Variability of urinary albumin to creatinine ratio and eGFR are independently associated with eGFR slope in Japanese with type 2 diabetes: a three-year, single-center, retrospective cohort study.

BACKGROUND: To evaluate the seasonal variability of urinary albumin to creatinine ratio (UACR) and eGFR and these effects on three-year eGFR slope in persons with type 2 diabetes (T2D). METHODS: A total of 1135 persons with T2D were analyzed in this single-center, retrospective cohort study in Japan. The standard deviation (SD) of UACR (SD [UACR]) and SD of eGFR (SD [eGFR]) were calculated for each person's 10-point data during the three years, and a multiple linear regression analysis was performed to evaluate associations with eGFR slope. A sensitivity analysis was performed in a group with no medication changes (n = 801). RESULTS: UACR exhibited seasonal variability, being higher in winter and lower in spring, early summer, and autumn especially in the UACR ≥ 30 mg/g subgroup, while eGFR showed no seasonal variability. The eGFR slope was significantly associated with SD (eGFR) (regression coefficient -0.170 [95% CI -0.189--0.151]) and SD (UACR) (0.000 [-0.001-0.000]). SGLT-2 inhibitors, baseline eGFR, and baseline systolic blood pressure (SBP) were also significantly associated. These associated factors, except baseline SBP, were still significant in the sensitivity analysis. CONCLUSIONS: The UACR showed clear seasonal variability. Moreover, SD (UACR) and SD (eGFR) were independently associated with a three-year eGFR slope in persons with T2D. TRIAL REGISTRATION: This study was not registered for clinical trial registration because it was a retrospective observational study.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

EMpowerment of PArents in THe Intensive Care: A multicentre validation study in Japan.

BACKGROUND: The importance of assessing family satisfaction in paediatric intensive care units (PICUs) is becoming increasingly recognised. The survey, EMpowerment of Parents in THe Intensive Care "EMPATHIC-30", was designed to assess family satisfaction and has been translated and implemented in several countries but not yet in Japan. OBJECTIVES: The objective of this study was to translate, culturally adapt, and validate the EMPATHIC-30 questionnaire in Japanese and to identify potential factors for family-centred care satisfaction. METHODS: We translated and adapted for patient-reported outcome measures via a 10-step process outlined by the Principles of Good Practice. Four paediatric PICUs in Japan participated in the validation study, and the parental enrolment criterion was a child with a PICU stay of >24 h. Reliability was measured by Cronbach's α, and congruent validity was tested with overall satisfaction-with-care scales by correlation analysis. Multivariate linear regression modelling was conducted to identify factors related to each domain of the Japanese EMPATHIC-30. RESULTS: A total of 163 parents (mean age: 31.9 ± 5.4 years; 81% were mothers) participated. The five domains of the Japanese EMPATHIC-30 showed high reliability (α = 0.87 to 0.97) and congruent validity, demonstrating high correlations with overall satisfaction in nurses (r = 0.75) and doctors (r = 0.76). Multivariate modelling found that elective admission, mechanical ventilation, and parents who had experience of a family member in an adult intensive care unit had higher satisfaction scores in all five domains (p < 0.05). Moreover, Buddhists assigned higher satisfaction scores in the Care and Treatment domain (p = 0.03). CONCLUSIONS: The Japanese EMPATHIC-30 questionnaire has demonstrated adequate reliability and validity measures. We also identified that elective admission, mechanical ventilation, and having previous adult intensive care unit experience of a family member were factors in assigning higher scores for all satisfaction domains. PICU clinicians need to be cognisant of ethical, cultural, and religious factors relating to the critically ill child and their family.

A balanced mitral leaflet and large ring strategy avoids systolic anterior motion in Barlow's disease.

