Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Concordance between metabolic dysfunction-associated steatotic liver disease and nonalcoholic fatty liver disease.

AIM: A multisociety consensus group proposed a new nomenclature for metabolic dysfunction-associated steatotic liver disease (MASLD). Although patients with nonalcoholic fatty liver disease (NAFLD) are expected to be reclassified as patients with MASLD under the new nomenclature, the concordance between MASLD and NAFLD remains unclear. Moreover, waist circumference could be adjusted by ethnicity for diagnosing MASLD; however, there are limited data on the optimal waist circumference in the Japanese population. METHODS: This cross-sectional study was conducted on 3709 Japanese patients with NAFLD. The primary endpoint was the prevalence of MASLD in patients with NAFLD. The difference between the original waist circumference criteria (>94 cm for men and >80 cm for women) and the Japanese metabolic syndrome criteria (≥85 cm for men and ≥90 cm for women) for concordance between NAFLD and MASLD was also investigated. RESULTS: According to the original criteria, the prevalence of MASLD in patients with NAFLD was 96.7%. Similarly, according to the Japanese waist circumference criteria, 96.2% of patients with NAFLD could be reclassified as those with MASLD. The concordance rate was significantly higher in the original criteria than in the Japanese criteria (p = 0.02). CONCLUSIONS: NAFLD could be considered MASLD using the original MASLD criteria in the Japanese population, and insights from NAFLD research could be applied to MASLD.

Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

BACKGROUND AND AIM: Immune checkpoint inhibitors pose the risk of immune-related adverse events (irAEs). Recent data suggest that irAEs may be associated with a favorable prognosis. This study aimed to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable hepatocellular carcinoma. METHODS: The study enrolled 130 patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab between November 2020 and January 2023 at a single center. The relationship between irAEs and both response rate and post-treatment outcomes was investigated. RESULTS: Out of the 130 patients, irAEs developed in 36 (27.7%) patients. The irAE group exhibited a significantly longer progression-free survival (PFS) than the non-irAE group, with a median PFS of 8.9 compared with 4.6 months (P < 0.01). No difference was found in the overall survival between the irAE and non-irAE groups. The irAE group demonstrated significantly higher disease control rate (DCR) than the non-irAE group (97.0% vs 65.5%, P < 0.01). The analysis by irAE severity revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 vs 4.6 months, P = 0.007) and higher DCR (100% vs 65.5%, P < 0.01) than the non-irAE group. Furthermore, hypothyroidism correlated with a favorable PFS (8.9 vs 5.4 months, P = 0.02), DCR (100% vs 71.3%, P = 0.03), and overall response rate (58.3% vs 18.5%, P = 0.005). CONCLUSION: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.

Photocatalytic degradation process of antibiotic sulfamethoxazole by ZnO in aquatic systems: a dynamic kinetic model based on contributions of OH radical, oxygenated radical intermediates and dissolved oxygen.

The photocatalytic degradation process of sulfamethoxazole (SMX) using ZnO in aquatic systems has been systematically studied by varying initial SMX concentration from 0 to 15 mgL-1, ZnO dosage from 0 to 4 gL-1 and UV light intensity at the light source from 0 to 18 W(m-lamp length)-1 at natural pH. Almost complete degradations of SMX were achieved within 120 min for the initial SMX concentration ≤15 mgL-1 with ZnO dosage of 3 gL-1 and UV light intensity of 18 W(m-lamp length)-1. The photocatalytic degradation process was found to be interacted with the dissolved oxygen (DO) consumption. With oxygen supply through the gas-liquid free-surface, the DO concentration decreased significantly in the initial SMX degradation phase and increased asymptotically to the saturated DO concentration after achieving about 80% SMX degradation. The change in DO concentration was probably controlled by the oxygen consumption in the formation of oxygenated radical intermediates. A novel dynamic kinetic model based on the fundamental reactions of photocatalysis and the formation of oxygenated radical intermediates was developed. In the modeling the dynamic concentration profiles of OH radical and DO are considered. The dynamics of SMX degradation process by ZnO was simulated reasonably by the proposed model.

