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Adrenocortical carcinoma (ACC) is a rare malignant tumor. Genetic abnormalities that may represent therapeutic targets and prognostic factors in ACC remain unclear. Besides being one of the main cellular defense mechanisms that regulates antioxidant pathways for detoxifying reactive oxygen species (ROS), the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) promotes tumor proliferation by increasing metabolic activity. In surgical specimens from 12 cases of nonmetastatic ACCs and nine cases of benign adrenocortical adenoma (ACA), we investigated gene mutation and protein expressions for Nrf2 and the preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy‐glucose positron emission tomography. Three of five ACCs with a Weiss score of 7 to 9 were Nrf2 mutants; these ACCs had higher expression of Nrf2 and higher preoperative SUVmax. The other seven ACCs had a Weiss score of 3 to 6; these seven ACCs and all the ACAs were non‐Nrf2 gene mutants. Patients with a Weiss score of 7 to 9 and Nrf2 mutant ACC had shorter overall survival. Based on Helsinki scoring, three ACCs with a Helsinki score greater than 17 had Nrf2 mutants, higher expression of Nrf2, higher preoperative SUVmax, and shorter overall survival. Our findings indicate that Nrf2 activation and the associated increase in metabolism play roles in ACC, in particular in ACC with a Weiss score of 7 to 9 and a Helsinki score of greater than 17. Three of five adrenocortical carcinomas with a Weiss score of 7 to 9 were Nrf2 mutants with higher expression of Nrf2, higher glucose uptake in PET, and shorter overall survival, suggesting that activation of Nrf2 and the associated increase in metabolism play roles in the progression of adrenocortical carcinoma.

BackgroundThe prevalence of non-alcoholic steatohepatitis (NASH) in Japanese patients with severe obesity is extremely high. The aim of the present study was to evaluate the metabolic and histological effects of laparoscopic sleeve gastrectomy (LSG) on NASH and liver fibrosis in Japanese patients with severe obesity.MethodsBetween June 2008 and March 2019, all 79 patients with severe obesity who underwent LSG were included in the study. Sixty-eight patients had an intraoperative liver biopsy performed at the time of LSG. Ultrasound-guided liver biopsies were performed in patients with fibrosis at 12 months after LSG.ResultsNASH was present in 43 patients (63.2%), and 10 patients had a unique feature in which their fibrosis were observed without steatosis at the time of LSG. Of the 28 patients with NASH, 25 showed improvement and no longer met the diagnostic criteria of NASH at 12 months after LSG. Mean pericellular fibrosis scores showed significant improvement from 1.62 at baseline, to 1.50, 1.00, and 0.78, respectively (p < 0.001). Univariate analysis of the preoperative predictors in the improvement of fibrosis showed significant effects in preoperative weight (p = 0.037), HbA1c (p = 0.037), and serum insulin (p = 0.037). Multivariate analysis revealed HbA1c to be the only preoperative predictor of improvement in fibrosis (p = 0.004; odds ratio 0.440, 95% CI 0.229–0.842).ConclusionsLSG has great potential as an effective treatment for patients with NASH.

Succinate dehydrogenase (SDH)‐deficient renal cell carcinoma (RCC) is mainly associated with a mutation in the SDHB gene and sometimes with mutations in the SDHC or SDHD genes. However, only three cases of succinate dehydrogenase A (SDHA)‐deficient RCC have been reported, and the relation between SDHA mutations and RCC has not been clarified. This study assessed the role of SDHA gene mutations in human RCC. We investigated SDHA/B/C/D gene mutations in 129 human RCCs. Targeted next‐generation sequencing and direct Sanger sequencing revealed single nucleotide variants (SNVs) of the SDHA gene with amino acid sequence variations in 11/129 tumors, while no SDHB/C/D gene mutations were found. Tumor cells with SNVs of the SDHA gene were characterized by eosinophilic cytoplasm and various patterns of proliferation. Immunohistochemistry examination found that the 11 tumors with SNVs of the SDHA gene showed significant reduction of SDHA protein and SDHB protein expression compared to the 19 tumors without SDHA or SDHB mutations (both P < .0001). Western blotting showed a greater decrease in the expression of SDHA and SDHB proteins in the 11 tumors with SNVs of the SDHA gene than in the 19 tumors without (both P < .0001). There was a positive correlation between SDHA and SDHB protein levels (P < .0001). On immunohistochemistry and Western blotting, the 11 tumors with SNVs of the SDHA gene had higher protein expression for nuclear factor E2‐related factor 2 (Nrf2) compared to the 19 tumors without the mutation (P < .01). These observations suggest that SDHA gene mutations might be associated with a subset of RCC. Succinate dehydrogenase (SDH) A gene mutation was identified in 11 out of 129 human renal cell carcinoma (RCC) samples by targeted next‐generation sequencing and direct Sanger sequencing, while no SDHB/C/D gene mutations were detected. Immunohistochemistry and western blotting identified a reduction of SDHA and SDHB protein expression in the tumors with SDHA gene mutations. These findings suggest that SDHA gene mutations might be linked to a subset of RCC.

