and 42.9% at 6 months, and 9.3 and 57.1% at 1-year, respectively. Conclusions Longer time to stent dysfunction is expected when systemic chemotherapy following DS suppresses tumour progression; DS is slated to be a standard treatment for MGOO even in patients with pancreaticobiliary cancer and a long lifespan.

Background Two main therapeutic approaches are currently used for locally advanced pancreatic cancer (LAPC): chemoradiotherapy and systemic chemotherapy. It remains unclear which approach may be more promising, or whether these strategies should be considered alternative or complementary therapeutic options in the management of LAPC. Clinical outcomes and safety were assessed for S-1 plus concurrent radiotherapy (S-1 + RT) and gemcitabine plus nab-paclitaxel (GnP) in patients with LAPC. Methods We conducted a pooled exploratory analysis of individual patient data derived from two multi-institutional randomized phase II trials conducted by the Japan Clinical Oncology Group (JCOG1106 and JCOG1407). JCOG1106 evaluated S-1 + RT with or without induction chemotherapy. JCOG1407 compared GnP with modified FOLFIRINOX. Based on the results of these trials, S-1 + RT and GnP were selected as promising regimens for chemoradiotherapy and systemic chemotherapy, respectively. The primary endpoint of this study was progression-free survival (PFS). Inverse probability of treatment weighting (IPTW) with stabilized weights was applied based on the propensity score to account for baseline imbalances between the two groups. Results A total of 113 patients were included. After adjustment for patient characteristics, Kaplan–Meier curves showed median PFS, overall survival (OS), and distant metastasis-free survival (DMFS) of 10.2 vs. 9.3 (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.60–1.30), 19.1 vs. 21.2 (HR, 0.73; 95% CI, 0.48–1.11), and 11.5 vs. 13.1 months (HR, 0.73; 95% CI, 0.49–1.08) for S-1 + RT and GnP, respectively. Treatment received after protocol therapy differed substantially: 77.5% in the S-1 + RT group received single-agent chemotherapy, whereas 50.0% in the GnP group, received more intensive regimens, including multi-agent chemotherapy or chemoradiotherapy. Conclusions GnP may offer advantages in suppressing micrometastatic disease, whereas S-1 + RT may provide benefits in local disease control. These findings suggest that both approaches represent important and complementary therapeutic options for LAPC. Prospective randomized studies are warranted to determine the optimal initial strategy.

BackgroundMajor hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC.MethodsOf the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed.ResultsGrade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387–1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310–1.447)] arms.ConclusionsThe safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

The Egyptian Rousettus bat (Rousettus aegyptiacus) is a common fruit bat species that is distributed mainly in Africa and the Middle East. Bats serve as reservoir hosts for numerous pathogens. Human activities, such as hunting bats for food, managing vermin, and causing habitat loss, elevate the likelihood of transmission of bat pathogens to humans and other animals. Consequently, bat cell lines play a crucial role as research materials for investigating viral pathogens. However, the inherent limitation of finite cell division in primary cells necessitates the use of immortalized cells derived from various bat tissues. Herein, we successfully established six fibroblast cell lines derived from an infant bat heart and lungs and an elderly bat heart. Three of the six cell lines, called K4DT cells, were transduced by a combination of cell cycle regulators, mutant cyclin‐dependent kinase 4, cyclin D1, and human telomerase reverse transcriptase. The other three cell lines, named SV40 cells, were transfected with simian virus 40 large T antigen. Transgene protein expression was detected in the transduced cells. All three K4DT cell lines and one lung‐derived SV40 cell line were virtually immortalized and nearly maintained the normal diploid karyotypes. However, the two other heart‐derived SV40 cell lines had aberrant karyotypes and the young bat‐derived cell line stopped proliferating at approximately 40 population doublings. These bat cell lines are valuable for studying pathogen genomics and biology. Egyptian Rousettus bats serve as a reservoir for pathogens. Fibroblast cell lines K4DT and SV40 were established to overcome the limited cell division of primary bat cells. While three K4DT and one SV40 cell lines were virtually immortalized with normal karyotypes, two SV40 lines had aberrant karyotypes. These bat cell lines are valuable tools for the study of viral pathogens.