Effect of fatty liver and fibrosis on hepatocellular carcinoma development in patients with chronic hepatitis B who received nucleic acid analog therapy.

The number of patients with fatty liver has been increasing worldwide; however, the significance of fatty liver in patients with chronic hepatitis B who are receiving nucleic acid analog (NA) therapy remains unclear. Thus, we aimed to determine whether fatty liver affects the development of hepatocellular carcinoma (HCC) in patients receiving NA therapy. This study included 445 patients who received NA therapy, and the development of HCC was investigated. The primary outcome was the association between fatty liver and HCC development. During a mean follow-up period of 7.4 years, 46 patients (10.3%) developed HCC. No significant difference in the cumulative incidence of HCC was observed between patients with fatty liver and those without (p = 0.17). Multivariable analysis for age, gender, platelet count, alanine aminotransferase level at 1 year following NA therapy, and fatty liver revealed that the presence of fatty liver was not a significant factor for HCC development (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.5-1.9). In another multivariable analysis for advanced fibrosis, gender, and fatty liver, advanced fibrosis was found to be a significant factor for HCC development (HR: 9.50, 95% CI: 5.1-18) but not fatty liver (HR: 0.90, 95% CI: 0.5-1.7). In conclusion, in patients with chronic hepatitis B who received NA therapy, advanced fibrosis was found to be an important risk factor for HCC development but not fatty liver, suggesting the importance of providing treatment before the progression of liver fibrosis regardless of the presence of fatty liver.

Improvement of glycaemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 1 study).

AIM: To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycaemic control and treatment satisfaction in patients with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued current therapy. The primary endpoint was the mean change in glycated haemoglobin over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire scores, body weight and metabolic indices. RESULTS: In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. Glycated haemoglobin levels were significantly reduced in the semaglutide group in both plans [plan A, 7.8% ± 1.0% to 7.8% ± 0.7% (liraglutide) vs. 7.9% ± 0.7% to 7.3% ± 0.7% (semaglutide), p < .01; plan B, 7.8% ± 1.0% to 7.9% ± 1.2% (dulaglutide) vs. 7.8% ± 0.8% to 7.1% ± 0.6% (semaglutide), p < .01]. Semaglutide also improved Diabetes Treatment Satisfaction Questionnaire scores in both groups (plan A, +0.1 vs. +8.3, p < .01; plan B, -1.2 vs. +3.5, p < .01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. CONCLUSIONS: Once-weekly semaglutide administration improved glycaemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite glucagon-like receptor-1 receptor agonist treatment.

Risk of cardiovascular disease in lean patients with nonalcoholic fatty liver disease.

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) are highly at risk for cardiovascular disease (CVD). However, the risk of developing CVD in patients with lean NAFLD is not yet fully understood. Therefore, this study aimed to compare the CVD incidence in Japanese patients with lean NAFLD and those with non-lean NAFLD. METHODS: A total of 581 patients with NAFLD (219 with lean and 362 with non-lean NAFLD) were recruited. All patients underwent annual health checkups for at least 3 years, and CVD incidence was investigated during follow-up. The primary end-point was CVD incidence at 3 years. RESULTS: The 3-year new CVD incidence rates in patients with lean and non-lean NAFLD were 2.3% and 3.9%, respectively, and there was no significant difference between two groups (p = 0.3). Multivariable analysis adjusted for age, sex, hypertension, diabetes, and lean NAFLD/non-lean NAFLD revealed that age (every 10 years) as an independent factor associated with CVD incidence with an odds ratio (OR) of 2.0 (95% confidence interval [CI]: 1.3-3.4), whereas lean NAFLD was not associated with CVD incidence (OR: 0.6; 95% CI: 0.2-1.9). CONCLUSIONS: CVD incidence was comparable between patients with lean NAFLD and those with non-lean NAFLD. Therefore, CVD prevention is needed even in patients with lean NAFLD.

Alanine aminotransferase levels as therapeutic targets after nucleotide/nucleoside analog therapy in patient with chronic hepatitis B.

