Remarkable response to capmatinib in a patient with intrahepatic cholangiocarcinoma harboring TFG-MET fusion.

Dysregulation of mesenchymal-epithelial transition factor (MET) gene due to amplification, mutation, and fusion has been reported in various types of human cancers. Recently, the efficacy of small-molecule tyrosine kinase inhibitors (TKIs) targeting MET has been demonstrated in a wide range of MET-dysregulated tumors. The majority of biliary tract cancers including intrahepatic cholangiocarcinoma (iCCA) are diagnosed at an advanced stage, and the utility of conventional chemotherapy is limited. Here, we present a case of metastatic iCCA harboring TFG-MET gene fusion, which demonstrated a remarkable response to treatment with capmatinib, a selective MET inhibitor. The patient was a 46-year-old man diagnosed with iCCA with hepatic, intraabdominal lymph nodes, and peritoneal metastases. Comprehensive genomic profiling (CGP) revealed TFG-MET gene fusion in his tumor. After becoming refractory to standard chemotherapy, he received capmatinib, which resulted in a marked shrinkage of the liver masses and lymph node metastases, as well as a drastic decrease in serum CA19-9 level. Our case reinforces the importance of CGP in exploring targeted therapy and supports the potential role of capmatinib in the treatment of tumors harboring MET fusions.

Protocol digest of a randomized phase III trial comparing S-1-based chemoradiotherapy with/without nivolumab for unresectable locally advanced or borderline resectable pancreatic cancer: JCOG1908E (PENETRATE).

Pancreatic cancer remains a highly lethal disease with a 5-year survival proportion of <10%. Chemoradiotherapy is a treatment option for unresectable locally advanced (UR-LA) or borderline resectable (BR) pancreatic cancer, but its efficacy is not sufficient. Induction of the synergistic effect of irradiation and immune checkpoint inhibitors can be an attractive strategy. An open-label randomized phase III trial has been conducted since October 2020 to confirm the superiority of nivolumab plus S-1-based chemoradiotherapy over S-1-based chemoradiotherapy alone in patients with UR-LA or BR pancreatic cancer. A total of 216 patients will be enrolled in 14 institutions within 3.5 years. The primary endpoint of the safety run-in part is dose-limiting toxicity, and that of the phase III part is overall survival. This trial was registered at the Japan Registry of Clinical Trials as jRCT2080225361 (https://jrct.niph.go.jp/latest-detail/jRCT2080225361).

Efficacy of highly bioavailable oral curcumin in asymptomatic or mild COVID-19 patients: a double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Even after the peak of the COVID-19 pandemic, the number of mild cases remains high, requiring continuous control. Curcumin, owing to its anti-inflammatory properties, can suppress vital proliferation and cytokine secretion in animal models. We developed a highly absorbable curcumin, curcuRouge® (cR), which is approximately 100 times more orally bioavailable than conventional curcumin. We evaluated the effect of cR on the inhibition of disease progression in asymptomatic or mildly symptomatic COVID-19 patients. METHODS: This study evaluated the effect of 7-day oral intake of cR (360 mg twice daily). Patients within 5 days of COVID-19 diagnosis were randomly assigned to a placebo or cR group in a double-blind manner. RESULTS: Primary endpoint events [body temperature (BT) ≥ 37.5 °C and saturation of percutaneous oxygen (SpO2) < 96%] were fewer than expected, and the rate of these events was 2.8% in the cR group (2/71) and 6.0% in the placebo group (4/67); hazard ratio (HR) = 0.532, 95% confidence interval (CI) 0.097-2.902. Patients receiving cR tended to take fewer antipyretic medications than those receiving placebo (HR = 0.716, 95% CI 0.374-1.372). Among patients with a normal range of BT at baseline, the BT change rate was significantly (p = 0.014) lower in the cR group (- 0.34%) versus placebo (- 0.01%). CONCLUSION: The relative suppression of event rates and antipyretic medications taken, and significant decrease of subclinical BT support the anti-inflammatory effects of cR in asymptomatic or mildly symptomatic patients with COVID-19. TRIAL REGISTRATION: Japan Registry of Clinical Trials (CRB5200002).

Colorectal cancer harboring EGFR kinase domain duplication response to EGFR tyrosine kinase inhibitors.

Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare, recurrent oncogenic variant that constitutively activates EGFR in non-small-cell lung cancer. Herein, we report the case of a 70-year-old man with resectable colorectal adenocarcinoma who underwent surgery followed by adjuvant therapy. He relapsed with multiple liver metastases and received standard chemotherapy until his disease became refractory. Comprehensive genomic profiling of his postoperative colorectal cancer tissue revealed EGFR-KDD. He was treated with an EGFR tyrosine kinase inhibitor (TKI), afatinib and achieved a partial response (- 55%) after 8 weeks; however, he developed massive malignant ascites after 13 weeks. Osimertinib, another EGFR-TKI, controlled his tumors for 9 months. Patient-derived cancer organoids from his malignant ascites confirmed sensitivity to EGFR-TKIs. The findings suggest that EGFR-TKIs can be a potential treatment option for this molecular subgroup.

[Current Status and Issues of Companion Diagnostics in Cancer Genomic Medicine].

As of December 2023, there are 5 types of cancer gene panel tests covered by public insurance in Japan. Four of them partly feature companion diagnostics. When cancer gene panel test is used for the purpose of comprehensive gene profiling (CGP), a total of 56,000 points(44,000 points for the test administration fee and 12,000 points for the expert panel fee) can be claimed, whereas if the cancer gene panel test is used for the purpose of companion diagnostics, hospitals can claim only the reimbursement as a companion diagnostics, which fee is much cheaper than that of CGP. Therefore, cancer gene panel tests are rarely used as a companion diagnosis in daily clinical practice. Even when the test is performed as a CGP test, since its indication is limited to patients who have completed or are expected to complete standard chemotherapy, most biomarkers associated with approved drugs are already evaluated with stand-alone companion diagnostics at the time of CGP test application. On the other hand, there are some approved drugs, such as pembrolizumab for TMB-H or entrectinib or larotrectinib for NTRK fusion gene, for which there is no stand-alone companion diagnostics and the eligibility for these drugs cannot be judged without the results of CGP test. This paper discusses the current status and issues of companion diagnostics in cancer genomic medicine.

Response to capmatinib in a patient with neuroendocrine carcinoma of the gallbladder origin harboring MET amplification.

Neuroendocrine carcinoma (NEC) of the gallbladder origin is particularly rare, accounting for only 0.38% of primary malignancies of the gallbladder, and standard therapies are limited. The MET gene encodes the tyrosine kinase receptor, c-Met. Pathogenic variants of MET, such as MET exon 14 skipping and MET amplification, result in excessive downstream signaling that promotes tumor progression. A MET inhibitor, capmatinib, blocks signaling of c-Met and has been approved by the Food and Drug Administration for non-small cell lung cancer with MET exon 14 skipping. The effectiveness of capmatinib has been reported in other cancers with MET amplification, but NEC with MET variants has not been reported. Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6 weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13 weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial.

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Cultural engagement and prevalence of pain in socially isolated older people: a longitudinal modified treatment policy approach.

Background: It remains uncertain whether cultural engagement positively influences the reduction of pain risk, particularly depending on the social isolation status. The aim of this study was to examine the impact of cultural engagement on the reduction of pain prevalence over a 6-year follow-up period among older people, particularly those experiencing different dimensions of social isolation. Methods: This study was a prospective longitudinal study. We analysed the English Longitudinal Study of Ageing cohort, consisting of 6468 community-dwelling adults aged ≥50 years old who provided data in waves 6 (2012-2013), 7 (2014-2015), 8 (2016-2017), and 9 (2018-2019). Self-reported cultural engagement (going to museums, art galleries, exhibitions, the theatre, concerts, or the opera) measured in waves 6-8 was used as the exposure variable. Meanwhile self-reported moderate-to-severe pain in wave 9 was used as the outcome variable. Social isolation was considered in waves 6-8, and the possibility of effect modification was captured by assessing each component of the social isolation index: not married or cohabiting with a partner, fewer than monthly contact with children/other immediate family/friends, and not engaging in any organisations, religious groups, or committees. Findings: The estimated pain prevalence was 29.2% (95% confidence interval, 28.1-30.3; reference) after adjusting for time-variant, time-invariant, and loss to follow-up factors. Cultural engagement led to a reduction in pain prevalence to 24.1% for all individuals, representing a decrease of 5.1% (95% confidence interval, 0.6-9.6; P-value, 0.03). In older people who were not married or cohabiting, cultural engagement resulted in a decrease in pain prevalence to 25.8%, a reduction of 3.4% (95% confidence interval, 0.4-6.4; P-value, 0.01). For those with less frequent contact with close family members, the pain prevalence decreased to 25.3%, a reduction of 3.9% (95% confidence interval, 0.2-7.6; P-value, 0.03). Meanwhile, other dimensions of social isolation did not show a significant reduction in pain prevalence. Interpretation: Cultural engagement may help to reduce the risk of pain in socially isolated older adults. Those who were single or living alone and had less frequent contact with immediate family were particularly vulnerable. While cultural engagement might help certain socially isolated older people feel better, its effectiveness varies, highlighting the need for targeted interventions. Funding: The Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number (22K17648, Ikeda).

