CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry.

An emerging group of spindle cell neoplasms harboring fusions involving NTRK or non-NTRK kinase genes often share characteristic S100 and/or CD34 expression; however, the diagnostic utility of immunohistochemical stains is not well established in this family owing to their lack of specificity. Recently, CD30 expression in spindle cell neoplasms with kinase gene fusions, such as NTRK, BRAF, RAF1, and RET, has been increasingly identified. We herein report a 10-year-old girl with high-grade spindle cell sarcoma of the neck. Prior to histopathological evaluation, flow cytometry (FCM) analysis and touch smear cytology of the tumor tissue revealed CD34+ and dimCD30+ spindle cell populations. Histopathologically, the case was characterized by monomorphic spindle-shaped cytomorphology with CD30, S100, and CD34 positivity and harbored close similarities with spindle cell neoplasms with NTRK or non-NTRK gene fusions. Subsequently, a comprehensive next-generation sequencing sarcoma panel identified a rare PLEKHH2::ALK fusion, and a diagnosis of ALK-rearranged spindle cell neoplasm was made. The patient showed significant tumor response to single-agent treatment with alectinib, an ALK-tyrosine kinase inhibitor. This case supports that CD30 is expressed in an ALK-rearranged mesenchymal neoplasm. The benefit of the early detection of CD30 expression by FCM for a prompt diagnosis and treatment is highlighted in the context of an aggressive clinical course. This case represents a learning experience regarding the need to the check the status of CD30 expression in these tumors and suggests the potential clinical benefits of CD30-targeted therapy.

Prognostic Impact of Stromal Profiles Educated by Gastric Cancer.

BACKGROUND: Cancer-associated fibroblasts exhibit diversity and have several subtypes. The underlying relationship between the diversity of cancer-associated fibroblasts and their effect on gastric cancer progression remains unclear. In this study, mesenchymal stem cells were differentiated into cancer-associated fibroblasts with gastric cancer cell lines; clinical specimens were used to further investigate the impact of cancer-associated fibroblast diversity on cancer progression. METHODS: Nine gastric cancer cell lines (NUGC3, NUGC4, MKN7, MKN45, MKN74, FU97, OCUM1, NCI-N87, and KATOIII) were used to induce mesenchymal stem cell differentiation into cancer-associated fibroblasts. The cancer-associated fibroblasts were classified based on ACTA2 and PDPN expression. Cell function analysis was used to examine the impact of cancer-associated fibroblast subtypes on cancer cell phenotype. Tissue samples from 97gastric patients who underwent gastrectomy were used to examine the clinical significance of each subtype classified according to cancer-associated fibroblast expression. RESULTS: Co-culture of mesenchymal stem cells with nine gastric cancer cell lines revealed different subtypes of ACTA2 and PDPN expression in differentiated cancer-associated fibroblasts. Cancer-associated fibroblast subtypes with high ACTA2 plus PDPN expression levels significantly increased gastric cancer cell migration, invasion, and proliferation. The cancer-associated fibroblast subtype with ACTA2 plus PDPN expression was an independent prognostic factor along with lymph node metastasis for patients who had gastric cancer and were undergoing surgery. CONCLUSIONS: Cancer-associated fibroblasts are educated by gastric cancer cells during the development of cancer-associated fibroblast diversity. Differentiated cancer-associated fibroblasts with distinct expression patterns could affect gastric cancer progression and enable prognostic stratification for gastric cancer.

Performance of ChatGPT and Bard in self-assessment questions for nephrology board renewal.