AIM: Alanine aminotransferase (ALT) is a criterion for the introduction of nucleotide/nucleoside analog (NA), and ALT levels are decreased by NA treatment. However, the association between post-treatment ALT levels and hepatocellular carcinoma (HCC) risk remains unclear. To fill this gap, we aimed to establish a target value of ALT level during NA treatment. METHODS: In total, 413 patients with chronic hepatitis B who received entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. The subsequent development of HCC was examined and a target value of ALT level during NA treatment as a risk marker for HCC was evaluated. RESULTS: The median follow-up duration was 5.1 years, during which time 27 patients (8.6%) developed HCC. ALT level at the start of treatment was not associated with HCC development (p = 0.08). When stratified by ALT at 1 year after NA initiation, the cumulative 3- and 5-year rates of HCC for patients with ALT ≥21 IU/L were 11.5% and 18.1%, and those with ALT <21 IU/L was 2.3% and 6.5%, respectively. Patients with ALT <21 IU/L had a significantly lower risk of HCC development compared with patients with ALT ≥21 IU/L (p = 0.002). In multivariable analysis adjusting age, sex, and platelet counts, ALT ≥21 IU/L was an independent risk factor of HCC development with hazard ratio of 4.5 (95% confidence interval: 1.01-20.4). CONCLUSIONS: ALT <21 IU/L at 1 year after NA initiation has a lower risk of HCC and could be used as a target value for NA treatment.

The monitoring of oil production process by deep learning based on morphology in oleaginous yeasts.

BACKGROUND: Monitoring jar fermenter-cultured microorganisms in real time is important for controlling productivity of bioproducts in large-scale cultivation settings. Morphological data is used to understand the growth and fermentation states of these microorganisms during monitoring. Oleaginous yeasts are used for their high productivity of single-cell oils but the relationship between lipid productivity and morphology has not been elucidated in these organisms. RESULTS: In this study, we investigated the relationship between the morphology of oleaginous yeasts (Lipomyces starkeyi and Rhodosporidium toruloides were used) and their cultivation state in a large-scale cultivation setting using a real-time monitoring system. We combined this with deep learning by feeding a large amount of high-definition cell images obtained from the monitoring system to a deep learning algorithm. Our results showed that the cell images could be grouped into 7 distinct groups and that a strong correlation existed between each group and its biochemical activity (growth and oil-productivity). CONCLUSIONS: This is the first report describing the morphological variations of oleaginous yeasts in a large-scale cultivation, and describes a promising new avenue for improving productivity of microorganisms in large-scale cultivation through the use of a real-time monitoring system combined with deep learning. KEY POINTS: • A real-time monitoring system followed the morphological change of oleaginous yeasts. • Deep learning grouped them into 7 distinct groups based on their morphology. • A correlation between the cultivation state and the shape of the yeast was observed.

COVID-19 mRNA vaccination status and concerns among pregnant women in Japan: a multicenter questionnaire survey.

BACKGROUND: mRNA vaccination is an effective, safe, and widespread strategy for protecting pregnant women against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, information on factors such as perinatal outcomes, safety, and coverage of mRNA vaccinations among pregnant women is limited in Japan. Therefore, this study aimed to investigate the perinatal outcomes, coverage, adverse effects, and short-term safety of mRNA vaccination as well as vaccine hesitancy among pregnant women. METHODS: We conducted a multicenter online survey of postpartum women who delivered their offspring at 15 institutions around Tokyo from October 2021 to March 2022. Postpartum women were divided into vaccinated and unvaccinated groups. Perinatal outcomes, COVID-19 prevalence, and disease severity were compared between the two groups. Adverse reactions in the vaccinated group and the reasons for being unvaccinated were also investigated retrospectively. RESULTS: A total of 1,051 eligible postpartum women were included. Of these, 834 (79.4%) had received an mRNA vaccine, while 217 (20.6%) had not, mainly due to concerns about the effect of vaccination on the fetus. Vaccination did not increase the incidence of adverse perinatal outcomes, including fetal morphological abnormalities. The vaccinated group demonstrated low COVID-19 morbidity and severity. In the vaccinated group, the preterm birth rate, cesarean section rate, and COVID-19 incidence were 7.2%, 33.2%, and 3.3%, respectively, compared with the 13.7%, 42.2%, and 7.8% in the unvaccinated group, respectively. Almost no serious adverse reactions were associated with vaccination. CONCLUSIONS: mRNA vaccines did not demonstrate any adverse effects pertaining to short-term perinatal outcomes and might have prevented SARS-CoV-2 infection or reduced COVID-19 severity. Concerns regarding the safety of the vaccine in relation to the fetus and the mother were the main reasons that prevented pregnant women from being vaccinated. To resolve concerns, it is necessary to conduct further research to confirm not only the short-term safety but also the long-term safety of mRNA vaccines.

