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Liquid biopsy (LB) is an essential tool for obtaining tumor‐derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell‐free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor‐derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers. A multigene panel for plasma liquid biopsy (LB) can also be applied to bile cell‐free DNA to identify mutations in biliary duct cancers. A machine learning approach was successfully applied to classify possible tumor‐derived variants among the prefiltered variant calls of a multigene panel. Bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

Background Cavernous transformation of the portal vein (CTPV) due to extrahepatic portal vein obstruction is a rare vascular anomaly. Since its symptoms usually appear in childhood, most of the adult cases are detected unexpectedly with other diseases. Only a few reports have described surgical difficulties in patients with CTPV. We report a case of pancreatic head cancer with CTPV in a patient who underwent pancreaticoduodenectomy. Case presentation A 77-year-old man with epigastric and back pain was referred to our hospital. Computed tomography revealed a tumor in the pancreatic head and a CTPV near the hepatic hilum. CTPV consisted of two main collateral vessels connected by multiple surrounding small vessels. Also, portal vein obstruction was observed near the hepatic hilum, which was far from the pancreatic head tumor. After confirming that there was no distant metastasis by a thorough whole-body search, we performed a pancreaticoduodenectomy following neoadjuvant chemotherapy. During the operation, we carefully manipulated the area of the CTPV and omitted lymph node dissection in the hepatoduodenal ligament to prevent massive venous bleeding and intestinal congestion. Pancreaticoduodenectomy was performed without any intraoperative complications and the postoperative course was uneventful. Complete tumor resection was histologically confirmed. Conclusion Although pancreaticoduodenectomy for patients with CTPV involves many surgical difficulties, we successfully performed it by determining specific treatment strategies tailored to the patient and following careful and delicate surgical procedures.

Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival. We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I–III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m2, intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0·87 with a non-inferiority margin of 1·25 (power 80%; one-sided type I error 2·5%). This trial is registered at UMIN CTR (UMIN000000655). 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0·57 (95% CI 0·44–0·72, pnon-inferiority<0·0001, p<0·0001 for superiority), associated with 5-year overall survival of 24·4% (18·6–30·8) in the gemcitabine group and 44·1% (36·9–51·1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group. Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients. Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.

Entrainment is characterized by phase response curves (PRCs), which provide a summary of responses to perturbations at each circadian phase. The synchronization of mammalian circadian clocks is accomplished through the receipt of a variety of inputs from both internal and external time cues. A comprehensive comparison of PRCs for various stimuli in each tissue is required. Herein, we demonstrate that PRCs in mammalian cells can be characterized using a recently developed estimation method based on singularity response (SR), which represents the response of desynchronized cellular clocks. We confirmed that PRCs can be reconstructed using single SR measurements and quantified response properties for various stimuli in several cell lines. SR analysis reveals that the phase and amplitude after resetting are distinguishable among stimuli. SRs in tissue slice cultures reveal tissue-specific entrainment properties. These results demonstrate that SRs can be employed to unveil entrainment mechanisms with diverse stimuli in multiscale mammalian clocks. Current methods to assess circadian biological parameters can be labor intensive. Here, the authors establish a method for estimating circadian entrainment characteristics using simple experiments and mathematical modeling, revealing the responsiveness of circadian rhythms to diverse stimuli in the mammalian circadian clock.

Other iatrogenic immunodeficiency lymphoproliferative disorders (oii-LPD) are defined as lymphoid proliferations or lymphomas that occur in patients taking immunosuppressive agents (ISA) for autoimmune disorders (AID). Although methotrexate and tumor necrosis factor-alpha inhibitors cause oii-LPD, the association between corticosteroids and lymphomagenesis remains unknown. Herein, we present the case of a 51-year-old woman with oii-LPD caused by corticosteroid use for autoimmune hemolytic anemia (AIHA). The diagnosis of AIHA was made in May 2016, and AIHA had been well-controlled for 5 years with oral prednisolone (PSL). During a regular follow-up visit in March 2022, an abnormal increase in atypical lymphoid cells in the peripheral blood was found. The bone marrow biopsy specimens showed local aggregations of large cells that were identified as lymphoplasmacytic cells and plasma cells, and that were positive for cluster of differentiation (CD)19 and CD20, with apparent nucleoli among the diffuse infiltration of atypical small lymphocytes. The large cells were partially positive for the Epstein–Barr encoding region in situ hybridization and latent membrane protein 1, which confirmed Epstein–Barr virus (EBV)-affected lymphomagenesis. To our knowledge, this is the first report of an oii-LPD case shown to be induced by corticosteroid use for AID.