OBJECTIVES: Mitral valve repair for Barlow's disease offers good outcomes but excessive and myxomatous valvular tissue is associated with systolic anterior motion. Although valvular disease might progress after repair and cause long-term systolic anterior motion, few reports focus on this aspect. Herein, we will review our 16-year experience with mitral valve repair for Barlow's disease and systolic anterior motion incidence. METHODS: We retrospectively reviewed surgical outcomes of 92 cases of mitral valve repair using a balanced leaflet/large ring strategy plus median sternotomy for Barlow's disease (median age 45.1 ± 12.7 years old [19-72], 37 females) from 2004 to 2019. Concomitant surgeries, except for tricuspid valve or anti-arrhythmic surgeries, were excluded. RESULTS: The follow-up period was 5.8 ± 4.4 years with no deaths. Patients had mitral regurgitation of grade 3/4 (15 cases) or 4/4 (77 cases) due to anterior leaflet (3 cases), posterior leaflet (75 cases), or bileaflet (14 cases) prolapse, with chord elongation (39 cases), chord rupture (22 cases), or a combination of both (14 cases). All cases required ring annuloplasty (median size of 33.0 ± 5.4 mm) combined with leaflet resection (91 cases), chord intervention (12 cases), or indentation closure (2 cases). No case had short- or long-term SAM. The freedom-from-mitral-regurgitation (of greater than grade 2/4) rate was 94.1% over 5 years and 76.0% over 10 years without reoperation. CONCLUSIONS: Our two-pronged strategy for mitral valve repair in Barlow's disease avoids systolic anterior motion over the long-term, with good outcomes.

Safety and Efficacy of Compression Therapy to Prevent Chemotherapy-Induced Peripheral Neuropathy in Lower Extremities of Breast Cancer Patients: A Pilot Study.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic adverse event for breast cancer patients receiving taxane antimitotic agents. We evaluated the effectiveness of compression therapy against CIPN in the lower extremities of breast cancer patients receiving taxanes. Methods Eligible patients scheduled for perioperative treatment with taxanes for early-stage breast cancer were enrolled. Each patient wore latex-free surgical gloves and compression socks, putting on two layers of each 15 minutes before the administration of taxanes and removing them 15 minutes after administration. Peripheral neuropathy (PN) was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The primary endpoint was the incidence of CTCAE version 4.0 grade 2 or higher CIPN in the lower extremities during the entire period of perioperative chemotherapy with taxanes. Results PN assessment by CTCAE in the lower extremities, the primary outcome, showed that 13.3% developed grade 2 sensory disturbances, and 8.3% developed grade 2 motor disturbances. The incidence of CTCAE grade 2 or higher PN in the hands was 26.7% for sensory disturbances and 13.3% for motor disturbances during the entire study period. No patient had grade 3 or higher PN. No adverse events due to compression therapy were observed. Conclusion Compression of the lower extremities with compression socks tended to reduce the incidence of CIPN compared to the general incidence. Compression therapy may help prevent the development of CIPN.

Aortic valve area index values of Trifecta implants correlate with energy loss and increased valve stress.

Biological valves are becoming more frequently used in aortic valve replacement. While several reports have evaluated the performance of biological valves, echocardiography studies during exercise stress remain scarce. Furthermore, no current reports compare rate changes in the aortic valve area of biological valves under increased exercise load. Here, we performed exercise stress echocardiography in patients after AVR with Trifecta or Inspiris valves and compared the rates of change in aortic valve areas (AVA). In addition, hydrodynamic analysis at rest was conducted with four-dimensional flow magnetic resonance imaging (4D-flow MRI). Exercise stress echocardiography was performed in seven Trifecta and seven Inspiris patients who underwent AVR at our hospital while 4D flow MRI was performed in all but two Trifecta cases. Comparing the percentage change in AVA when loaded to 25 W versus at rest, Trifecta was greater than Inspiris (28.7 ± 36.0 vs - 0.8 ± 12.4%). The smaller AVA at rest was considered causative for this. Meanwhile, Trifecta systolic energy loss in the prosthetic valve segment on 4D-flow MRI (97.5 ± 35.9 vs 52.7 ± 25.3 mW) was higher than Inspiris. The opening of the Trifecta valve was considered to be restricted at rest and this may reflect the current reports of early valve degradation requiring reoperation. Taken together, we observed that the Trifecta design may promote faster wear due to higher valve stress.