BACKGROUND: Large language models (LLMs) have impacted advances in artificial intelligence. While LLMs have demonstrated high performance in general medical examinations, their performance in specialized areas such as nephrology is unclear. This study aimed to evaluate ChatGPT and Bard in their potential nephrology applications. METHODS: Ninety-nine questions from the Self-Assessment Questions for Nephrology Board Renewal from 2018 to 2022 were presented to two versions of ChatGPT (GPT-3.5 and GPT-4) and Bard. We calculated the correct answer rates for the five years, each year, and question categories and checked whether they exceeded the pass criterion. The correct answer rates were compared with those of the nephrology residents. RESULTS: The overall correct answer rates for GPT-3.5, GPT-4, and Bard were 31.3% (31/99), 54.5% (54/99), and 32.3% (32/99), respectively, thus GPT-4 significantly outperformed GPT-3.5 (p < 0.01) and Bard (p < 0.01). GPT-4 passed in three years, barely meeting the minimum threshold in two. GPT-4 demonstrated significantly higher performance in problem-solving, clinical, and non-image questions than GPT-3.5 and Bard. GPT-4's performance was between third- and fourth-year nephrology residents. CONCLUSIONS: GPT-4 outperformed GPT-3.5 and Bard and met the Nephrology Board renewal standards in specific years, albeit marginally. These results highlight LLMs' potential and limitations in nephrology. As LLMs advance, nephrologists should understand their performance for future applications.

Protocol for the nationwide registry of patients with polycystic kidney disease: japanese national registry of PKD (JRP).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP). METHODS: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). RESULTS: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. CONCLUSIONS: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice.

Clinical significance of postoperative complications after pancreatic surgery in time-to-complication and length of postoperative hospital stay: a retrospective study.

PURPOSE: We retrospectively analyzed pancreatectomy patients and examined the occurrence rate and timing of postoperative complications (time-to-complication; TTC) and their impact on the length of postoperative hospital stay (POHS) to clarify their characteristics, provide appropriate postoperative management, and improve short-term outcomes in the future. METHODS: A total of 227 patients, composed of 118 pancreaticoduodenectomy (PD) and 109 distal pancreatectomy (DP) cases, were analyzed. We examined the frequency of occurrence, TTC, and POHS of each type of postoperative complication, and these were analyzed for each surgical procedure. Complications of the Clavien-Dindo (CD) classification Grade II or higher were considered clinically significant. RESULTS: Clinically significant complications were observed in 70.3% and 36.7% of the patients with PD and DP, respectively. Complications occurred at a median of 10 days in patients with PD and 6 days in patients with DP. Postoperative pancreatic fistula (POPF) occurred approximately 7 days postoperatively in both groups. For the POHS, in cases without significant postoperative complications (CD ≤ I), it was approximately 22 days for PD and 11 days for DP. In contrast, when any complications occurred, POHS increased to 30 days for PD and 19 days for DP (each with additional 8 days), respectively. In particular, POPF prolonged the hospital stay by approximately 11 days for both procedures. CONCLUSION: Each postoperative complication after pancreatectomy has its own characteristics in terms of the frequency of occurrence, TTC, and impact on POHS. A correct understanding of these factors will enable timely therapeutic intervention and improve short-term outcomes after pancreatectomy.

Dynamics of perioperative pancreatic exocrine function in patients undergoing reconstruction after gastrectomy for gastric cancer.

BACKGROUND: Each method of reconstruction after gastrectomy results in a change in the digestive and absorptive status. However, there are few reports on the changes in pancreatic exocrine function after gastrectomy. We conducted this study to investigate the dynamics of pancreatic exocrine function after gastrectomy according to the method of reconstruction performed. METHODS: The subjects of this study were 45 patients who underwent pancreatic exocrine function tests preoperatively and postoperatively, from among all patients who underwent gastrectomy for gastric cancer at our hospital between September, 2020 and March, 2022. We assessed pancreatic exocrine function using the Pancreatic Function Diagnostant (PFD) test. RESULT: The mean preoperative PFD test result values for the distal gastrectomy (DG) Billroth I reconstruction (B-I) group and the DG Roux-en-Y reconstruction (R-Y) group were 62.6 and 67.3 (p = 0.36), respectively, and the mean postoperative PFD test result values for each group were 65.8 and 46.9 (p = 0.0094), respectively. A significant decrease in postoperative pancreatic function was observed in the DG R-Y group but not in the DG B-I group. The logistic regression analysis identified that age and the R-Y group were significantly correlated with a 10% decrease in the PFD value after gastrectomy. CONCLUSIONS: Our study suggests that R-Y reconstruction may result in more impaired pancreatic exocrine function than B-I reconstruction.