Magnetoencephalography (MEG) provides crucial information in diagnosing focal epilepsy. However, dipole estimation, a commonly used analysis method for MEG, can be time-consuming since it necessitates neurophysiologists to manually identify epileptic spikes. To reduce this burden, we developed the automatic detection of spikes using deep learning in single center. In this study, we performed a multi-center study using six MEG centers to improve the performance of the automated detection of neuromagnetically recorded epileptic spikes, which we previously developed using deep learning. Data from four centers were used for training and evaluation (internal data), and the remaining two centers were used for evaluation only (external data). We used a five-fold subject-wise cross-validation technique to train and evaluate the models. A comparison showed that the multi-center model outperformed the single-center model in terms of performance. The multi-center model achieved an average ROC-AUC of 0.9929 and 0.9426 for the internal and external data, respectively. The median distance between the neurophysiologist-analyzed and automatically analyzed dipoles was 4.36 and 7.23 mm for the multi-center model for internal and external data, respectively, indicating accurate detection of epileptic spikes. By training data from multiple centers, automated analysis can improve spike detection and reduce the analysis workload for neurophysiologists. This study suggests that the multi-center model has the potential to detect spikes within 1 cm of a neurophysiologist’s analysis. This multi-center model can significantly reduce the number of hours required by neurophysiologists to detect spikes.

The clinicopathologic features and prognostic impact of MYD88 L265P ( MYD L265P ) and CXCR4 mutations ( CXCR4 Mut ) have been well reported, although little is known regarding the impact of chromosomal aberrations (CA) detected by chromosome banding analysis (CBA) in symptomatic Waldenström’s macroglobulinemia (sWM). Thus, we investigated the clinicopathologic features and prognostic impact in sWM with CAs identified by CBA. We retrospectively analyzed the clinicopathologic results and genomic alterations by droplet digital PCR, fluorescence in situ hybridization (FISH), and CBA using the G-banding method in bone marrow samples from sWM patients collected between April 2010 and March 2024 at our institute. The relationship between CAs and clinicopathologic features was evaluated, as well as the time to next treatment (TTNT). Thirty-five patients were enrolled. The median age was 71 years, and the median hemoglobin level was 10.1 g/dL. The median serum IgM and M-protein levels were 3,009 mg/dL and 2.95 g/dL, respectively. MYD L265P was found in 30/35 patients (85.7%), whereas CXCR4 Mut was found in 3/35 patients (8.6%). Deletion 6q identified by FISH in 5/18 patients (28%), and CAs using CBA in 9/34 patients (26%), including 4/34 (12%) complex karyotypes. sWM with CAs had more anemia ( p  = 0.04) and hypoalbuminemia ( p  = 0.007), in addition to higher serum M-protein and IgM levels ( p  = 0.03). With a median follow-up of 73 months, the median TTNT in patients with and without CAs was 27 and 68 months, respectively. CAs with CBA may be associated with clinical aggressiveness and shorter TTNT in sWM.

