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Background: Perioperative use of immune checkpoint blockade (ICB) improves survival in patients with early-stage cancer. Treatment-related adverse events (AEs), frequently involve the endocrine system which may increase perioperative complications and affect quality of life. Objective: We conducted a meta-analysis to elucidate the impact of adding ICB to conventional neoadjuvant/adjuvant therapy on the incidence of endocrine AEs. Design: A systematic review and meta-analysis of randomize-controlled trials (RCTs). Data sources and methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed for RCTs comparing groups with and without the addition of ICB to conventional perioperative therapy in patients with cancer. Outcomes included all-grade and grade 3–5 thyroiditis, hyperthyroidism, hypothyroidism, adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, and hyperglycemia. The odds ratios (ORs) of all-grade and grade 3–5 endocrine were pooled using the random-effect model meta-analysis. Results: Twenty-four RCTs comprising 12,199 patients were identified for meta-analysis. The addition of ICB was associated with higher incidence of thyroiditis [all grade: OR = 3.53 (95% confidence interval (CI): 1.88–6.64)], hyperthyroidism [all-grade: 7.18 (4.30–12.01); grade 3–5: 3.93 (1.21–12.82)], hypothyroidism [all-grade: 5.39 (3.68–7.90); grade 3–5: 3.63 (1.18–11.11)], adrenal insufficiency [all-grade: 3.82 (1.88–7.79); grade 3–5: 5.91 (2.36–14.82)], hypophysitis [all-grade: 10.29 (4.97–21.3); grade 3–5: 5.80 (1.99–16.92)], and type 1 diabetes mellitus [all-grade: 2.24 (1.06–4.74); grade 3–5: 3.49 (1.21–10.08)]. The cumulative incidence of each grade 3–5 endocrine AE was low (

Summary: Indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is a potential target to unlock the immunosuppressive tumor microenvironment. Correlations between IDO1 and immune checkpoint inhibitor (ICI) efficacy remain unclear. Herein, we investigated IDO1 transcript expression across cancers and clinical outcome correlations. High IDO1 transcripts were more frequent in uterine (54.2%) and ovarian cancer (37.2%) but varied between and within malignancies. High IDO1 RNA expression was associated with high expression of PD-L1 (immune checkpoint ligand), CXCL10 (an effector T cell recruitment chemokine), and STAT1 (a component of the JAK-STAT pathway) (all multivariable p

Abstract Background The efficacy and safety of adjunctive therapy are unclear in bipolar depression. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of second-generation antipsychotic, lamotrigine, lithium, or valproate therapy used in adjunction with lamotrigine, lithium, or valproate monotherapy in bipolar depression. A literature search of major electronic databases was conducted in February 2021, and all articles published until then were eligible. Two researchers independently screened relevant publications, extracted data, and evaluated methodological quality according to the Cochrane criteria. Results Five studies met the inclusion criteria. The meta-analysis revealed significant differences in the following outcomes: (i) remission rates from depressive episodes (risk ratio [RR]: 1.23, 95% confidence interval [CI] 1.01–1.50, p = 0.04), (ii) improvement in depressive symptoms (standardized mean difference [SMD]: 0.21, 95% CI 0.09–0.34, p = 0.001), (iii) improvement in quality of life (SMD: 0.22, 95% CI 0.06–0.37, p = 0.005), and (iv) rate of adverse events during the study period (RR: 1.12, 95% CI 1.03–1.22, p = 0.008). There was no significant difference between adjunctive therapy and monotherapy in the emergence of suicide-related behaviors, dropout rate during the study period, or rate of manic switching. Conclusions Our results suggest that adjunctive second-generation antipsychotics, lamotrigine, lithium, or valproate increase both the benefits and risks in patients with bipolar depression, although there is no significant difference in severe adverse events. Adjunctive therapy should be provided through shared decision-making while considering the patients’ condition in clinical settings.

Mutations of RAS are commonly seen in human cancers, especially in lung, colorectal, and pancreatic adenocarcinoma. Despite huge effort for decades, targeting RAS mutations has been ‘‘undruggable’’ because of the molecular instability of RAS protein inhibition. However, the recent discovery of the KRAS G12C inhibitor paved the way to expand therapeutic options for patients with cancer harboring the KRAS G12C mutation. At the same time, the successful development of immune checkpoint inhibitors (ICIs) drastically changed the paradigm of cancer treatment and resulted in a better understanding of the tumor immune microenvironment in patients with KRAS-mutant cancer. This review describes the following: the clinical characteristics of cancer with KRAS mutation; successful development of the KRAS G12C inhibitor and its impact on the tumor immune microenvironment; and potential new avenues such as the combination strategy using KRAS inhibitor and ICI, with preclinical and clinical rationales for overcoming resistance to inhibition of KRAS to improve therapeutic efficacy for patients with cancer harboring KRAS mutations.