Ultrahigh-throughput screening of Trichoderma reesei strains capable of carbon catabolite repression release and cellulase hyperproduction using a microfluidic droplet platform.

Trichoderma reesei is the most well-known cellulase producer in the biorefinery industry. Its cellulase biosynthesis is repressed by glucose via carbon catabolite repression (CCR), making CCR-releasing strains with cellulase hyperproduction desirable. Here, we employed a microfluidic droplet platform to culture and screen T. reesei mutants capable of CCR release and cellulase overproduction from extensive mutagenesis libraries. With 3 mutagenesis rounds, about 6.20 × 103 droplets were sorted from a population of 1.51 × 106 droplets in a period of 4.4 h; 76 recovery mutants were screened on flask fermentation, and 2 glucose uptake retarded mutants, MG-9-3 and MG-9-3-30, were eventually isolated. We also generated a hypercellulase producer, M-5, with CCR release via a single mutagenesis round. The hyphal morphology and molecular mechanisms in the mutants were analyzed. This versatile approach combined with a comprehensive understanding of CCR release mechanisms will provide innovative and effective strategies for low-cost cellulase production.

A Case of Migration of a Hydrogel Spacer for Radiotherapy into the Pulmonary Artery.

A 67-year-old man was referred to our hospital for the diagnosis and treatment of prostate cancer. Multidisciplinary discussion led to intensity-modulated radiotherapy preceded by hormone therapy. Before radiotherapy, a biodegradable hydrogel spacer (HS) was placed between the prostate and rectum to reduce radiation injury risk. Three weeks postplacement, pelvic magnetic resonance imaging revealed HS migration into the pelvic vein. Subsequent whole-body contrast-enhanced computed tomography (CECT) revealed HS migration into the pulmonary artery. The patient showed no symptoms or clinical signs. Radiotherapy was completed uneventfully. Complete absorption of the migrated HS was confirmed using CECT images 5 months postplacement.

Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice.

BACKGROUND: We aimed to investigate the efficacy and safety of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (u-HCC) based on whether they had previously received systemic therapy, as well as the association of atezolizumab plus bevacizumab with early alpha-fetoprotein (AFP) response in real-world practice. METHODS: A total of 52 patients with u-HCC were treated with atezolizumab plus bevacizumab between October 2020 and April 2021. The Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were used to evaluate radiological responses. RESULTS: The patients received atezolizumab plus bevacizumab as 1st-line (n = 23), 2nd-line (n = 16), 3rd-line (n = 6), 4th-line (n = 3), 5th-line (n = 3), or 6th-line (n = 1) therapy. According to RECIST, the objective response rate (ORR) and disease control rate (DCR) in all patients were 15.4% and 57.7%. In the 1st-line patients, ORR and DCR based on RECIST 1.1 were 27.3% and 81.8%. The median time to progression (TTP) assessed by RECIST was significantly longer among patients receiving atezolizumab plus bevacizumab as 1st-line therapy than in patients receiving atezolizumab plus bevacizumab as later-line therapy (P < 0.001). Patients with an AFP response (reduction ≥ 20% from baseline) at 6 weeks had a significantly longer TTP assessed by RECIST than those without an AFP response (P = 0.02). CONCLUSION: Patients who received atezolizumab plus bevacizumab as 1st-line therapy had better clinical outcome than those who received atezolizumab plus bevacizumab in later lines. The AFP response at 6 weeks could be a predictor of disease progression.