[...]we retrospectively reviewed consecutive patients with CAD who were managed at the National Hospital Organization Disaster Medical Center between April 2010 and March 2024. Clinical data extracted from medical records included age, sex, hemoglobin (Hb) level, serum total bilirubin concentration, serum IgM concentration, cold agglutinin titer, presence of splenomegaly, bone marrow chromosomal abnormalities, gene mutation status, percentage of lymphocytes and plasma cells in the bone marrow, frequency of red blood cell transfusions, response to initial therapy, time to response, duration of response, and adverse events related to therapy.Bone marrow specimens were reviewed to confirm the diagnosis of primary CAD and to exclude other lymphoproliferative disorders, including LPL/WM, multiple myeloma, and marginal zone lymphoma. The overall response rate (ORR) was calculated as the percentage of patients who achieved CR or PR. Serum IgM levels and cold agglutinin titers were recorded before treatment (“pre”) and at their lowest levels after treatment (“post”). Response data Case Treatment Duration of follow up, months Time to PR, weeks (Hb, g/dL, ΔHb) Time to CR, weeks (Hb, g/dL, ΔHb) Duration of response, months IgM reduction, % (pre, post, mg/dL) ΔCA titer pre →post Disese status at last follow up Treatment related Adverse event 1 6 cycles of R-CHOP R every 3 M for 45 M 114 M 24W (10.7, + 1.7) 36W (12.4, + 3.4) 110 M 94% (1077, 70) 4096 → 256 CR Grade3 neutropenia Grade2 infection 2 6 cycles of R-CHOP R every 2 M for 8 M 92 M 4W (10.3, + 2.2) 7W (12.5, + 4.5) 90 M 51% (203, 100) 256 → 512 PR Grade3 neutropenia 3 2cycles of R-CHOP 1 cycles of R 27 M 2W (10.5, + 3.2) 4W (12.9, + 5.6) 26 M 94% (888, 57) 512 → < 4 CR Grade3 neutropenia 4 6 cycles of R-CHOP R every 3 M for 20 M 112 M 3W (11.7, + 0.5) 41W (12.1, + 0.9) 110 M 62% (232, 88) 2048 → < 4 PR Grade3 neutropenia Grade2 infection 5 1 cycles of BR 14 M 1W (11, + 1.6) - 14 M 55% (162, 74) 512 → 128 PR - Median (range) - 92 M (14–114) 3W (1–24) 21.5 M (4–41) 90 M (14–110) 62% (51–94) - - Abbreviations: PR pertial response, CR complete response, Hb hemoglobin, ΔHb the change of Hb from base line, IgM immunoglobulin M, ΔCA titer the change of cold aggrutinin titer from base line, R-CHOP rituximab, cyclophosphamide, doxorubicin, Vincristine, and prednisolone, R rituximab, M months, BR bendamustine and rituximab, W weeks, M months Treatment regimens included reduced-dose rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; n = 4) [13] and bendamustine plus rituximab (BR; n = 1).

Background Monoclonal gammopathy of renal significance (MGRS) is characterized as renal impairment caused by monoclonal protein but does not fulfill the criteria for specific hematologic malignancies. Most MGRS cases involve IgG, IgA, or light chains, but IgM‐MGRS remains poorly understood. Case We present a 74‐year‐old woman with IgM‐κ monoclonal proteinuria who initially declined further evaluation. Later, anemia was identified, and a systemic work‐up revealed monoclonal immunoglobulin deposition disease in the kidney and symptomatic Waldenström macroglobulinemia. Treatment with a Bruton's tyrosine kinase inhibitor, namely tirabrutinib, rapidly resolved both proteinuria and anemia. Conclusion This case highlights the importance of early renal biopsy and prompt intervention in suspected IgM‐MGRS.

Identification of factors that regulate chromatin condensation is important for understanding of gene regulation. High-mobility group AT-hook (HMGA) proteins 1 and 2 are abundant nonhistone chromatin proteins that play a role in many biological processes including tissue stem-progenitor cell regulation, but the nature of their protein function remains unclear. Here we show that HMGA2 mediates direct condensation of polynucleosomes and forms droplets with nucleosomes. Consistently, most endogenous HMGA2 localized to transposase 5– and DNase I–inaccessible chromatin regions, and its binding was mostly associated with gene repression, in mouse embryonic neocortical cells. The AT-hook 1 domain was necessary for chromatin condensation by HMGA2 in vitro and in cellulo, and an HMGA2 mutant lacking this domain was defective in the ability to maintain neuronal progenitors in vivo. Intrinsically disordered regions of other proteins could substitute for the AT-hook 1 domain in promoting this biological function of HMGA2. Taken together, HMGA2 may regulate neural cell fate by its chromatin condensation activity. High-mobility group AT-hook (HMGA) proteins 1 and 2 are nonhistone chromatin proteins involved in different biological processes. Here the authors reveal that HMGA2 is a bona fide chromatin condensation factor that undergoes liquid–liquid phase separation, and that its chromatin condensation activity is important for the maintenance of mouse neural progenitor cells.