Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease.

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of ß-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to ß-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

Clinical impact of proteinuria on renal function and treatment outcomes in patients with radioiodine-refractory thyroid cancer treated with lenvatinib.

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

Assessing Potential Risks of Future Redo Transcatheter Aortic Valve Replacement in Asian Patients.

Background: In the Asian cohort, data are limited on the risk for coronary obstruction due to sinus of Valsalva (SOV) sequestration in redo transcatheter aortic valve replacement (TAVR) procedures. Objectives: The aim of this study was to assess the potential risk for coronary obstruction in simulated redo TAVR in Asian patients. Methods: Post-TAVR computed tomographic data from 788 patients who received balloon-expandable (BE) SAPIEN 3 transcatheter aortic valves (TAVs) and 334 patients who received self-expanding (SE) Evolut R or Evolut PRO TAVs were analyzed. The risk for coronary obstruction due to SOV sequestration in redo TAVR, defined as the TAV commissure level above the sinotubular junction (STJ) and a TAV-to-STJ distance <2.0 mm in each coronary sinus, was retrospectively evaluated. Results: The potential risks for coronary obstruction due to SOV sequestration at 1 or both coronary arteries were identified in 52.1% of the BE TAV group and 71.3% of the SE TAV group (P < 0.001). After adjusting for multiple covariates, STJ diameter, STJ height, TAV oversizing degree by area, and implantation depth were independently associated with SOV sequestration risk in the BE TAV group, whereas STJ diameter and implantation depth were independently associated with SOV sequestration risk in the SE TAV group. Conclusions: Coronary obstruction due to SOV sequestration in redo TAVR may occur in a substantial number of Asian patients. This finding suggests the importance of considering the structural feasibility of future redo TAVR when implanting the first TAV, especially in Asian patients with long life expectancy.

Impact of Transjugular Intracardiac Echocardiography-Guided Self-Expandable Transcatheter Aortic Valve Implantation on Reduction of Conduction Disturbances.

BACKGROUND: A high permanent pacemaker implantation (PPI) risk remains a concern of self-expandable transcatheter aortic valve implantation, despite the continued improvements in implantation methodology. We aimed to assess the impact of real-time direct visualization of the membranous septum using transjugular intracardiac echocardiography (ICE) during transcatheter aortic valve implantation on reducing the rates of conduction disturbances including the need for PPI. METHODS: Consecutive patients treated with Evolut R and Evolut PRO/PRO+ from February 2017 to September 2022 were included in this study. We compared outcomes between the conventional implantation method using the 3-cusps view (3 cusps without ICE group), the recent method using cusp-overlap view (cusp overlap without ICE group), and our novel method using ICE (cusp overlap with ICE group). RESULTS: Of the 446 patients eligible for analysis, 211 (47.3%) were categorized as the 3 cusps without ICE group, 129 (28.9%) were in the cusp overlap without ICE group, and 106 (23.8%) comprised the cusp overlap with ICE group. Compared with the 3 cusps without ICE group, the cusp overlap without ICE group had a smaller implantation depth (2.2 [interquartile range, 1.0-3.5] mm versus 4.3 [interquartile range, 3.3-5.4] mm; P<0.001) and lower 30-day PPI rates (7.0% versus 14.2%; P=0.035). Compared with the cusp overlap without ICE group, the cusp overlap with ICE group had lower 30-day PPI rates (0.9%; P=0.014), albeit with comparable implantation depths (1.9 [interquartile range, 0.9-2.9] mm; P=0.150). Multivariable analysis showed that our novel method using ICE with the cusp-overlap view was independently associated with a 30-day PPI rate reduction. There were no group differences in 30-day all-cause mortality (1.4% versus 1.6% versus 0%; P=0.608). CONCLUSIONS: Our novel implantation method using transjugular ICE, which enable real-time direct visualization of the membranous septum, achieved a predictably high position of prostheses, resulting in a substantial reduction of conduction disturbances requiring PPI after transcatheter aortic valve implantation.

The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results.

Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene ERBB, is known to be mutated or amplified in various malignant diseases, and many HER2-targeted therapies (including monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors) have been investigated. HER2 overexpression is observed in ~30% of patients with osteosarcoma, and HER2-targeted therapy for osteosarcoma has also been investigated, along with the prognostic and/or predictive value of HER2. An effective HER2-targeted therapy for osteosarcoma has not been established, however. An antibody-drug conjugate (ADC), i.e., trastuzumab deruxtecan (T-DXd), has been approved for the treatment of HER2-positive malignant diseases such as breast cancer and gastric cancer. T-DXd showed promising efficacy in a tumor-agnostic clinical trial, but even T-DXd did not demonstrate sufficient efficacy against HER2-positive osteosarcoma. In this review, the underlying reasons/mechanisms for the failure of HER2-targeted treatments for osteosarcoma (including T-DXd) are discussed, and the potential and future direction of HER2-targeted therapy is described.

Inflammatory myofibroblastic tumors: recent progress and future of targeted therapy.

An inflammatory myofibroblastic tumor is a rare component of bone and soft-tissue sarcomas that has distinct pathological features as a lymphoplasmacytic inflammatory infiltrate. As is the case for other non-small round cell sarcomas, surgical resection remains the standard treatment strategy for inflammatory myofibroblastic tumors, but recurrence is possible. Concerning systemic therapy, the available data for conventional chemotherapy (such as those of doxorubicin-based regimens) are limited, and case reports of anti-inflammatory inflammatory myofibroblastic tumor treatments describe some degree of symptom relief and efficacy against tumor progression. However, as more information about cancer genomics accumulates, the potential for molecularly targeted therapies for inflammatory myofibroblastic tumors has become more promising. Approximately half of inflammatory myofibroblastic tumors harbor anaplastic lymphoma kinase (ALK) fusion genes, and the other half could have potentially targetable fusion genes or mutations such as ROS1, NTRK and RET; case reports demonstrating the clinical efficacy of treatments targeted to inflammatory myofibroblastic tumor have been published, as have several prospective clinical trials. Few drugs are approved for the treatment of inflammatory myofibroblastic tumor, and most of them were approved for tumor-agnostic indications. Drugs that could be used for pediatric indications and dosing in inflammatory myofibroblastic tumor have also not been established. To provide effective targeted therapy for rare diseases such as inflammatory myofibroblastic tumor, it is necessary to obtain clinical evidence by designing and performing clinical trials and to find a path toward regulatory approval.

Comparison of Paclitaxel plus Carboplatin versus Observation in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck.

INTRODUCTION: Although systemic therapy, including multi-kinase inhibitors and cytotoxic chemotherapy, is an option for recurrent or metastatic adenoid cystic carcinoma of the head and neck (HNACC), it is not proven whether these therapies can prolong overall survival (OS). The present study investigated the impact of cytotoxic chemotherapy on survival outcomes compared with observation without chemotherapy. METHODS: We retrospectively reviewed the medical records of the patients diagnosed with recurrent or metastatic HNACC. We compared the survival outcomes, including survival time from recurrence/metastasis (OS) patients who received systemic chemotherapy with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6) (TC) on day 1 of a 3-week cycle and observation alone. Subgroup analysis was conducted to identify patients who can get benefit from TC. RESULTS: Seventy-five patients (32 in TC and 43 in observation) were analyzed. There was no difference in median OS between TC and observation (52.2 months vs. 44.0 months, hazard ratio 0.76, 95% confidence interval 0.32-1.30, p = 0.21). Landmark analysis to reduce immortal bias also showed no difference between TC and observation in terms of OS. Subgroup analysis showed nonsignificant trends toward longer OS in asymptomatic patients with pulmonary metastasis and without bone metastasis. CONCLUSIONS: In our non-randomized comparison, patients who underwent TC did not show prolonged survival time from recurrence and/or metastasis diagnosis compared with observation alone in patients with recurrent or metastatic HNACC. Although systemic chemotherapy is a possible option for metastatic/recurrent HNACC, initial observation might be a valid strategy for asymptomatic patients without extrapulmonary diseases. Further research is warranted to identify the optimal patients and therapeutic regimens to prolong OS in HNACC.