Atropodiastereoselective 5N-Acylation of 1,5-Benzodiazepin-2-ones with (S)-2-Phenylpropanoyl and (S)-2-Phenylbutanoyl Chlorides.

5N-Acylation of 1N-methyl-1,5-benzodiazepin-2-ones with (S)-2-phenylpropanoyl and (S)-2-phenylbutanoyl chlorides afforded the (a1S,a2S,S)-atropisomer (I) diastereoselectively over the (a1R,a2R,S)-isomer (II) in the ratio of 1:0.06-0.15. The preferential formation of I may be explained by the thermodynamically preferable π-π stacking interaction between two benzene rings in the benzodiazepine ring and the acyl chloride during the reaction. Analysis using ab initio calculations (RI-MP2/6-31+G(d) level of theory) for the acylation reaction indicated the π-π stacking interaction in the transition state. Furthermore, isomer I was shown to be thermodynamically more stable than II. The higher stability of I may be caused by the folded form of the two benzene rings, which was revealed by NMR, X-ray, and computational analyses.

Plasma Renin Activity Predicts Prognosis and Liver Disease-Related Events in Liver Cirrhosis Patients with Ascites Treated by Tolvaptan.

BACKGROUND AND AIMS: A retrospective study was to analyze the association of plasma renin activity (PRA) with overall survival and liver disease-related events in decompensated liver cirrhosis with ascites treated by tolvaptan. METHODS: We included 196 patients with decompensated cirrhosis treated with tolvaptan and for whom hepatic ascites had remained uncontrolled by conventional diuretics. Factors associated with prognosis and appearance of liver disease-related events were investigated, including vasopressin, sympathetic nervous system hormones (adrenaline, noradrenaline, and dopamine), and the renin-angiotensin system (PRA and aldosterone) at the beginning of tolvaptan treatment. RESULTS: Age, history of hepatocellular carcinoma (HCC), and PRA were identified as independent factors for prognosis after tolvaptan treatment. The median survival time in patients with PRA ≥9.5 ng/mL/h at the beginning of tolvaptan treatment was significantly shorter than in patients with PRA <9.5 ng/mL/h (193 vs. 893 days, p < 0.001). PRA and a history of HCC were independent factors for the occurrence of liver disease-related events. The median event-free period in patients with PRA ≥3.2 ng/mL/h was significantly shorter than that of patients with PRA <3.2 ng/mL/h (89 vs. 222 days, p < 0.001). CONCLUSIONS: PRA is an independent predictor of prognosis and appearance of liver disease-related events in patients with decompensated cirrhosis who have started tolvaptan treatment.

Isolated Bone Recurrence of Medulloblastoma With MYCN Amplification and TP53 Loss: A Case Report.

Extraneural recurrence of a medulloblastoma is rare with dismal prognosis. A 9-year-old girl with medulloblastoma was treated with gross total resection followed by a combination of chemotherapy and radiotherapy. Fourteen months after treatment completion, she developed multifocal bone metastases. Despite chemotherapy combined with irradiation, she died 18 months after recurrence due to progressive disease. Fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue sections revealed MYCN amplification and TP53 loss, consistent with the genetic alterations of a rapidly progressive subgroup of recurrent medulloblastomas. In clinical practice, dismal biologic features can be determined using fluorescence in situ hybridization in defective materials.

Nobiletin and 3'-Demethyl Nobiletin Activate Brown Adipocytes upon ß-Adrenergic Stimulation.

