Prediction of Mismatch Repair Status in Endometrial Cancer from Histological Slide Images Using Various Deep Learning-Based Algorithms.

The application of deep learning algorithms to predict the molecular profiles of various cancers from digital images of hematoxylin and eosin (H&E)-stained slides has been reported in recent years, mainly for gastric and colon cancers. In this study, we investigated the potential use of H&E-stained endometrial cancer slide images to predict the associated mismatch repair (MMR) status. H&E-stained slide images were collected from 127 cases of the primary lesion of endometrial cancer. After digitization using a Nanozoomer virtual slide scanner (Hamamatsu Photonics), we segmented the scanned images into 5397 tiles of 512 × 512 pixels. The MMR proteins (PMS2, MSH6) were immunohistochemically stained, classified into MMR proficient/deficient, and annotated for each case and tile. We trained several neural networks, including convolutional and attention-based networks, using tiles annotated with the MMR status. Among the tested networks, ResNet50 exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.91 for predicting the MMR status. The constructed prediction algorithm may be applicable to other molecular profiles and useful for pre-screening before implementing other, more costly genetic profiling tests.

Investigation of the metabolic and endocrinological differences between daily and weekly growth hormone replacement therapy, somapacitan, in patients with adult growth hormone deficiency: A real-world pilot study.

In this real-world pilot study, we evaluated the metabolic and endocrinological effects in patients with adult growth hormone deficiency (AGHD) who switched from daily growth hormone (GH) replacement therapy to weekly GH replacement therapy using somapacitan. Eleven patients with AGHD, whose medical treatment aside from GH replacement therapy did not change, were enrolled. We investigated the metabolic and endocrinological parameters between at switching and 6 months after switching from daily GH formulation to somapacitan. The results showed that body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and liver functions were significantly improved 6 months after switching compared to those at switching (each P < .05). Besides, the improvement in HOMA-IR was significantly associated with the period of daily GH replacement therapy before switching (P = .048), while age, sex, improvement in BMI or liver functions, presence of any hormonal deficiency, and the existence of any hormonal replacement therapy significantly associated (P > .05). In addition, switching to GH replacement therapy did not affect endocrinological parameters. In conclusion, this study might indicate that weekly GH replacement therapy with somapacitan could have more beneficial points than daily GH replacement therapy. Considering the cohort of this study was small, future studies with larger cohorts should be necessary to confirm the results of this study.

Clinical evaluations of pituitary apoplexy in incidental nonfunctional pituitary adenomas.

Pituitary apoplexy is an uncommon syndrome that often results in spontaneous hemorrhage or infarction of pituitary tumors or glands. We previously reported pituitary apoplexy occurred most frequently in nonfunctional pituitary adenomas among all types of pituitary incidentalomas. In the present study, we aimed to investigate the characteristics of pituitary apoplexy in patients with incidental nonfunctional pituitary adenomas. 65 patients with pituitary incidentaloma were enrolled. All patients underwent clinical/endocrinological/pathological investigations. As a result, 33 patients were diagnosed with nonfunctional pituitary adenomas. Of these, 12.1% of patients had pituitary apoplexy. There was no difference in tumor diameter, age, or sex between the apoplexy and the non-apoplexy groups. However, the liver enzymes aspartate transaminase and alanine aminotransferase were significantly higher, and plasma sodium and chloride levels were significantly lower in the apoplexy group than in the non-apoplexy group (each P < .05). In addition, low-density lipoprotein-cholesterol was significantly higher in the apoplexy group than in the non-apoplexy group (P < .05). Besides, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin deficiencies were significantly more frequent in the apoplexy group than in the non-apoplexy group (each P < .05), and growth hormone and adrenocorticotropic hormone deficiencies were more frequent in the apoplexy group than in the non-apoplexy group (P = .09 and.08, respectively). Furthermore, tumor diameter was not associated with pituitary apoplexy, whereas thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies were significantly associated with the apoplexy group (each P < .05). Hence, the present study indicated that pituitary apoplexy could not be related to tumor diameter. Moreover, hormonal deficiencies, hepatic dysfunction, hyponatremia or hypochloremia, and dyslipidemia might be indicators of pituitary apoplexy. There could be the possibility the treatment for dyslipidemia prevents pituitary apoplexy.

Clinical investigation of a unique type of hypothalamic adrenal insufficiency.