Differences in glycemic trends due to reconstruction methods after proximal gastrectomy from the perspective of continuous glucose-monitoring.

PURPOSE: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer. METHODS: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks. RESULTS: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively). CONCLUSION: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer.

Changes in and clinical utility of maximum phonation time and repetitive saliva swallowing test scores after esophagectomy.

BACKGROUND: Postoperative pneumonia in patients with esophageal cancer occurs due to swallowing dysfunction and aspiration. Recently, maximum phonation time (MPT) assessment and repetitive saliva swallowing test (RSST) have been focused on as swallowing function assessment methods that can identify patients as high risk for pneumonia. We aimed to evaluate the clinical utility of MPT assessment and RSST in patients undergoing oncological esophagectomy. METHODS: In total, 47 consecutive patients who underwent esophagectomy for esophageal cancer between August 2020 and July 2023 were eligible. The perioperative changes in MPTs and RSST scores were examined. In addition, univariate and multivariate analyses were performed to identify the predictive factors of postoperative pneumonia. RESULTS: The median MPTs before surgery and on postoperative days (PODs) 3, 6, and 10 were 18.4, 7.2, 10.6, and 12.4 s, respectively; postoperative MPTs were significantly lower than preoperative MPT. In addition, the MPT of POD 6 was significantly longer than that of POD 3 (P < 0.05). Meanwhile, there were no significant changes in perioperative RSST scores. Overall, 8 of 47 patients (17.0%) developed pneumonia postoperatively. A short MPT on POD 6 was one of the independent predictive factors for the incidence of postoperative pneumonia (odds ratio: 12.6, 95% confidence interval: 1.29-123, P = 0.03) in the multivariate analysis. CONCLUSIONS: The MPT significantly decreased after esophagectomy. However, the RSST score did not. The MPT on POD6 can be a predictor of postoperative pneumonia.

New Diagnostic Modality Combining Mass Spectrometry and Machine Learning for the Discrimination of Malignant Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: An intraductal papillary mucinous neoplasm (IPMN) is a pancreatic tumor with malignant potential. Although we anticipate a sensitive method to diagnose the malignant conversion of IPMN, an effective strategy has not yet been established. The combination of probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning provides a promising solution for this purpose. METHODS: We prospectively analyzed 42 serum samples obtained from IPMN patients who underwent pancreatic resection between 2020 and 2021. Based on the postoperative pathological diagnosis, patients were classified into two groups: IPMN-low grade dysplasia (n = 17) and advanced-IPMN (n = 25). Serum samples were analyzed by PESI-MS, and the obtained mass spectral data were converted into continuous variables. These variables were used to discriminate advanced-IPMN from IPMN-low grade dysplasia by partial least square regression or support vector machine analysis. The areas under receiver operating characteristics curves were obtained to visualize the difference between the two groups. RESULTS: Partial least square regression successfully discriminated the two disease classes. From another standpoint, we selected 130 parameters from the entire dataset by PESI-MS, which were fed into the support vector machine. The diagnostic accuracy was 88.1%, and the area under the receiver operating characteristics curve was 0.924 by this method. Approximately 10 min were required to perform each method. CONCLUSION: PESI-MS combined with machine learning is an easy-to-use tool with the advantage of rapid on-site analysis. Here, we show the great potential of our system to diagnose the malignant conversion of IPMN, which would be a promising diagnostic tool in clinical settings.

Prognostic factors of IgA nephropathy presenting with mild proteinuria at the time of diagnosis (a multicenter cohort study).