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.

Abstract Background TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported. Case presentation A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions. Conclusion This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.

Background: No meta-analysis has assessed the pooled frequencies of adverse events (AEs) induced by concomitant nivolumab plus ipilimumab regimen for anticancer-medications-naïve malignancies. Furthermore, no meta-analysis has compared detailed safety profiles between four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1) and four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3). Objectives of this study was estimating AE frequencies, and comparison of AE frequencies between N3I1 and N1I3 regimens. Methods: Four major electronic databases were searched; both interventional and observational studies were included. All primary cancer types were permitted. Patients should not have been previously treated with any anti-cancer medications. The frequency of AEs was pooled using a random-model meta-analysis using the generic inverse variance method. Protocol registration: UMIN000044090. Results: Forty articles representing 48 populations with 4,677 patients were included in the study. The pooled frequencies for key indicators were as follows: any AE, 81.3% (95% confidence interval (CI) 77.5-85.1); grade 3 or higher AE, 40.6% (95% CI: 35.7–45.5); serious AE, 32.7% (95% CI: 22.4–43.1); AE leading to discontinuation, 28.3% (95% CI: 23.7–32.8); and treatment-related death, 0.7% (95% CI: 0.4–1.1). AEs with the highest incidence were fatigue (27.9%, 95% CI: 22.6–33.3), followed by diarrhea (26.0%, 95% CI: 21.5–30.5), pruritus (24.6%, 95% CI: 20.3–28.8), rash (24.0% 95% CI: 19.3–28.7), and elevated aspartate aminotransferase (21.2%, 95% CI: 14.9–27.5). Subgroup analyses demonstrated that N3I1, compared to N1I3, less frequently induced any AE (N1I3 95.7%, N3I1 84.5%, p = 0.003), grade 3 or higher AE (N1I3 64.3%, N3I1 35.7%, p

Coral reefs are complex ecosystems composed of many interacting species. One ecologically important group consists of zoantharians, which are closely related to reef-building corals. Like corals, zoantharians form mutualistic symbioses with dinoflagellate micro-algae (family Symbiodiniaceae), but their associations remain underexplored. To examine the degree to which zoantharians exhibit altered symbiont dynamics under changing environmental conditions, we reciprocally transplanted colonies of Zoanthus sansibaricus between intertidal (2 m) and subtidal (26 m) depths within a reef in Okinawa, Japan. At this location, Z. sansibaricus can associate with three Symbiodiniaceae species from two genera distributed along a light and depth gradient. We developed species-specific molecular assays and sampled colonies pre‐ and post-transplantation to analyze symbiont community diversity. Despite large environmental differences across depths, we detected few symbiont compositional changes resulting from transplantation stress. Colonies sourced from the intertidal zone associated with mixtures of a “shallow” Symbiodinium sp. and a “shallow” Cladocopium sp. independent of whether they were transplanted to shallow or deep waters. Colonies sourced from the subtidal zone were dominated by a “deep” Cladocopium sp. regardless of transplant depth. Subtidal colonies brought to shallow depths did not transition to the presumably high-light adapted shallow symbionts present in the new environment, but rather bleached and died. These patterns mirror observations of highly stable coral-algal associations subjected to depth transplantation. Our results indicate that Zoanthus-Symbiodiniaceae symbioses remain stable despite stress, suggesting these important reef community members have relatively low capacity to shuffle to more stress-tolerant micro-algae in response to ongoing climate change.

Abstract Background TAFRO syndrome, which was first reported in 2010 in Japan, is a relatively rare disease characterized by thrombocytopenia, anasarca, fever, renal impairment, reticulin fibrosis, and organomegaly. Although this disease is considered similar to multicentric Castleman disease, some of the clinical features, such as thrombocytopenia, are different from typical cases of multicentric Castleman disease. In addition, the etiology of TAFRO syndrome remains unknown and controversial. There have only been a few cases of TAFRO syndrome complicated with adrenal gland lesions, and all of them have had hemorrhagic involvement. Case presentation This report describes the case of a 46-year-old Asian man who presented with fever, epigastric pain, and back pain for 1 month. A computed tomographic scan revealed ascites, mild lymphadenopathy, and left adrenal necrosis without hemorrhage. A blood test showed thrombocytopenia, anemia, and elevated C-reactive protein, alkaline phosphatase, and creatinine levels. Based on the edema, severe thrombocytopenia, fever, reticulin myelofibrosis shown by bone marrow biopsy, mild lymphadenopathy, and progressive renal insufficiency, we diagnosed this patient as having TAFRO syndrome. He was successfully treated by immediate administration of glucocorticoids and tocilizumab. Conclusions There have been no previous reports of a case of TAFRO syndrome complicated with adrenal necrosis. Because the biopsy of the left adrenal gland revealed necrosis without any evidence of hemorrhage, we concluded that the unilateral adrenal necrosis in this case was caused by either ischemia from infarction or organomegaly itself under severe hypercytokinemia. This unusual clinical course is useful for further analysis of the etiology of TAFRO syndrome.