A Machine Learning Model to Predict the Histology of Retroperitoneal Lymph Node Dissection Specimens.

BACKGROUND/AIM: While post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) benefits patients with teratoma or viable germ cell tumors (GCT), it becomes overtreatment if necrosis is detected in PC-RPLND specimens. Serum microRNA-371a-3p correctly predicts residual viable GCT with 100% sensitivity; however, prediction of residual teratoma in PC-RPLND specimens using current modalities remains difficult. Therefore, we developed a machine learning model using CT imaging and clinical variables to predict the presence of residual teratoma in PC-RPLND specimens. PATIENTS AND METHODS: This study included 58 patients who underwent PC-RPLND between 2005 and 2019 at the University of Tsukuba Hospital. On CT imaging, 155 lymph nodes were identified as regions of interest (ROIs). The ResNet50 algorithm and/or Support Vector Machine (SVM) classification were applied and a nested, 3-fold cross-validation protocol was used to determine classifier accuracy. RESULTS: PC-RPLND specimen analysis revealed 35 patients with necrosis and 23 patients with residual teratoma, while histology of 155 total ROIs showed necrosis in 84 ROIs and teratoma in 71 ROIs. The ResNet50 algorithm, using CT imaging, achieved a diagnostic accuracy of 80.0%, corresponding to a sensitivity of 67.3%, a specificity of 90.5%, and an AUC of 0.84, whereas SVM classification using clinical variables achieved a diagnostic accuracy of 74.8%, corresponding to a sensitivity of 59.0%, a specificity of 88.1%, and an AUC of 0.84. CONCLUSION: Our machine learning models reliably distinguish between necrosis and residual teratoma in clinical PC-RPLND specimens.

Aberrant Glycosylation in Pancreatic Ductal Adenocarcinoma 3D Organoids Is Mediated by KRAS Mutations.

Aberrant glycosylation in tumor cells is a hallmark during carcinogenesis. KRAS gene mutations are the most well-known oncogenic abnormalities but their association with glycan alterations in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. We employed patient-derived 3D organoids to culture pure live PDAC cells, excluding contamination by fibroblasts and immune cells, to gasp the comprehensive cancer cell surface glycan expression profile using lectin microarray and transcriptomic analyses. Surgical specimens from 24 PDAC patients were digested and embedded into a 3D culture system. Surface-bound glycans of 3D organoids were analyzed by high-density, 96-lectin microarrays. KRAS mutation status and expression of various glycosyltransferases were analyzed by RNA-seq. We successfully established 16 3D organoids: 14 PDAC, 1 intraductal papillary mucinous neoplasm (IPMN), and 1 normal pancreatic duct. KRAS was mutated in 13 (7 G12V, 5 G12D, 1 Q61L) and wild in 3 organoids (1 normal duct, 1 IPMN, 1 PDAC). Lectin reactivity of AAL (Aleuria aurantia) and AOL (Aspergillus oryzae) with binding activity to α1-3 fucose was higher in organoids with KRAS mutants than those with KRAS wild-type. FUT6 (α1-3fucosyltransferase 6) and FUT3 (α1-3/4 fucosyltransferase 3) expression was also higher in KRAS mutants than wild-type. Meanwhile, mannose-binding lectin (rRSL [Ralstonia solanacearum] and rBC2LA [Burkholderia cenocepacia]) signals were higher while those of galactose-binding lectins (rGal3C and rCGL2) were lower in the KRAS mutants. We demonstrated here that PDAC 3D-cultured organoids with KRAS mutations were dominantly covered in increased fucosylated glycans, pointing towards novel treatment targets and/or tumor markers.

Patient characteristics correlate with diagnostic performance of photodynamic diagnostic assisted transurethral resection of bladder tumors: A retrospective, single-center study.