BACKGROUND: Clinical factors affecting renal prognosis in patients with immunoglobulin A nephropathy (IgAN) and low urinary protein excretion (U-Prot) remain unclear. This study evaluated such factors in patients with clinical grade I (CG-I) IgAN with U-Prot < 0.5 g/day. METHODS: This secondary analysis of a previous retrospective study included 394 patients with CG-I IgAN. The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine levels from baseline. Factors related to renal prognosis were examined using univariate and multivariate Cox regression analyses. CG-I was divided into C-Grade Ia (CG-Ia) (n = 330) with baseline eGFR ≥ 60 ml/min/1.73 m2, and C-Grade Ib (CG-Ib) (n = 64) with baseline eGFR < 60 ml/min/1.73 m2. Outcome incidence was compared between conservative and aggressive therapy (corticosteroids and/or tonsillectomy) groups. RESULTS: Overall outcome incidence was significantly higher in CG-Ib than in CG-Ia; the cumulative incidence was significantly higher in CG-Ib (hazard ratio, 9.67; 95% confidence interval, 2.90-32.23). Older age, higher IgA levels, eGFR < 60 mL/min/1.73 m2, lower eGFR at baseline were independent prognostic factors for CG-I. Older age, lower eGFR, higher IgA levels at baseline, and U-Prot remission at 1-year post-diagnosis were independent prognostic factors for CG-Ib. Aggressive therapy tended to suppress the cumulative outcome incidence compared with conservative therapy in CG-Ib (p = 0.087). CONCLUSION: An eGFR < 60 mL/min/1.73 m2 is a significant predictor of renal prognosis in patients with IgAN and U-Prot < 0.5 g/day.

Public support for patients with intractable diseases in Japan: impact on clinical indicators from nationwide registries in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD. METHODS: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020. RESULTS: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001). CONCLUSIONS: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment.

Analysis of surgical outcomes and risk factors for anastomotic leakage following trans-hiatal resection of esophagogastric junction cancer.

BACKGROUND: The trans-hiatal lower esophagectomy is considered less invasive than the trans-thoracic esophagectomy for resection of esophagogastric junction (EGJ) cancer. However, the optimal procedure remains controversial and should be determined while considering both oncological and safety aspects. METHODS: This retrospective study comprised 124 patients that underwent curative resection for EGJ cancer. The study analysis included 93 patients with tumor centers located within 2 cm of the EGJ. Clinicopathological findings and surgical outcomes were compared between patients treated using trans-hiatal and trans-thoracic approaches. RESULTS: Sixty-three patients underwent lower esophagectomy using the trans-hiatal approach (TH-G). The remaining 30 patients underwent esophagectomy using the trans-thoracic approach (TT-E). The TH-G group were older, had a lower prevalence of lymphatic spread, shorter length of esophageal invasion, and shorter operative duration compared to the TT-E group. Although no significant differences in the frequency of postoperative complications, a higher proportion of patients in the TH-G group developed anastomotic leakage (16% vs. 7%, p = 0.33). Univariate and multivariate analyses demonstrated that cardiac comorbidity was an independent risk factor for anastomotic leakage (odds ratio, 5.24; 95% CI, 1.06-25.9; P < 0.05) in TH-G group. Further examination revealed that preoperative cardiothoracic ratio (CTR) with 50% or greater could be surrogate marker as risk factor for anastomotic leakage in TH-G group (35% vs. 7.5%, p < 0.05). CONCLUSIONS: The trans-hiatal approach can be used for resection of EGJ cancer. However, special attention should be paid to the prevention of anastomotic leakage in patients with cardiac comorbidities or a large preoperative CTR.

The inter-prefectural regional disparity of healthcare resources and representative surgical procedures in orthopaedics and general surgery: a nationwide study in Japan during 2015-2019.