A Learning Program for Treatment Recommendations by Molecular Tumor Boards and Artificial Intelligence.

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system. Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03). Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

Completion of adjuvant S-1 chemotherapy after surgical resection for biliary tract cancer: A single center experience.

BACKGROUNDS: A recent randomized control trial (JCOG1202; ASCOT trial) demonstrated the efficacy of adjuvant S-1 chemotherapy (ASC) for biliary tract cancer (BTC) after surgical resection; however, the significance of the completion of ASC in the real-world setting remains unknown. METHODS: Data of consecutive patients who underwent surgical resection for biliary tract cancer (BTC) from 2011 to 2021 were retrospectively reviewed. Of these, patients who underwent ASC were enrolled in this study. Patients were divided into two groups according to whether ASC was completed: the completion group and the non-completion group. Clinicopathological features and survival outcomes were assessed. RESULTS: Of the 223 patients with BTC who underwent surgical resection, 75 patients who underwent ASC were included for analysis. Among them, 48 (64.0 %) completed the intended ASC course, while 27 cases (36.0 %) discontinued the treatment. The most common reason for the discontinuation was adverse event (n = 16, 59.3 %), followed by disease recurrence (n = 9, 33.3 %). Patients in the completion group showed significantly better overall survival (OS) (p < 0.001) and recurrence-free survival (RFS) (p < 0.001) compared to the non-completion group. Further, after excluding the patients in the non-completion group who discontinued ASC due to disease recurrence, the significance of ASC completion was retained for both OS and RFS. CONCLUSION: The completion of ASC was associated with improved prognosis in patients with BTC after surgical resection. The achievement of ASC should be the goal after surgical resection, while further study may be warranted regarding the resistance of ASC.

The Association between fatigue and physical activity in patients hospitalized with subacute stroke.

BACKGROUND: Little is known about the association between fatigue and physical activity in patients hospitalized with subacute stroke. OBJECTIVES: The aim of this study was to investigate the association between fatigue and physical activity in patients hospitalized with subacute stroke. METHODS: This cross-sectional study enrolled 244 consecutive patients with stroke who were admitted to a subacute rehabilitation ward at our hospital. We assessed fatigue with the Fatigue Assessment Scale (FAS) and used an accelerometer (Active style Pro HJA750-C, OMRON) to record the mean duration of sedentary behavior, light-intensity physical activity (LIPA), and moderate-to-vigorous-intensity physical activity (MVPA). We assessed all factors at 1 month after stroke. Multivariate linear regression analysis revealed the associations between FASscore and objectively measured physical activity. RESULTS: In total, we analyzed 85 patients. The duration of the sedentary behavior was significantly associated with the FAS score (ß = 1.46, p = 0.037) and the Functional Balance Scale score (ß = -1.35, p = 0.045). The LIPA time was significantly associated only with the FBS score (ß = 1.38, p = 0.045), whereas MVPA was not associated with any variable.

Impact of tumor shrinkage pattern with biweekly triplet gemcitabine+cisplatin+S-1 regimen for biliary tract cancers: Implications for neoadjuvant therapy from the data of KHBO1401 (KHBO1401-1A study).

BACKGROUND: The multicenter randomized phase III KHBO1401 study (gemcitabine+cisplatin+S-1 [GCS] versus GC in biliary tract cancers [BTC]) demonstrated that GCS not only prolonged patient survival but also achieved a high response rate and that it should be good for neoadjuvant therapy. Therefore, to explore the possibilities of neoadjuvant therapy, we investigated the tumor shrinkage pattern. METHODS: Among the total of 246 patients enrolled in the KHBO1401, the tumor shrinkage pattern and survival were investigated in patients with measurable BTC (n=183, 74%; GCS, n=91; GC, n=92). RESULTS: The tumor shrinkage pattern could be divided to 4 categories based on the response at 100 days after enrollment: category A (<-30% in size), B (-30% to 0%), C (0% to +20%), and D (>+20%). The GCS arm included more category A and B cases (61 [67%] vs. 33 [36%], P<0.0001). Each category predicted best response and overall survival (P<0.0001). Category A showed sustained tumor response compared with category B; in GCS, the time to maximum tumor response was 165 ± 76 days in category A and 139 ± 78 in category B. Categories C and D did not achieve tumor shrinkage. The maximum tumor shrinkage size in category A was -53% in the GCS arm and -65% in the GC arm (P=0.0892). Twenty percent of patients in the GCS showed tumor regrowth 154 ± 143 days later. CONCLUSION: GCS provided faster and greater tumor shrinkage with better survival in comparison to GC, although 20% of patients showed re-growth after 6 cycles.