Hypothalamic adrenal insufficiency (AI) is a rare but distinct type of AI. The leading cause of hypothalamic AI is a secondary side-effect of exogenous steroid intake, particularly in large amounts and/or long-term periods. The next cause would be the effect of the tumor in the hypothalamic lesions. We show here 9 cases of hypothalamic AI without any disorder on imagings and a history of steroid administration. All patients had general fatigue; 7 patients (77.8%) had a history of hypoglycemia; 5 patients (55.6%) had a history of hypotension. None of the patients had hyponatremia, hyperkalemia, or eosinophilia. Their morning plasma adrenocorticotropic hormone (ACTH) value was low at 8.5 ± 4.2 pg/mL, and serum cortisol value was low at 4.5 ± 1.3 µg/dL. All patients demonstrated normal responses during the corticotropin-releasing hormone loading (CRH) test but inadequate responses during the insulin tolerance test (ITT). After hydrocortisone replacement therapy, their morning plasma ACTH and serum cortisol values were significantly recovered (P < .05). Moreover, more than half of the patients were fine after discontinuing hydrocortisone replacement therapy. These results indicate that this unique type of hypothalamic AI has a curable clinical course making hydrocortisone replacement therapy a novel therapeutic option.

Inhibition of NR5A1 Phosphorylation Alleviates a Transcriptional Suppression Defect Caused by a Novel NR0B1 Mutation.

Context: Mutations in the NR0B1 gene, also well-known as the DAX1 gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to NR0B1 mutations may be compensated by inducing loss of function of NR5A1 protein. Patient: A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel NR0B1 mutation, c.1222C>T(p.Gln408Ter). Methods: NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter. Results: TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. Conclusion: The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations.

Adrenal Hemorrhage in a Cortisol-Secreting Adenoma Caused by Antiphospholipid Syndrome Revealed by Clinical and Pathological Investigations: A Case Report.

Due to its rarity, adrenal hemorrhage is difficult to diagnose, and its precise etiology has remained unknown. One of the pivotal mechanisms of adrenal hemorrhage is the thrombosis of the adrenal vein, which could be due to thrombophilia. However, detailed pathological evaluation of resected adrenal glands is usually required for definitive diagnosis. Here, we report a case of a cortisol-secreting adenoma with concomitant foci of hemorrhage due to antiphospholipid syndrome diagnosed both clinically and pathologically. In addition, the tumor in this case was pathologically diagnosed as cortisol-secreting adenoma, although the patient did not necessarily fulfill the clinical diagnostic criteria of full-blown Cushing or sub-clinical Cushing syndrome during the clinical course, which also did highlight the importance of detailed histopathological investigations of resected adrenocortical lesions.

Surgical Orthodontic Treatment Involving Mandibular Premolar Extraction in Patient with Mandibular Retrusion Associated with Temporomandibular Joint Osteoarthritis.

Here, we report retention following surgical orthodontic treatment in a patient with vertical maxillary excess associated with temporomandibular joint osteoarthritis (TMJOA) and marked mandibular retrusion. The patient was a man aged 20 years 10 months who presented with the chief complaint of maxillary protrusion. The facial profile was of the convex type due to marked mandibular retrusion. In addition, the patient had a gummy smile. Intraoral findings revealed a Class II molar relation, +11 mm overjet, and 0 mm overbite. Mandibular dentition arch length discrepancy showed crowding of -2 mm, and the maxillary dentition showed a spaced arch of +5 mm. Panoramic radiographs confirmed flattening of the condylar head and proliferation of the bone margin. Cephalometric analysis of the skeletal pattern revealed that, horizontally, the maxilla was anterior and the mandible posterior; vertically, a dolichofacial pattern was noted. The anterior maxillary tooth axis was standard, but the anterior mandibular tooth axis showed labial inclination. Based on these findings, skeletal maxillary protrusion associated with TMJOA was diagnosed. Surgical orthodontic treatment comprised bilateral mandibular first premolar extraction with two-jaw surgery and genioplasty. Orthodontic treatment was performed with a multibracket system using a 0.22-slot pre-adjusted edgewise appliance. At 2 years and 11 months after initiation of treatment, the maxilla was transposed 6 mm upwards by orthognathic surgery and the mandible 17 mm anteriorly and 5 mm upwards by counterclockwise rotation. At 3 years and 10 months, the Pogonion was moved 6 mm anteriorly by genioplasty. At 4 years, orthodontic treatment was concluded on confirming satisfactory occlusion and improvement in facial features. At 2 years after completion of treatment, occlusion and the maxillofacial morphology remain stable, with almost no relapse. In addition, no temporomandibular joint disorder symptoms have occurred. Careful comprehensive follow-up observation will be continued.