BACKGROUND: Few reports have examined the localized regional disparity in representative surgical procedures in orthopaedics and general surgery globally. This study aimed to clarify the inter-prefectural regional disparity and relationships between healthcare resources and representative surgical procedures using a nationwide database in Japan. METHODS: The number of medical specialists in orthopaedics, general surgery, and anaesthesiology, as well as the number of hospitals, and the incidence of representative surgical procedures in orthopaedics and general surgery were evaluated annually per 100,000 inhabitants/people by prefecture in Japan during 2015-2019. Medium-sized regional disparities were evaluated using the Gini coefficient. Correlation coefficients were calculated for the defined variables and ageing rate. We also compared the urban and rural regional disparities in all study variables. RESULTS: The annual average number/incidence and Gini coefficients were 110.6 and 0.11 for femur fracture surgery, 106.3 and 0.09 for cholecystectomy, 14.2 and 0.11 for orthopaedic surgeon specialists, 17.6 and 0.09 for general surgeon specialists, 5.9 and 0.13 for anaesthesiology specialists, and 8.1 and 0.21 for hospitals, respectively. The correlation coefficients by the incidence of femur fracture surgery were 0.74 for orthopaedic surgeon specialists (p < 0.001), 0.63 for hospitals (p < 0.001), and 0.62 for the ageing rate (p < 0.001); those by the incidence of cholecystectomy were 0.60 for general surgeon specialists (p < 0.001) and 0.59 for hospitals (p < 0.001). The number/incidence of orthopaedic surgeon specialists, hospitals, femur fracture surgery, and cholecystectomy, as well as the ageing rate, were significantly higher in rural prefectures than in urban prefectures (p < 0.05). CONCLUSIONS: Inter-prefectural regional disparity was small, although certain items were unevenly distributed in the rural prefectures, which is contrary to our expectations. Higher prevalence was recognised in rural prefectures due to the higher ageing rate; however, supply and demand are balanced. This study provides basic data for healthcare policy development in a medium-sized community. LEVEL OF EVIDENCE: III.

[A Case of Delayed-Onset Acute Interstitial Nephritis following Nivolumab Treatment in a Patient with Advanced Esophagogastric Junction Cancer].

An 81-year-old man with advanced esophagogastric junction cancer with paraaortic lymph node metastasis was treated with S-1 plus oxaliplatin and nivolumab combination chemotherapy. Subsequently, conversion surgery was performed, and the patient was discharged without postoperative complications. Two months after discharge, the patient developed fever, fatigue, and anorexia. Intravenous antibiotic therapy was started; however, the symptoms did not improve. Urine biochemical tests revealed significantly elevated N-acetyl-ß-D-glucosaminidase and ß-microglobulin levels, and acute interstitial nephritis was suspected. Steroid therapy was initiated, and the patient's symptoms improved. A renal biopsy performed at the same time the nivolumab treatment was initiated led to the diagnosis of immune-related interstitial nephritis, a probable adverse event of the treatment. Although immune-related adverse events associated with immune checkpoint inhibitors are typically colitis, interstitial pneumonia, and endocrine disturbances, we observed severe interstitial nephritis in the patient. Clinicians should also consider the possible occurrence of immune-related adverse events >2 months after administering treatment.

[A case of primary peritoneal cancer diagnosed with a duodenal stricture].

A 69-year-old female patient visited the previous hospital with anorexia and vomiting. She had weight loss and emaciation and was admitted to the hospital with a duodenal stenosis diagnosis due to superior mesenteric artery syndrome by computed tomography (CT). Conservative treatment with nutritional therapy was performed, but with no improvement;thus, the patient was referred to our hospital. We re-examined the patient to determine the cause of her disease. CT and magnetic resonance imaging findings revealed peritoneal thickening of the pelvic floor, suggesting malignant disease such as peritoneal dissemination. Therefore, we performed diagnostic laparoscopy and harvested peritoneal tissue. She was diagnosed with primary peritoneal carcinoma by histopathological examination and immunohistochemical staining techniques. Thereafter, she underwent chemotherapy for primary peritoneal cancer at the gynecology department of our hospital but died of the primary disease. Primary peritoneal cancer is frequently diagnosed by abdominal distention and abdominal pain due to ascites accumulation. We report this case because of the rarity of primary peritoneal cancer triggered by duodenal stricture.