It is known that prostate cancer usually presents as adenocarcinoma, frequently metastasizes to bone, appears osteoblastic on radiographs, and shows elevated PSA. Herein, we describe a case of an 80-year-old man diagnosed with prostate cancer presenting as adenocarcinoma and small cell carcinoma in different areas as well as osteolytic bone metastases in the ilium, right rib, vertebrae, and bilateral femurs with markedly elevated CEA (2391 ng/mL) and Pro-GRP (2610 pg/mL). Occasionally, prostate cancer can appear as osteolytic bone metastases, and in this case, it is possible that the prostate cancer contained small cell carcinoma.

Background/Aim: In the CheckMate-141 trial regarding head and neck cancer (HNC), nivolumab conferred a survival benefit to patients. However, the best treatment sequence of chemotherapy and anti-PD-1/PD-L1 therapy in these cancers is unclear. Patients and Methods: This was an observational study using data collected prospectively from 97 HNC patients treated with nivolumab at our institutions. Twenty-two HNC patients who received paclitaxel-based chemotherapy before (pre-PTX, n=12) and after (post-PTX, n=10) nivolumab were evaluated. Results: The median follow-up time was 15.9 months (range=6.9-35.9 months). There was a significant difference in the overall response rate (ORR) between pre-PTX (17%) and post-PTX (70%) (p=0.027). Similarly, time to progression (TTP) was significantly longer after nivolumab than before nivolumab (post-PTX, 7.4 months; pre-PTX, 4.9 months, p=0.020). Conclusion: Paclitaxel-based chemotherapy had a better ORR and TTP after nivolumab than before nivolumab for HNC. The sequential administration of anti-PD-1 therapy followed by paclitaxel-based chemotherapy could be a better strategy for HNC. [ABSTRACT FROM AUTHOR]

Background/Aim: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib. Patients and Methods: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib. Results: The disease control rate was better in patients with lower NLR (<8; 89%) than higher NLR (≥8; 25%) (p=0.05). Median progression-free survival and overall survival were longer in patients with lower NLR than higher NLR (4.0 vs. 1.6 months, p<0.05; and 10.2 vs. 3.8 months, p<0.05, respectively). Patients whose NLR on day 14 decreased compared to baseline had a slightly higher overall response rate than patients without NLR decrease (42.9% vs. 0%, p=0.19). Conclusion: The baseline NLR is a potential prognostic marker, and the change of NLR can be an early indicator of response for ATC patients treated with lenvatinib. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 66-year-old woman with stage IV transverse colon adenocarcinoma receiving irinotecan plus panitumumab presented with fever and back pain. Topics discussed include administration of fluorouracil, leucovorin, oxaliplatin, and bevacizumab; majority of treatments involving corticosteroids with good response; and administration of ceftriaxone for possible urinary tract infection.

Background/aim: In the CheckMate-141 trial regarding head and neck cancer (HNC), nivolumab conferred a survival benefit to patients. However, the best treatment sequence of chemotherapy and anti-PD-1/PD-L1 therapy in these cancers is unclear., Patients and Methods: This was an observational study using data collected prospectively from 97 HNC patients treated with nivolumab at our institutions. Twenty-two HNC patients who received paclitaxel-based chemotherapy before (pre-PTX, n=12) and after (post-PTX, n=10) nivolumab were evaluated., Results: The median follow-up time was 15.9 months (range=6.9-35.9 months). There was a significant difference in the overall response rate (ORR) between pre-PTX (17%) and post-PTX (70%) (p=0.027). Similarly, time to progression (TTP) was significantly longer after nivolumab than before nivolumab (post-PTX, 7.4 months; pre-PTX, 4.9 months, p=0.020)., Conclusion: Paclitaxel-based chemotherapy had a better ORR and TTP after nivolumab than before nivolumab for HNC. The sequential administration of anti-PD-1 therapy followed by paclitaxel-based chemotherapy could be a better strategy for HNC., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib., Patients and Methods: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib., Results: The disease control rate was better in patients with lower NLR (<8; 89%) than higher NLR (≥8; 25%) (p=0.05). Median progression-free survival and overall survival were longer in patients with lower NLR than higher NLR (4.0 vs. 1.6 months, p<0.05; and 10.2 vs. 3.8 months, p<0.05, respectively). Patients whose NLR on day 14 decreased compared to baseline had a slightly higher overall response rate than patients without NLR decrease (42.9% vs. 0%, p=0.19)., Conclusion: The baseline NLR is a potential prognostic marker, and the change of NLR can be an early indicator of response for ATC patients treated with lenvatinib., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)