BACKGROUND: Identification of patient subclasses that correlate with the diagnostic performance of photodynamic diagnostic (PDD)-assisted transurethral resection of bladder tumors (TURBT) may improve outcomes. METHODS: Data were extracted from patients that underwent PDD-assisted TURBT at the University of Tsukuba Hospital between 2018 and 2023. Sensitivity and specificity were evaluated based on PDD findings (excluding WL findings) and pathology results. Cluster analysis using uniform manifold approximation and projection and k-means methods was performed, focusing on patients with malignant lesions. RESULTS: A total of 267 patients and 2082 specimens were extracted. Sensitivity was lowest with regard to BCG treatment (53.7 %), followed by flat lesions (57.2 %), urine cytology class ≥ III (62.9 %), and recurrent tumors (64.5 %). In the cluster analysis of 231 patients with malignant lesions, two showed lower sensitivity: Cluster 3 (62.4 %), consisting of patients with recurrent tumors and post-BCG treatment, and Cluster 4 (55.7 %), consisting of patients with primary tumors and urine cytology class ≥ III. Clusters 1 and 2, consisting of patients without BCG treatment and patients with lower urine cytology classes, exhibited higher sensitivities (94.4 % and 87.7 %). Among all clusters, Cluster 4 had the highest proportion of specimens which were negative for both PDD and white light (WL) findings but actually had malignant lesions (20.8 %). CONCLUSIONS: PDD-assisted TURBT sensitivity was lower in subclasses after BCG treatment or with cytology class III or higher. Random biopsy for PDD/WL double-negative lesions may improve diagnostic accuracy in these subclasses.

Hypoxia at 3D organoid establishment selects essential subclones within heterogenous pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is especially hypoxic and composed of heterogeneous cell populations containing hypoxia-adapted cells. Hypoxia as a microenvironment of PDAC is known to cause epithelial-mesenchymal transition (EMT) and resistance to therapy. Therefore, cells adapted to hypoxia possess malignant traits that should be targeted for therapy. However, current 3D organoid culture systems are usually cultured under normoxia, losing hypoxia-adapted cells due to selectivity bias at the time of organoid establishment. To overcome any potential selection bias, we focused on oxygen concentration during the establishment of 3D organoids. We subjected identical PDAC surgical samples to normoxia (O2 20%) or hypoxia (O2 1%), yielding glandular and solid organoid morphology, respectively. Pancreatic cancer organoids established under hypoxia displayed higher expression of EMT-related proteins, a Moffitt basal-like subtype transcriptome, and higher 5-FU resistance in contrast to organoids established under normoxia. We suggest that hypoxia during organoid establishment efficiently selects for hypoxia-adapted cells possibly responsible for PDAC malignant traits, facilitating a fundamental source for elucidating and developing new treatment strategies against PDAC.

Adult genitourinary sarcoma: analysis using hospital-based cancer registry data in Japan.

BACKGROUND: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. RESULTS: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.

Retroperitoneal sarcoma: a 10-year follow-up analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: We sought clinical characteristics, survival outcomes, and prognostic factors for overall survival of retroperitoneal sarcoma in Japan. METHODS: A Japanese hospital-based cancer registry database with a pivotal 10-year follow-up was used to identify and enroll patients, registered from 106 institutions, diagnosed with retroperitoneal sarcoma in 2008-2009. Treating hospitals were divided by hospital care volume; high-volume hospitals and low-volume hospitals were defined as ≥ 4 and < 4 cases/year, respectively. RESULTS: A total of 91 men and 97 women were included, with a median age of 64 years. The most common histological type was liposarcoma in 101 patients, followed by leiomyosarcoma in 38 patients. The 5-year and 10-year overall survival rates were 44.1 and 28.3%. The majority of patients (n = 152, 80.9%) were treated at low-volume hospitals. High-volume hospital patients had higher 10-year overall survival rates than low-volume hospital patients (51.2% vs 23.2%, P = 0.026). Multivariate analysis revealed age over 60 years, treatment in low-volume hospitals and chemotherapy were independent predictors of unfavorable survival while treatment with surgery was an independent predictor of favorable survival. CONCLUSIONS: The possibility of surgical removal was suggested to be the most important prognostic factor for retroperitoneal sarcoma. Better survival was shown in patients treated at high-volume hospitals in our series.