The Geriatric Nutritional Risk Index as a prognostic factor in older adult patients with locally advanced head and neck cancer receiving definitive chemoradiotherapy with tri-weekly cisplatin.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. The Geriatric Nutritional Risk Index (GNRI) is a screening tool to predict the risk of morbidity and mortality in the older adult. Nutritional management is key during CCRT but the association between prognosis and initial nutritional status in older adults with LAHNC undergoing CCRT remains unknown. MATERIALS AND METHODS: Patients ≥65 years old with LAHNC who received definitive CCRT with cisplatin (80 mg/m2 or 100 mg/m2, every three weeks, three times) between 2012 and 2018 were included. Patients without completion of radiotherapy were excluded. Patients were stratified into two groups based on the GNRI (≦98 or > 98). Overall survival (OS) and event-free survival (EFS) were analyzed by the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was adopted to identify prognostic factors. GNRI, sex, T and N categories were prespecified as variables for multivariable analysis. RESULTS: The median age of 111 patients (88 male, 79%) was 69 years (interquartile range: 67-71), among which 23 patients had low GNRI (20 male, 87%) and 88 patients had high GNRI (68 male, 77%). Baseline clinical characteristics were not statistically different between the two groups. OS was significantly worse in the low GNRI group than in the high GNRI group (p = 0.048). There was no statistical difference in EFS between the two groups (p = 0.12). Multivariable analysis revealed that low GNRI (hazard ratio [HR]: 3.17, 95% confidence interval [95%CI]: 1.12-8.96, p = 0.029) and higher N category (HR: 4.37, 95% CI: 1.58-12.06, p = 0.004) were associated with worse OS. For EFS, the higher N category was significantly associated with a worse outcome (HR: 2.54, 95% CI: 1.16-5.59, p = 0.02). DISCUSSION: Poorer nutritional status before initiation of CCRT was associated with worse OS in older adults with LAHNC in the definitive setting. The GNRI is a convenient tool for predicting OS in older adult patients with LAHNC treated with CCRT.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib.

BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.

Clinical characteristics of sarcoma cases in which long-term disease control was achieved with trabectedin treatment: A retrospective study.

Trabectedin is a therapeutic option for patients with advanced sarcoma. While a randomized trial demonstrated its prolonged progression-free survival (PFS), the reported PFS was <6 months. Some patients can achieve long-term disease control with this treatment. However, the reference information is insufficient. Herein, we retrospectively reviewed 51 sarcoma patients who received trabectedin. We analyzed the clinicopathological features, trabectedin dose, administration schedule, and clinical outcomes, including the overall response rate (ORR) and PFS. Among them, we assessed the detailed data of patients who achieved long-term disease control (PFS >1 year). The ORR in the 49 evaluable patients was 8%, and the median PFS in 51 patients was 7.5 months. Six patients (12%) achieved PFS of >1 year. Five of the six patients had metastatic lesions at trabectedin initiation. The pathological subtypes were myxoid liposarcoma (n = 2), leiomyosarcoma (n = 2), synovial sarcoma (n = 1), and Ewing sarcoma (n = 1). The final administration dose was the minimum dose (0.8 mg/m2) in two patients who continued the treatment over 20 cycles. The best radiological response was partial response (PR) in two myxoid liposarcoma patients and stable disease in four. The durations from trabectedin initiation to the first response in the two PR cases were 163 and 176 days, respectively. Our results support the validity of continuing trabectedin at a sustainable dose and interval in patients who can tolerate it. These results may be useful when considering the clinical application of trabectedin.

Machine learning approach to stratify complex heterogeneity of chronic heart failure: A report from the CHART-2 study.