Brown adipose tissue (BAT) specifically regulates energy expenditure via heat production. Nobiletin (NOB), a natural polymethoxylated flavone present in citrus fruits, can activate thermogenesis in the BAT of high-fat diet-induced obese mice. The activity of BAT is directly regulated by ß-adrenergic stimulation. In this study, we report the effects of NOB on BAT activation using ß-adrenergic agonists. We observed that when HB2 brown adipocyte cell lines are stimulated with ß-adrenergic agonists, NOB enhances the expression of uncoupling protein 1 (UCP1), which is associated with the mitochondrial energy metabolism in these cells. Moreover, NOB increases the mRNA expression of the brown adipokines neuregulin-4 (Nrg4) and fibroblast growth factor-21 (FGF-21) and the secretion of FGF-21. These results suggest that NOB can enhance the thermogenic functions of brown adipocytes and promote brown adipokine secretion due to enhanced ß-adrenergic stimulation. In addition, 3'-demethyl nobiletin (3'-DMN), an NOB CYP-enzyme metabolite, can increase UCP1 mRNA expression. Both NOB and 3'-DMN significantly promoted mitochondrial membrane potential in HB2 adipocytes following ß-adrenergic stimulation. Therefore, we believe that NOB could be a promising candidate for activating BAT under ß-adrenergic stimulation and preventing the onset of obesity.

Lymphocytic panhypophysitis and anti-rabphilin-3A antibody with pulmonary sarcoidosis.

PURPOSE: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. METHODS AND RESULTS: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. CONCLUSION: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.

Do the benefits of sodium-glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes?

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are well-established means of improving glycemia and preventing cardio-renal events in patients with type 2 diabetes. However, their efficacy and safety have yet to be fully characterized in patients with type 1 diabetes (T1D). We studied patients with T1D who regularly attended one of five diabetes centers and treated with an SGLT2i (ipragliflozin or dapagliflozin) for >52 weeks, and the changes in HbA1c, body mass, insulin dose, and laboratory data were retrospectively evaluated and adverse events (AEs) recorded during December 2018 to April 2021. A total of 216 patients with T1D were enrolled during the period. Of these, 42 were excluded owing to short treatment periods and 15 discontinued their SGLT2i. The mean changes in glycated hemoglobin (HbA1c), body mass, and insulin dose were -0.4%, -2.1 kg, and -9.0%, respectively. The change in HbA1c was closely associated with the baseline HbA1c (p < 0.001), but not with the baseline body mass or renal function. The basal and bolus insulin doses decreased by 18.2% and 12.6%, respectively, in participants with a baseline HbA1c <8%. The most frequent AE was genital infection (2.8%), followed by diabetic ketoacidosis (DKA; 1.4%). None of the participants experienced severe hypoglycemic events. In conclusion, the administration of an SGLT2i in addition to intensive insulin treatment in patients with T1D improves glycemic control and body mass, without increasing the incidence of hypoglycemia or DKA.

Examination of Suprahyoid Muscle Resection and Other Factors Affecting Swallowing Function in Patients With Advanced Oral Cancer After Surgical Resection and Reconstruction.

Dysphagia is one of the most common adverse effects associated with oral cancer therapy and could greatly impair postoperative quality of life. The objective of this study was to analyze postoperative swallowing outcomes and factors influencing postoperative swallowing function in patients with advanced oral cancer who underwent primary reconstruction after surgical resection to identify patients at risk of experiencing severe dysphagia after immediate reconstruction of surgical defects, and to determine an ideal approach to provide appropriate perioperative interventions. The swallowing status was evaluated at 4 week postoperatively using the Functional Oral Intake Scale. We also analyzed the effects of patient, tumor, surgical, and other factors on postoperative swallowing function. The study included 67 patients. At 4 weeks postoperatively, 11 patients showed reduced swallowing function, whereas 56 patients showed good swallowing function. The number of resected suprahyoid muscles (odds ratio, 1.55; 95% confidence interval, 1.03-2.32; P=0.035) was an independent factor influencing postoperative swallowing function. Thus, among patients who underwent radical resection of oral cancer with primary reconstruction, those with extensive resection of the suprahyoid muscles were at higher risk of developing postoperative dysphagia. These findings are expected to facilitate increased vigilance for dysphagia, better counseling, and appropriate rehabilitation interventions.