INTRODUCTION: Esophageal cancer is often diagnosed at an advanced stage and with distant metastases. While cardiac metastases from solid tumors have been reported in 0.2%–6.5% of postmortem cases, solitary cardiac metastases remain exceedingly rare. Infective endocarditis, a life-threatening condition typically associated with valvular involvement and bacteremia, has not been widely associated with cardiac metastases. Here, we present an extremely rare case of esophageal squamous cell carcinoma directly invading the left atrium during chemotherapy, which was further complicated by infective endocarditis.CASE PRESENTATION: A 52-year-old female who presented with chest and back pain and progressive dysphagia was diagnosed with esophageal squamous cell carcinoma following an endoscopic biopsy. Chemotherapy and chemoradiotherapy resulted in inadequate tumor control. During the second course of second-line chemoimmunotherapy, the patient developed a high fever, followed by seizures and loss of consciousness, and required emergency intubation. Echocardiography revealed a mobile mass 5 × 30 mm in size attached to the posterior wall of the left atrium. To prevent further embolic complications, emergency surgery was performed, which revealed a tumor invading the left atrial wall. Histopathological findings revealed a necrotic mass containing keratinizing squamous cell carcinoma fragments and a septic thrombus, consistent with infective endocarditis originating from the tumor surface. The patient did not regain consciousness following surgery, possibly because of hypoxic–ischemic brain injury following seizure-induced hypoxemia. Infection control remained poor, and the patient died of sepsis on POD 56.CONCLUSIONS: Direct invasion of the left atrium by esophageal squamous cell carcinoma is rare, and infective endocarditis arising from tumor surfaces within the cardiac chamber is exceptionally uncommon, particularly in immunosuppressed patients. In this case, surgery was performed to prevent further embolic events and remove the infected tumor mass. Although the direct source of the infection was surgically removed, infection control remained difficult, likely due to persistent infection under immunosuppressive conditions and the use of cardiopulmonary bypass. This case highlights the challenges of managing infective endocarditis in patients with cancer and suggests that early surgical intervention may help reduce embolic risk, even when complete infection control cannot be achieved.

gene variants have been reported in a proportion of patients with familial Hirschsprung disease (F-HSCR), and certain variants are also associated with hereditary medullary thyroid carcinoma (MTC). Clinical guidelines have been developed to support decision-making regarding the timing of prophylactic surgery based on individual risk stratification. These recommendations emphasize the importance of tailoring the timing of thyroidectomy to the specific risk category assigned to each genetic variant, with the goal of preventing disease progression while minimizing unnecessary intervention. We encountered a case of F-HSCR associated with the germline c.1858T>C (p.C620R) activating variant in exon 10, which is known to confer moderate risk for MTC. Although only a limited number of MTC cases have been reported in the context of Hirschsprung disease (HD), and it remains unclear whether the management should align with that of MEN2A, we initiated surveillance for MTC in this family. No elevation of key markers, including carcinoembryonic antigen (CEA) or calcitonin, was observed, and no cases of MTC were detected across generations. However, a pheochromocytoma (PHEO) was diagnosed in one family member through screening for plasma-free metanephrines (fMNs). We present our findings in this family and provide a review of relevant literature.

Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder. This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20-75 years with recurrent major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0-17 or ≥18). Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was -1.34 for vortioxetine 10 mg ( = 0.0300) and -1.77 for vortioxetine 20 mg ( = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was -3.11 (10 mg dose) and -3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥18), and -2.08 (10 mg) and -2.61 (20 mg) for patients with a lower baseline score (0-17). This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816.

Background Pheochromocytomas (PCC) and paragangliomas (PGL) are catecholamine-producing neuroendocrine tumors. According to the World Health Organization Classification 2017, all PCC/PGL are considered to have malignant potential. There is growing evidence that PCC/PGL represent a metabolic disease that leads to aerobic glycolysis. Cellular energy metabolism involves both transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and succinate dehydrogenase (SDH) subtypes, but the association of these substances with PCC/PGL is largely unknown. Methods We investigated SDHB gene mutation and protein expressions for SDHB and Nrf2 in surgical specimens from 29 PCC/PGL. We also assessed preoperative maximum standard glucose uptake (SUVmax) on [ 18 F]fluorodeoxy-glucose positron emission tomography and mRNA levels for Nrf2 . Results Among 5 PCC/PGL with a PASS Score ≥ 4 or with a moderately to poorly differentiated type in the GAPP Score, 4 were metastatic and found to be SDHB mutants with homogeneous deletion of SDHB protein. SDHB mutants showed a higher expression of Nrf2 protein and a higher preoperative SUVmax than non- SDHB mutants with a PASS < 4 or a well-differentiated GAPP type. Furthermore, protein expression of Nrf2 was positively associated with preoperative SUVmax. The Nrf2 mRNA level positively correlated with malignant phenotype, higher expression for Nrf2 protein and SDHB gene mutant, but negatively correlated with expression for SDHB protein. There was also a positive correlation between Nrf2 mRNA level and SUVmax. Conclusion These results suggest that activation of Nrf2 and elevated metabolism play roles in PCC/PGL with malignant potential that have SDHB gene mutation and SDHB deficiency.

Trastuzumab deruxtecan (T-DXd), a high-payload antibody drug conjugate, has been reported to exert potent antitumor effects and has recently shown promising efficacy against human epidermal growth factor receptor 2 (HER2)-positive adenocarcinoma. Despite its high efficacy, interstitial lung disease (ILD) is a severe adverse event (AE) associated with T-DXd. This report describes a patient who was successfully treated with a dose-reduced T-DXd challenge after recovery from ILD. Little disease progression was observed during the treatment interruption period; thus, the effect of T-DXd was considered to have been maintained. T-DXd may induce ILD, and re-administration under careful observation is considered an important option for treating patients with HER2-positive breast cancer.

BackgroundLittle is known about the long-term outcomes and prognostic factors with non-curative endoscopic submucosal dissection (ESD) in elderly patients with early gastric cancer.MethodsClinicopathological findings and long-term outcomes were evaluated in 87 patients with early gastric cancer (EGC) aged ≥ 75 years who were treated with non-curative ESD. Prognostic factors for overall survival (OS) were analyzed with the Kaplan–Meier method and a Cox proportional hazards model.ResultsDuring the follow-up period, among 27 patients who died of any cause, only one patient died of gastric cancer. OS probabilities after 3 and 5 years were 89.7% and 79.3%, respectively. Univariate analyses revealed that Eastern Cooperative Oncology Group performance status 2–3, Charlson comorbidity index (CCI) ≥ 3, neutrophil/lymphocyte ratio ≥ 3.3, prognostic nutritional index < 44.8, distal tumor location and macroscopically depressed or flat configuration were associated with poor OS. Cox multivariate analysis revealed high CCI (≥ 3) to be an independent prognostic factor associated with OS (hazard ratio: 2.63, 95% confidence interval [CI] 1.06–6.49, P = 0.037).ConclusionsCCI may be a useful parameter for decision-making regarding additional surgery for elderly patients with gastric cancer treated by non-curative ESD.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases, including oral cancer. Cancer cells usually escape from the immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα, in the tumor microenvironment of oral squamous cell carcinoma (OSCC), performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating to seven immune-related factors and several clinicopathological statuses. However, the immune checkpoint-related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that the keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference in tumor immunity in the originating epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC, might be different in the originating epithelium, keratinized or non-keratinized.