Background Although second‐line treatment for pancreatic cancer has been proven to have survival benefit, it is not clear which is the most preferred regimen. This study compared the efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) and sequential chemotherapy (FOLFIRI/FOLFOX) as a second‐line treatment regimen for unresectable pancreatic cancer. Method This was a retrospective single‐center analysis of all patients who initiated treatment with mFOLFIRINOX or sequential chemotherapy from December 2014 to May 2019 as a second‐line treatment for unresectable pancreatic cancer. The sequential chemotherapy group included all patients who initiated sequential chemotherapy. For efficacy analysis, the primary endpoint was overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. For safety analysis, we assessed the incidence of grade ≥3 adverse events in all patients. Results Seventy‐four patients (mFOLFIRINOX group, n = 44; sequential chemotherapy group, n = 30) were included. OS tended to be slightly prolonged in the mFOLFIRINOX group than in the sequential chemotherapy group (median 10.6 [95% confidence interval CI 5.9–13.8] vs. 8.5 [95% CI 5.0–12.2] months; hazard ratio 1.40 [95% CI 0.71–2.71]). The objective response rate and disease control rate were 8.1% and 64.9%, respectively, in the mFOLFIRINOX group and 3.8% and 42.3%, respectively, in the sequential chemotherapy group. In safety analysis, the grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 40.9%, 6.8%, and 18.2%, respectively, in the mFOLFIRINOX group and 3.3%, 0%, and 3.3%, respectively, in the sequential chemotherapy group. Conclusions Whereas efficacy tended to be slightly better in the mFOLFIRINOX group than in the sequential chemotherapy group, given the higher incidence of grade ≥3 adverse events with mFOLFIRINOX than with sequential chemotherapy, sequential chemotherapy is a regimen with better risk–benefit balance than mFOLFIRINOX, and can be considered a second‐line treatment option for patients with unresectable pancreatic cancer. We compared the efficacy and safety of mFOLFIRINOX and sequential chemotherapy for second‐line treatment of unresectable pancreatic cancer. In efficacy results, the Kaplan–Meier curves showed that OS, the primary endpoint, tended to be consistently higher in the mFOLFIRINOX group than in the sequential chemotherapy group, however, the difference was not significant.

The prognosis of patients with multiple myeloma (MM) has recently improved due to the emergence of new molecular targeting agents. However, MM remains incurable because MM stem cells are resistant to these agents. Therefore, it is essential to develop strategies to eradicate MM stem cells. We have previously demonstrated that MM cells cultured under prolonged hypoxic conditions (1% O ) (i.e., hypoxia-adapted MM cells; MM-HA cells) exhibited stem-cell-like characteristics. γδ T cells attack tumor cells by recognizing butyrophilin (BTN) 3A1 and BTN2A1, which are activated by the intracellular accumulation of isopentenyl pyrophosphate (IPP), an intermediate in the mevalonate pathway. In the present study, we investigated the cytotoxicity of γδ T cells against MM-HA stem-like cells. We used a combination of flow cytometry, liquid chromatography-tandem mass spectrometry, and western blotting methods to investigate the cytotoxicity of γδ T cells against MM-HA cells and measured the amounts of IPP in MM-HA cells and their supernatants. The cytotoxicity of γδ T cells against MM-HA cells was significantly lower than that against MM cells cultured under normoxic conditions (20% O ; MM-Normo). Furthermore, the concentration of IPP in MM-HA cells was lower than that in MM-Normo cells. The expression of mevalonate decarboxylase and farnesyl diphosphate synthase proteins were decreased in MM-HA-cells. The cytotoxicity of γδ T cells against MM-HA cells was suppressed by the reduced IPP accumulation by modulating the mevalonate pathway in MM-HA cells.

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in EYS detected in our previous study along with structural variants (SVs) in EYS and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in EYS in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.