AIMS: Current approaches to classify chronic heart failure (HF) subpopulations may be limited due to the diversity of pathophysiology and co-morbidities in chronic HF. We aimed to elucidate the clusters of chronic patients with HF by data-driven approaches with machine learning in a hospital-based registry. METHODS AND RESULTS: A total of 4649 patients with a broad spectrum of left ventricular ejection fraction (LVEF) in the CHART-2 (Chronic Heart Failure Analysis and Registry in the Tohoku District-2) study were enrolled to this study. Chronic HF patients were classified using random forest clustering with 56 multiscale clinical parameters. We assessed the influence of the clusters on cardiovascular death, non-cardiovascular death, all-cause death, and free from hospitalization by HF. Latent class analysis using random forest clustering identified 10 clusters with four primary components: cardiac function (LVEF, left atrial and ventricular diameters, diastolic blood pressure, and brain natriuretic peptide), renal function (glomerular filtration rate and blood urea nitrogen), anaemia (red blood cell, haematocrit, haemoglobin, and platelet count), and nutrition (albumin and body mass index). All 11 significant clinical parameters in the four primary components and two disease aetiologies (ischaemic heart disease and valvular heart disease) showed statistically significant differences among the 10 clusters (P < 0.01). Cluster 1 (26.7% of patients), which is characterized by preserved LVEF (<59%, 37% of the total) with lowest brain natriuretic peptide (>111.3 pg/mL, 0.9%) and lowest left atrial diameter (>42 mm, 37.4%), showed the best 5 year survival rate of 98.1% for cardiovascular death, 95.9% for non-cardiovascular death, 92.9% for all-cause death, and 91.7% for free from hospitalization by HF. Cluster 10 (6.0% of the total), which is co-morbid disorders of all four primary components, showed the worst survival rate of 39.1% for cardiovascular death, 68.9% for non-cardiovascular death, 23.9% for all-cause death, and 28.1% for free from hospitalization by HF. CONCLUSIONS: These results suggest the potential applicability of the machine leaning approach, providing useful clinical prognostic information to stratify complex heterogeneity in patients with HF.

Association between pazopanib exposure and safety in Japanese patients with renal cell carcinoma or soft tissue sarcoma.

The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.

A Case of Chronic Heart Failure Complicated by Primary Biliary Cholangitis and Skeletal Myopathy.

Several autoantigens related to inflammatory myopathy have been identified. Antimitochondrial antibody M2 (AMA-M2) is known as one of the serologic hallmarks of primary biliary cholangitis (PBC). There have been several reports on the association between AMA-M2 and various types of inflammatory myopathy, including cardiomyopathy. We report a case of a 58-year-old man with decompensated heart failure who also had PBC and skeletal inflammatory myopathy. Endomyocardial biopsy revealed severe fibrotic replacement of the myocardium without massive inflammatory infiltration, which was pathologically similar to what happens in dilated cardiomyopathy (DCM). Although the potential relationship between chronic autoimmune inflammation and DCM has been discussed, the concept of the inflammatory DCM has not yet been established. When we see elevated liver enzymes, and which is not simply due to congestive hepatopathy, we should consider the coexisting disease such as PBC.

Trend in industry payments to infectious disease physicians in the United States: a seven-year analysis of nonresearch payments from the Open Payments Database between 2014 and 2020.

OBJECTIVE: To evaluate the trend in nonresearch payments made by the industries to the infectious disease physicians in the United States since the launch of the Open Payments Database and during the COVID-19 pandemic. METHODS: Descriptive analysis was performed for the nonresearch payments made to all infectious disease physicians listed in the Open Payments Database between 2014 and 2020. Using the generalized estimating equation models with panel data of monthly and yearly payment per physician, the payment trend since the inception of the Open Payments Database and during the early stage of the COVID-19 pandemic were evaluated. RESULTS: A total of 7901 (81.5%) infectious disease physicians received $156 837 987 in nonresearch payments between 2014 and 2020. Median annual payments were $197 to $220. Monthly nonresearch per-physician payments and number of physicians with payments rapidly decreased by 58.6% (95% CI: 49.7%‒65.9%, p < 0.001) and by 54.4% (95% CI: 52.7%‒56.1%, p < 0.001) at the beginning of the COVID-19 pandemic, respectively. However, the per-physician payments and number of physicians with payments slightly increased every month right after onset of the pandemic. Both per-physician payments and the number of physicians with payments decreased by 2.6% (95% CI: 0.45‒4.7, p 0.018) and 2.0% (95% CI: 1.6%‒2.4%, p < 0.001) since the inception of the Open Payments Database, respectively. DISCUSSION: The nonresearch payments and number of infectious disease physicians accepting payments had decreased since the inception of the Open Payments Database. Furthermore, the non-research payments to infectious disease physicians suddenly decreased by more than half due to the COVID-19 pandemic.

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: a systematic review and meta-analysis.

BACKGROUND: Platinum-doublet chemotherapy has been conventionally used for patients with advanced gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) but evidence of chemotherapy is based on studies with small sample sizes and remains scarce. Thus, we conducted a systematic review and meta-analysis to elucidate the efficacy of platinum-doublet chemotherapy for advanced GEP-NEC. METHODS: We performed a database search in PubMed/MEDLINE and EMBASE. Eligible studies were prospective and retrospective studies documenting the efficacy of platinum plus etoposide (EP) and platinum plus irinotecan (IP) for advanced GEP-NEC. Overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were pooled and weighted using generic inverse variance in a random-effects meta-analysis model. RESULTS: Nineteen studies including 1157 patients were identified. The ORR of the platinum-doublet regimen, EP, and IP was 49.1% (95% confidence interval [CI], 41.8-56.5), 44.4% (95% CI: 35.9-53.0), and 59.4% (95% CI: 48.0-70.8). The pooled median OS of the platinum-doublet regimen, EP, and IP was 12.9 months (95% CI:10.9-15.3), 12.9 months (95% CI: 10.8-15.4), and 12.9 months (95% CI: 6.0-27.8), and the pooled median PFS of the platinum-doublet regimen, EP, and IP was 5.4 months (95% CI: 4.5-6.4), 5.4 months (95% CI 4.5-6.5), and 4.0 months (95% CI: 1.4-11.7), respectively. CONCLUSION: Considerable response rate and survival time of the platinum-doublet regimen for advanced GEP-NEC were observed. IP and EP regimens can be reasonably applicable and these results provide a reference for oncologists in deciding the suitable regimen for patients with advanced GEP-NEC.

Challenges of Systemic Therapy Investigations for Bone Sarcomas.

Bone sarcoma is a rare component of malignant solid tumors that accounts for only ~0.2% of malignancies. Bone sarcomas present various histological types, and genomic mutations differ markedly by the histological types. Although there are vast mutations in various bone sarcomas, most of them are non-actionable, and even potential targetable mutations that are actionable targets in other malignancies have not shown the appropriate responses in clinical trials for bone sarcomas. Investigations of new systemic therapy, including molecular targeted therapies for bone sarcomas, have thus not progressed like those for other solid tumors. Another problem is that high rates of pediatric/adolescent and young adult patients have bone sarcomas such as osteosarcoma, and patient recruitment for clinical trials (especially randomized trials) is challenging. For pediatric patients, evaluations of tolerability and appropriate dose modifications of new drugs are needed, as their findings could provide the threshold for investigating new drugs for bone sarcomas. To solve these problems, improvements in registry systems, real world data, and pediatric extrapolation have been attempted. We review the issues regarding targeted drug investigations for bone sarcomas, focusing on the current clinical evidence and efforts to resolve these issues.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma　- A Single Institute Analysis.

BACKGROUND: Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. CONCLUSIONS: The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

A proposed clinical scoring system for initiation of lenvatinib treatment in radioiodine-refractory thyroid cancer patients.

PURPOSE: The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients. METHODS: We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups. RESULTS: A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib. CONCLUSION: Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

The structure of NLRP9 reveals a unique C-terminal region with putative regulatory function.

Nucleotide-binding and oligomerisation domain-like receptors (NLRs) can form inflammasomes that activate caspase-1 and pro-interleukin-1ß and induce pyroptosis. NLR family pyrin domain-containing 9 (NLRP9) forms an inflammasome and activates innate immune responses during virus infection, but little is known about this process. Here, we report the crystal and cryo-electron microscopy structures of NLRP9 in an ADP-bound state, revealing inactive and closed conformations of NLRP9 and its similarities to other structurally characterised NLRs. Moreover, we found a C-terminal region interacting with the concave surface of the leucine-rich repeat domain of NLRP9. This region is unique among NLRs and might be involved in the specific function of NLRP9. These data provide the structural basis for understanding the mechanism of NLRP9 regulation and activation.

Post-Systemic Chemotherapy Prognoses of Recurrent/Metastatic Soft Tissue Sarcoma Patients with Retroperitoneal/Intra-Abdominal Origin versus Those with Extremities/Trunk Origin.

BACKGROUND: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. METHODS AND PATIENTS: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts' characteristics, chemotherapy details, and prognoses. RESULTS: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1-6) in cohort R and three lines (range: 1-9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95% CI: 20.9-42.8) and 27.1 months (cohort E; 95% CI: 21.6-32.5) (p = 0.549). CONCLUSION: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.