Twisting of HeartMate II outflow graft 2.5 years after implantation-HM2 is still ongoing.

A 47-year-old woman with dilated cardiomyopathy underwent HeartMate II (HM2) implantation as a bridge-to-transplantation. Her postoperative course was good. However, 2.5 years after surgery, the outflow graft was found to be twisted and the graft and pump was exchanged. While HeartMate 3(HM3) twisting of the outflow graft is well documented, such malfunctions in HM2 are almost unknown. Although HM2 has since been discontinued, there are a significant number of patients using HM2 who are awaiting heart transplants or destination therapy. We caution that, even with HM2, the possibility of late-phase twisting requires vigilance.

Natto consumption suppresses atherosclerotic plaque progression in LDL receptor-deficient mice transplanted with iRFP-expressing hematopoietic cells.

Natto, known for its high vitamin K content, has been demonstrated to suppress atherosclerosis in large-scale clinical trials through a yet-unknown mechanism. In this study, we used a previously reported mouse model, transplanting the bone marrow of mice expressing infra-red fluorescent protein (iRFP) into LDLR-deficient mice, allowing unique and non-invasive observation of foam cells expressing iRFP in atherosclerotic lesions. Using 3 natto strains, we meticulously examined the effects of varying vitamin K levels on atherosclerosis in these mice. Notably, high vitamin K natto significantly reduced aortic staining and iRFP fluorescence, indicative of decreased atherosclerosis. Furthermore, mice administered natto showed changes in gut microbiota, including an increase in natto bacteria within the cecum, and a significant reduction in serum CCL2 expression. In experiments with LPS-stimulated macrophages, adding natto decreased CCL2 expression and increased anti-inflammatory cytokine IL-10 expression. This suggests that natto inhibits atherosclerosis through suppression of intestinal inflammation and reduced CCL2 expression in macrophages.

Effect of cardiopulmonary bypass on coagulation factors II, VII and X in a primate model: an exploratory pilot study.

OBJECTIVES: The use of cardiopulmonary bypass (CPB) in cardiac surgery is a major risk factor for postoperative bleeding. We hypothesized that consumptive coagulopathy and haemodilution influence the coagulation factors; therefore, we aimed to estimate the activity profiles of coagulation factors II, VII and X during CPB circulation. METHODS: A 120-min bypass was surgically established in cynomolgus monkeys (n = 7). Activities of coagulation factors II, VII and X were measured at 6 time points during the experiment (baseline, 0, 30, 60, 120 min of bypass and 60 min after bypass). To assess the influence of consumptive coagulopathy, the values were adjusted for haemodilution using the haematocrit values. Data were expressed as mean (standard deviation). RESULTS: Activities of coagulation factors decreased during the experiment. In particular, the activities for II, VII and X were decreased the most by 44.2% (5.0), 61.4% (4.3) and 49.0% (3.7) at 30 min following CPB initiation (P < 0.001, P < 0.001 and P < 0.001, respectively). Following adjustments for haemodilution, change magnitudes lessened but remained significant for factor VII. The adjusted concentration of factor VII was observed to decrease from the baseline to the initiation of bypass circulation. CONCLUSIONS: In conclusion, coagulation factor II, VII and X concentrations decreased during CPB. Following adjustment for haemodilution, a decrease in concentration was observed with factor VII.

Diurnal differences in urine flow in healthy young men in a light-controlled environment: a randomized crossover design.