Comorbid insomnia among breast cancer survivors and its prediction using machine learning: a nationwide study in Japan.

OBJECTIVE: Insomnia is an increasingly recognized major symptom of breast cancer which can seriously disrupt the quality of life during and many years after treatment. Sleep problems have also been linked with survival in women with breast cancer. The aims of this study were to estimate the prevalence of insomnia in breast cancers survivors, clarify the clinical characteristics of their sleep difficulties and use machine learning techniques to explore clinical insights. METHODS: Our analysis of data, obtained in a nationwide questionnaire survey of breast cancer survivors in Japan, revealed a prevalence of suspected insomnia of 37.5%. With the clinical data obtained, we then used machine learning algorithms to develop a classifier that predicts comorbid insomnia. The performance of the prediction model was evaluated using 8-fold cross-validation. RESULTS: When using optimal hyperparameters, the L2 penalized logistic regression model and the XGBoost model provided predictive accuracy of 71.5 and 70.6% for the presence of suspected insomnia, with areas under the curve of 0.76 and 0.75, respectively. Population segments with high risk of insomnia were also extracted using the RuleFit algorithm. We found that cancer-related fatigue is a predictor of insomnia in breast cancer survivors. CONCLUSIONS: The high prevalence of sleep problems and its link with mortality warrants routine screening. Our novel predictive model using a machine learning approach offers clinically important insights for the early detection of comorbid insomnia and intervention in breast cancer survivors.

Endurance Exercise Training-Attenuated Diabetic Kidney Disease with Muscle Weakness in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: The aim of this study was to evaluate protective effects of endurance exercise training against diabetic kidney disease (DKD) with muscle weakness by using male spontaneously diabetic Torii (SDT) fatty rats as type 2 diabetic animal models with obesity, hypertension, and hyperlipidemia. METHODS: Eight-week-old SDT fatty rats (n = 12) and Sprague-Dawley (SD) rats (n = 10) were randomly divided into exercise (Ex; SDT-Ex: n = 6, SD-Ex: n = 5) and sedentary groups (SDT-Cont: n = 6, SD-Cont: n = 5), respectively. Each group underwent regular treadmill exercise 4 times a week from ages 8-16 weeks. RESULTS: The exercise attenuated hypertension and hyperlipidemia and prevented increases in renal parameter levels without affecting blood glucose levels. In the SDT fatty rats, it prevented induction of renal morphological abnormalities in the interstitium of the superficial and intermediate layers of the cortex. Downregulated expression of endothelial nitric oxide synthase in the glomerulus of the SDT fatty rats was significantly upregulated by the exercise. The exercise upregulated the renal expressions of both medium-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor γ coactivator-1α related to fatty acid metabolism. It increased muscle strength and both muscle weight and cross-sectional area of type IIb muscle fibers in the extensor digitorum longus muscle in the SDT fatty rats. CONCLUSION: Endurance exercise training in type 2 diabetes ameliorates DKD by improving endothelial abnormality and enhancing fatty acid metabolism in addition to attenuated hypertension, hyperlipidemia, and muscle weakness independently of blood glucose levels.

Efficacy and safety of regorafenib dose-escalation therapy for Japanese patients with refractory metastatic colorectal cancer (RECC study).

BACKGROUND: Regorafenib significantly improves overall survival in previously treated metastatic colorectal cancer patients. However, various toxicities, such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited the use of regorafenib. These toxicities appear soon after treatment initiation. The ReDOS study demonstrated the effectiveness of a weekly dose-escalation therapy of regorafenib starting with a lower daily dose; however, its usefulness in Asian subjects is unknown. We conducted a phase II study to evaluate the safety and survival benefit of regorafenib dose-escalation therapy for Japanese patients. METHODS: Patients with sufficient organ function, who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3, if no severe drug-related toxicities were observed. The primary endpoint was cancer progression-free survival (PFS). Tumor response and progression were assessed radiologically every 8 weeks. This study was registered in the University Hospital Medical Information Network (UMIN#UMIN000028933). RESULTS: 57 patients were enrolled and all started regorafenib at 80 mg/day. 32 patients (56.1%) were subsequently escalated to 120 mg/day and 19 (33.3%) to 160 mg/day. Only 8 patients (14.0%) discontinued treatment because of adverse events. Median PFS was 1.9 months. Median overall survival was 8.9 months, the response rate was 0%, and the disease control rate was 31.6%. The most frequent adverse event greater than grade 3 was hypertension (19.3%), followed by HFSR (14.0%). CONCLUSIONS: Regorafenib dose-escalation therapy is well tolerated with PFS-like regorafenib standard therapy.

Intended preoperative trans-arterial embolization for large hepatocellular carcinoma: a retrospective cohort study.

BACKGROUND: Generally, a large tumor size of hepatocellular carcinoma (HCC) is associated with poor visibility and uncertainty in the surgical field which results in increased surgical difficulty as well as unfavorable postoperative outcomes. We performed intended preoperative trans-arterial embolization (TAE) in patients with a large HCC. In this study, we investigated the oncological significance of intended preoperative TAE for a large HCC, using a comparison between patients with and without TAE, and detailed analyses for pre- and post-TAE status. METHODS: A total of 411 patients who underwent hepatectomy for primary HCC at the University of Yamanashi Hospital between January 2007 and December 2018 were included in this study. The patients were divided into two groups: patients with larger HCCs (≥50 mm, n=51) and those with smaller HCC (<50 mm, n=360) according to the size of their HCCs. Comparison of clinicopathological features between these groups and clinical outcomes between the TAE and non-TAE groups were compared. In addition, a detailed analysis of each case in the TAE group was conducted, comparing clinicopathological factors between pre- and post-TAE status. RESULTS: The clinical unfavorable short- and long-term outcomes of patients with large HCCs (≥50 mm) were revealed compared to those with small HCCs (<50 mm). The prognostic analyses showed that a large tumor size and increased tumor markers, multiple tumor numbers, and others were adverse prognostic factors, and vascular invasions and residual tumors were included in the multivariate analysis. Further detailed analyses revealed that the average rates of change in tumor size and tumor shrinkage after TAE were - 48.6±35.6 mm and - 30.7±17.0%, respectively. Pathological high necrotic changes in the tumor, after multiple-times TAE aiming to a better effect, were related to a better prognosis in patients with large HCC. Poor prognostic factors became less common in patients who underwent intended preoperative TAE, and these patients had better prognoses. CONCLUSIONS: The large tumor size of HCC is associated with unfavorable outcomes; the intended preoperative TAE for large HCC patients performed multiple times aiming to affect the tumor as much as possible might improve their prognoses.

Prognostic impact of lymph node micrometastasis in patients with gastric cancer.

PURPOSE: The clinical significance of lymph node micrometastasis (LNMM) remains controversial in gastric cancer (GC). In this study, we investigated the prognostic impact of LNMM in patients with GC. METHODS: A total of 624 patients with pathologically lymph node metastasis-negative (pN0) and N1 status (pN1) who underwent gastrectomy between 2004 and 2018 were enrolled in this retrospective study. The diameter of tumor cell clusters in metastatic lymph nodes was measured in 120 patients with pN1 GC. RESULTS: Patients with lymph node tumors < 1500 µm in diameter (LNMM) had a significantly better prognosis than those with tumors ≥ 1500 µm in diameter (p = 0.012; log-rank test). Cox's proportional hazards model revealed that LNMM (p = 0.016), several dissected lymph nodes (p = 0.049), and the provision of adjuvant chemotherapy (p = 0.002) were independent prognostic factors for the overall survival of patients with pN1 GC. There was no significant difference in the overall survival between patients with LNMM who received chemotherapy and those who did not (p = 0.332). CONCLUSIONS: LNMM is associated with a favorable prognosis and maybe an independent prognostic marker in patients with pN1 GC. LNMM in GC may be considered a factor preventing adjuvant chemotherapy.