Identifying Clusters of Health Behaviors in a Japanese Working Population at Risk for Non-Communicable Diseases: A Latent Class Analysis of 12,168 Individuals.

Introduction: Noncommunicable diseases (NCDs) have become a significant global problem. Health behaviors are associated with NCDs, and characterizing populations using a public health approach can help provide specific interventions according to their characteristics. This study aims to examine the formation of clusters of health behavior combinations in the Japanese working population at risk of NCDs, taking into account the influences of age and gender, using latent class analysis. Methods: Participants were individuals at risk for NCDs but had not previously been diagnosed with any. Latent class analysis (LCA) was used to study clustering based on basic characteristics and health behaviors. All statistical analyses were conducted using R (Version 4.0.4) and the "poLCA" package (Version 1.6.0). Results: This study included 12,168 participants. LCA compared models with one to six latent classes. The five-class model was determined to be the most appropriate based on Bayesian Information Criterion, Akaike Information Criterion, and G^2 values, as well as distinguishable cluster characteristics. Cluster 1: "having healthy lifestyles but disliking hospitals"; Cluster 2: "women with healthy lifestyle behaviors"; Cluster 3: "general population"; Cluster 4: "middle-aged group in need of lifestyle improvement"; Cluster 5: "a group receiving treatment for lifestyle-related diseases." Conclusions: This study reveals discernible health behavior patterns in a sample of the Japanese population using large real-world data, suggesting the effectiveness of distinct approaches when considering a population approach to public health.

Impact of conversion surgery after chemotherapy in patients with initially unresectable and recurrent biliary tract cancer.

Purpose: Gemcitabine, cisplatin, and S-1 chemotherapy was superior to gemcitabine and cisplatin chemotherapy for progression-free survival and overall survival for unresectable and recurrent biliary tract cancer in a randomized phase III trial (KHBO1401). This study aimed to evaluate the outcome of conversion surgery after chemotherapy in biliary tract cancer patients (ancillary study, KHBO1401-3C). Methods: A total of 246 patients were enrolled in KHBO1401. We compared progression-free and overall survivals between the conversion surgery and non-conversion surgery groups. Results: Eight patients (3.3%) underwent conversion surgery with chemotherapy, seven of whom were diagnosed with unresectable disease and one with recurrence. Six and two patients received gemcitabine, cisplatin, and S-1 chemotherapy as well as gemcitabine and cisplatin chemotherapy, respectively. Three patients in the conversion surgery group who received gemcitabine, cisplatin, and S-1 chemotherapy showed no disease progression and survived without postoperative chemotherapy. Preoperative carbohydrate antigen 19-9 (CA19-9) level was a prognostic factor for conversion surgery. After correcting for immortal time bias, 1-year progression-free survival rates in the conversion surgery and non-conversion surgery groups were 50.0% and 19.0%, respectively (hazard ratio 0.343, 95% confidence interval 0.286-0.843, p = 0.0092). One-year overall survival rates in the conversion surgery and non-conversion surgery groups were 87.5% and 56.0%, respectively (hazard ratio 0.222, 95% confidence interval 0.226-0.877, p = 0.0197). Conclusions: Conversion surgery might be an option for the treatment of unresectable and recurrent biliary tract cancer in patients with normal preoperative CA19-9 level.

Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial).