BACKGROUND: Older men often experience nocturnal urination difficulties, reflected by diurnal differences in maximum urine flow (Qmax). Since lower urinary tract symptoms and pathological comorbidities are frequent in older men, it remains unclear whether this diurnal variation is a physiological or pathological phenomenon. Our aim was to quantify the diurnal variability of Qmax in healthy young participants under varying daylight conditions in a stable environment to discern potential underlying causes of nocturnal urination difficulties. METHODS: Twenty-one healthy young men were recruited in a 4-day study utilizing daytime (08:00-18:00) exposure with two light conditions in randomized order: dim (< 50 lx) or bright (~2500 lx). Day 1 was for acclimation, and urine flow was assessed from day 2. The participants urinated ad libitum during day 2 and then at fixed 3-4-h intervals thereafter (days 3-4). Regular urination Qmax at late night (04:00) on day 4 was compared with the nearest voided volume during daytime of day 3 (mDay). RESULTS: Morning Qmax scores (after bed-11:00) on day 2 were significantly lower than evening (17:00-before pre-sleep) in bright conditions and those of daytime (11:00-17:00), evening (17:00-before pre-sleep), and pre-sleep in dim conditions. Pre-sleep Qmax during the ad libitum period was significantly higher in dim than bright conditions. Late-night Qmax values (04:00) on day 4 were significantly lower than Qmax scores of mDay on day 3 in both light conditions. CONCLUSIONS: Healthy young men had a clear diurnal Qmax difference that decreased during late night and morning. In addition, the pre-sleep Qmax values in dim daylight were significantly higher than in bright daylight. Taken together, we conclude that late-night and morning decreases in Qmax are an instinctive physiological phenomenon in humans, and the diurnal difference of Qmax can be influenced by daylight conditions.

Safety and Feasibility Study of the Medical Care Pit Walking Support System for Rehabilitation of Acute Stroke Patients.

Stroke rehabilitation with mechanical assistance improves outcomes by facilitating repetition and relieving the care burden of therapy staff. Here, we tested the Medical Care Pit (MCP) walking assistance training device in the rehabilitation of eight acute stroke patients (median age 60.7 ± 16.3 years) who had recently suffered ischemic (three) or hemorrhagic (five) stroke (14.1 ± 6.5 days). Patients received standard rehabilitation approximately 5 days per week (weekdays only), plus MCP therapy twice a week, totaling four MCP sessions over 2 weeks. Fugl-Meyer Assessment-Lower Extremities (FMA-LE), Functional Ambulation Category (FAC), and other gait-associated parameters were measured. Over the 10.5 ± 1.6 days of therapy, MCP qualitatively assisted in gait analysis and real-time patient feedback while independent walking scores significantly improved (FAC 2.2 ± 0.8 to 3.1 ± 1.3, p = 0.020). FMA-LE scores also slightly improved but not to significance (p = 0.106). Objective burden on patients, as measured by modified Borg scale, was significantly improved (2.7 ± 1.6 to 2.0 ± 1.6, p = 0.014). In terms of questionnaires, anxiety scores for the physical therapist regarding gait training and falling with MCP significantly decreased (3.8 ± 2.3 to 1.0 ± 1.6; p = 0.027 and 3.1 ± 2.2 to 0.8 ± 1.3; p = 0.045) from the first to fourth sessions. Taken together, MCP, in addition to the usual rehabilitation program, was effective in gait rehabilitation for independent walking and relieved burdens on the patients. Such walking support systems may be an important part of acute stroke rehabilitation.

Variant allele frequency changes in TP53 predict pembrolizumab response in patients with metastatic urothelial carcinoma.

Prognoses for patients with metastatic urothelial carcinoma (mUC) have improved with pembrolizumab treatment, an immune checkpoint inhibitor, but clinical benefits are limited to a subset of patients. Therefore, a non-invasive biomarker to predict pembrolizumab response is required. The present study retrospectively examined genomic alterations in 25 plasma circulating tumor DNA (ctDNA) samples using targeted sequencing of 77 genes from 16 patients with mUC during pembrolizumab treatment. A total of 11 (68.8%) patients demonstrated ≥2 genomic alterations, including TP53 mutations (as defined by ctDNA-positive status). The proportion of responders to pembrolizumab in the ctDNA-positive group was higher compared with that in the ctDNA-negative group (72.7 vs. 20.0%). Furthermore, among all detected genomic alterations, variant allele frequency decreases in TP53 during pembrolizumab treatment were mainly associated with therapeutic response. Collectively, these data suggest that profiling of ctDNA in plasma, particularly TP53, may be useful for predicting and monitoring therapeutic responses to pembrolizumab in patients with mUC.

Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .