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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.

Summary: 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 β-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 β-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.

Abstract 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 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.

Abstract 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.

Abstract 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.

Abstract 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.

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 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.

Abstract Background Pneumocystis jirovecii pneumonia (PCP)-related risk factors among patients with solid tumors are not completely defined. Thus, we aimed to characterize PCP cases with underlying solid tumors, to highlight the factors contributing to its development besides the prolonged use of moderate-to-high dose corticosteroids. Methods We retrospectively reviewed the medical records of patients with solid tumors diagnosed with PCP between 2006 and 2018 at a cancer center in Tokyo, Japan. Demographic and clinical data were collected, which included malignancy types, total lymphocyte count, coexisting pulmonary disease, chemotherapy, radiation therapy, corticosteroid use, and PCP-attributable mortality. Results Twenty cases of PCP with solid tumors were documented in 151,718 patients and 788,914 patient-years. Lung cancer (n = 6, 30%) was the most common underlying tumor, followed by breast cancer (n = 3, 15%). Only six (30%) patients were taking a dosage of ≥20 mg prednisone equivalents daily for ≥4 weeks from the onset of PCP. Among the remaining 14 patients, seven (50%) had coexisting pulmonary diseases, 10 (71%) had received chemotherapy within 90 days prior to PCP diagnosis, seven (50%) had undergone chest radiation therapy before PCP diagnosis, seven (50%) had received only intermittent corticosteroids, and one (7%) received no corticosteroids. Mortality attributable to PCP was 40%. Conclusions More than half of the patients were not taking a dosage of ≥20 mg prednisone equivalents daily for ≥4 weeks. Multiple other factors (e.g., lymphocytopenia, radiation to chest) may have potentially contributed to PCP in patients with solid tumors in a composite manner. We need to establish a method for estimating the likelihood of PCP taking multiple factors into account in this patient population.

Abstract Since the body’s head and neck area affects many functions such as breathing, swallowing, and speaking, systemic treatments to head and neck cancer patients are important not only for survival but also for preserving functions and quality of life. With the progress that has been made in molecular targeted therapy, anti-EGFR antibody (cetuximab) and immune checkpoint inhibitors (nivolumab, pembrolizumab) have provided survival benefits to head and neck cancer patients and are approved for clinical practice. Clinical trials incorporating these new drugs for patients with locally advanced head/neck cancers are underway. However, the existing clinical evidence regarding molecular targeted drugs for head and neck cancers is based mostly on clinical trials allocated to squamous cell carcinoma patients. New targeted therapies for non-squamous cell carcinoma patients were recently reported, e.g., tyrosine kinase inhibitors for the treatment of thyroid cancers and HER2-targeted therapy for salivary gland cancers. With the goal of improving local control, molecular targeted treatment strategies as salvage local therapy are being investigated, including boron neutron capture therapy (BNCT) and near-infrared photoimmunotherapy (NIR-PIT). Herein the history and landscape of molecular targeted therapy for head and neck cancers are summarized and reviewed.

Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl-xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors.

Background. Doxorubicin is the key drug for treatment of advanced soft tissue sarcoma (STS). The appropriate dosage of doxorubicin, regarding monotherapy or the role of combination therapy, is unclear. Methods. We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who were treated with doxorubicin-based chemotherapies in our institution. Time to treatment failure (TTF), overall survival (OS), overall response, and prognostic factors for OS were evaluated. Results. Seventy-five patients were enrolled. The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant difference either in TTF or in OS. There were no significant differences in OS between combination therapy and monotherapy, but the TTF with combination therapy was better than monotherapy. The overall response for combination therapy indicated a better response rate. Less number of involved organs, no bulky mass, and a normal CRP level were independent favorable prognostic factors for OS. Conclusions. Combination therapy showed better response and TTF than monotherapy but did not show better OS. Possible prognostic factors for OS were indicated. This retrospective study was approved by the institutional review board. This trial is registered with UMIN000028787.

Polyplex micelles have demonstrated biocompatibility and achieve efficient gene transfection in vivo. Here, we investigated a polyplex micelle encapsulating genes encoding the tumor-associated antigen squamous cell carcinoma antigen recognized by T cells-3 (SART3), adjuvant CD40L, and granulocyte macrophage colony-stimulating factor (GM-CSF) as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC). Intraperitoneally administrated polyplex micelles were predominantly found in the lymph nodes, spleen, and liver. Compared with mock controls, the triple gene vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer cells, of which long-term surviving mice showed complete rejection when re-challenged with CT26 tumors. Moreover, the DNA vaccine inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung tumors in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+ DCs and CD4+/CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ T cells by neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine. In conclusion, a SART3/CD40L+GM-CSF gene-loaded polyplex micelle can be applied as a novel vaccine platform to elicit tumor rejection immunity regardless of the recipient MHC haplotype.

Abstract Background A massive amount of proteomic data is generated on a daily basis, nonetheless annotating all sequences is costly and often unfeasible. As a countermeasure, machine learning methods have been used to automatically annotate new protein functions. More specifically, many studies have investigated hierarchical multi-label classification (HMC) methods to predict annotations, using the Functional Catalogue (FunCat) or Gene Ontology (GO) label hierarchies. Most of these studies employed benchmark datasets created more than a decade ago, and thus train their models on outdated information. In this work, we provide an updated version of these datasets. By querying recent versions of FunCat and GO yeast annotations, we provide 24 new datasets in total. We compare four HMC methods, providing baseline results for the new datasets. Furthermore, we also evaluate whether the predictive models are able to discover new or wrong annotations, by training them on the old data and evaluating their results against the most recent information. Results The results demonstrated that the method based on predictive clustering trees, Clus-Ensemble, proposed in 2008, achieved superior results compared to more recent methods on the standard evaluation task. For the discovery of new knowledge, Clus-Ensemble performed better when discovering new annotations in the FunCat taxonomy, whereas hierarchical multi-label classification with genetic algorithm (HMC-GA), a method based on genetic algorithms, was overall superior when detecting annotations that were removed. In the GO datasets, Clus-Ensemble once again had the upper hand when discovering new annotations, HMC-GA performed better for detecting removed annotations. However, in this evaluation, there were less significant differences among the methods. Conclusions The experiments have showed that protein function prediction is a very challenging task which should be further investigated. We believe that the baseline results associated with the updated datasets provided in this work should be considered as guidelines for future studies, nonetheless the old versions of the datasets should not be disregarded since other tasks in machine learning could benefit from them.

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. [ABSTRACT FROM AUTHOR]