PURPOSE: Mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) are positive predictive markers for immune checkpoint inhibitors. However, data on the activity of nivolumab in advanced dMMR/MSI-H rare cancers and more accurate biomarkers are worth exploring. PATIENTS AND METHODS: We conducted a multicenter phase II, open-label, single-arm clinical trial to explore the effectiveness and safety of nivolumab monotherapy in patients with advanced rare cancers with dMMR/MSI-H, in parallel with immune phenotype analysis, to explore new biomarkers. A Bayesian adaptive design was applied. Characterization of peripheral blood mononuclear cells (PBMC) was characterized by multicolor flow cytometric analysis and CyTOF using samples collected before and after the intervention. The dMMR was identified by the complete loss of MLH1/MSH2/MSH6/PMS2. RESULTS: From May 2018 to March 2021, 242 patients were screened, and 11 patients were enrolled, of whom 10 were included in the full analysis. Median follow-up was 24.7 months (interquartile range, 12.4-31.5). Objective response rate was 60% [95% confidence interval (CI), 26.2-87.8] by central assessment and 70% (95% CI, 34.8-93.3) by local investigators. Median progression-free survival was 10.1 months (95% CI, 0.9-11.1). No treatment-related adverse events of grade 3 or higher were observed. Patients with a tumor mutation burden of ≥10/Mb showed a 100% response rate (95% CI, 47.8-100). Responders had increased T-bet+ PD-1+ CD4+ T cells in PBMC compared with nonresponders (P < 0.05). CONCLUSIONS: The trial met its primary endpoint with nivolumab, demonstrating clinical benefit in advanced dMMR/MSI-H rare solid cancers. Besides, the proportion of T-bet+ PD-1+ CD4+ T-cells may serve as a novel predictive biomarker.

Determinants of Anaerobic Threshold at Each Stage of Renal Dysfunction in Patients With Heart Disease.

Patients with heart disease have a low anaerobic threshold (AT), and the determinants of AT may differ, depending on the severity of renal dysfunction. This study aimed to verify the determinants of AT for each stage of renal function in patients with heart disease. We consecutively enrolled 250 patients with heart disease who underwent cardiopulmonary exercise testing in our institution. The patients were divided into 3 groups by their estimated glomerular filtration rate (eGFR): <45, 45 to 59, and ≥60 ml/min/1.73 m2. A multivariate linear regression analysis was performed to evaluate the independent determinants of AT for each group. In total, 201 patients were analyzed. AT decreased with the deterioration of renal function (eGFR <45, 10.9 ± 2.1 vs eGFR 45 to 59, 12.4 ± 2.5 vs eGFR ≥60, 14.0 ± 2.6 ml/min/kg, p <0.001). In the eGFR <45 group, left ventricular ejection fraction and hemoglobin were significantly associated with AT (ß = 0.427, p = 0.006 and ß = 0.488, p = 0.002, respectively). In the eGFR 45 to 59 and ≥60 groups, ΔPETO2 (end-tidal oxygen partial pressure from rest to AT) showed a significant association with AT (ß = 0.576, p <0.001 and ß = 0.308, p = 0.003, respectively). The determinants of AT depended on the stage of renal dysfunction in patients with heart disease. In conclusion, in the eGFR <45 group, the determinants of AT were left ventricular ejection fraction and hemoglobin, whereas in the eGFR 45 to 59 and eGFR ≥60 groups, the determinant of AT was ΔPETO2.

Safety and efficacy of neoadjuvant chemoradiotherapy with moderately hypofractionated intensity-modulated radiotherapy for resectable pancreatic cancer: A prospective, open-label, phase II study.

BACKGROUND: Resectable pancreatic cancer (RPC) is potentially resectable on admission, and the impact of neoadjuvant therapy on these tumors is controversial. Moreover, the safety and efficacy of neoadjuvant chemoradiotherapy with moderately hypofractionated intensity-modulated radiation therapy (NACIMRT) for RPC have not been studied. Here, we conducted a phase II study to evaluate the safety and efficacy of hypofractionated NACIMRT for RPC. METHODS: A total of 54 RPC patients were enrolled and treated according to the study protocol. We used moderately hypofractionated (45 Gy in 15 fractions) IMRT with gemcitabine to shorten the duration of radiotherapy and reduce gastrointestinal toxicity. The primary endpoint was overall survival (OS), and we subsequently analyzed the microscopically margin-negative resection (R0) rate, disease-free survival (DFS), and histologic effects and safety of NACIMRT. RESULTS: Median OS for the cohort was 40.0 months. Forty-two patients (77.8%) underwent pancreatectomy after NACIMRT. Median DFS was 20.3 months. The R0 resection rate was 95.2% (40/42) per protocol and 85.2% (46/54) for the cohort. There were no intervention-related deaths during the study period. Local treatment response, as assessed by the CAP classification, showed no residual tumor in 4.8% of patients. Overall, 23.9% of patients experienced CTCAE grade 3 or 4 during NACIMRT. Adjuvant therapy was initiated in 88% of patients undergoing resection. Postoperative complications grade ≥3b on the Clavien-Dindo scale occurred in 4.8% of patients. CA19-9 level at enrollment was an independent prognostic factor for OS and DFS. CONCLUSIONS: This is the first prospective study of hypofractionated IMRT as neoadjuvant therapy for RPC. Hypofractionated NACIMRT for RPC could be safely introduced with a high induction rate of adjuvant chemotherapy, with an overall survival of 40.0 months.

Association between worsening renal function severity during hospitalization and low physical function at discharge: a retrospective cohort study of older patients with heart failure and chronic kidney disease from Japan.

BACKGROUND: The number of hospitalized older patients with chronic heart failure, chronic kidney disease, and worsening renal function is rising in Japan. This study aimed to clarify the impact of the severity of worsening renal function during hospitalization on low physical function at discharge of these patients. METHODS: We included 573 consecutive heart failure patients who underwent phase I cardiac rehabilitation. Worsening renal function severity was defined according to elevation during hospitalization of baseline serum creatinine on admission: non-worsening renal function, serum creatinine < 0.2 mg/dL; worsening renal function II/I, serum creatinine ≥ 0.2 to < 0.5 mg/dL; worsening renal function III, and serum creatinine ≥ 0.5 mL/dL. Physical function was measured with the Short Performance Physical Battery. We compared background factors, clinical parameters, pre-hospitalization walking levels, Functional Independence Measure score, and physical function in the three renal function groups. Multiple regression analysis was performed with the Short Performance Physical Battery at discharge as the dependent variable. RESULTS: The final analysis included 196 patients (mean age 82.7 years, male 51.5%) categorized into three groups based on worsening renal function: worsening renal function grade III group (n = 55), worsening renal function grade II/I group (n = 36), and non-worsening renal function group (n = 105). There is no significant difference in walking levels before hospitalization between the three groups, but physical function at discharge was significantly lower in the worsening renal function III group. Moreover, worsening renal function III was an independent factor for low physical function at discharge. CONCLUSION: Worsening of renal function during hospitalization in older patients with heart failure and chronic kidney disease was strongly associated with low physical function at discharge, even after adjusting for other potentially confounding factors, such as pre-hospitalization walking levels, walking start day, and Geriatric Nutrition Risk Index at discharge. Notably, worsening renal function of mild or moderate severity (grade II/I) did not show a significant association with low physical function.

Comprehensive review of undifferentiated carcinoma of the pancreas: from epidemiology to treatment.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.

End-tidal oxygen partial pressure is a strong prognostic predictive factor in patients with cardiac disease.

BACKGROUND: Cardiopulmonary exercise testing (CPET) variables represent central and peripheral factors and combined factors in the pathology of patients with cardiac disease. The difference in end-tidal oxygen partial pressure from resting to anaerobic threshold (ΔPETO2 ) may represent predominantly peripheral factors. This study aimed to verify the prognostic significance of ΔPETO2 for major adverse cardiac and cerebrovascular events (MACCE) in cardiac patients, including comparison with the minute ventilation-carbon dioxide production relationship (VE/VCO2 slope), and peak oxygen uptake (VO2 ). METHODS: In total, 185 patients with cardiac disease who underwent CPET were consecutively enroled in this retrospective study. The primary endpoint was 3-year MACCE. The ability of ΔPETO2 , VE/VCO2 slope, and peak VO2 to predict MACCE was examined. RESULTS: Optimal cut-off values for predicting MACCE were 2.0 mmHg for ΔPETO2 (area under the curve [AUC]: 0.829), 29.8 for VE/VCO2 slope (AUC: 0.734), and 19.0 mL/min/kg for peak VO2 (AUC: 0.755). The AUC of ΔPETO2 was higher than those of VE/VCO2 slope and peak VO2 . The MACCE-free survival rate was significantly lower in the ΔPETO2 ≤ 2.0 group versus the ΔPETO2 > 2.0 group (44.4% vs. 91.2%, p < 0.001). ΔPETO2 ≤ 2.0 was an independent predictor of MACCE after adjustment for age and VE/VCO2 slope (hazard ratio [HR], 7.28; p < 0.001) and after adjustment for age and peak VO2 (HR, 6.52; p < 0.001). CONCLUSION: ΔPETO2 was a strong predictor of MACCE independent of and superior to VE/VCO2 slope and peak VO2 in patients with cardiac disease.