Toll-Like Receptor 7-Expressed Macrophages Are Involved in the Pathogenesis of Esophageal Achalasia and Esophagogastric Junction Outflow Obstruction.

INTRODUCTION: Esophageal achalasia is a typical esophageal motility disorder (EMD). Although viral infections have been hypothesized to play a role in the pathogenesis of esophageal achalasia, its etiology remains unclear. This study used esophageal muscle layer specimens collected during per-oral endoscopic myotomy (POEM) procedures to investigate the association between esophageal achalasia and esophagogastric junction outflow obstruction (EGJOO) and pattern recognition receptors. METHODS: Patients with esophageal achalasia and EGJOO who underwent POEM were allocated to the EMD group. Biopsies of the inner circular muscle were conducted during the POEM procedure. The control group comprised individuals diagnosed with esophageal squamous cell carcinoma who underwent surgical resection. Expression of pattern recognition receptors, including Toll-like receptor (TLR) 7, was examined by polymerase chain reaction. Immunohistochemical staining was performed to determine TLR7 expression sites in the esophageal muscle layer, and the relationship between TLR7 mRNA expression and clinical score was investigated. RESULTS: Our analysis revealed a notable upregulation of TLR7 mRNA levels within the muscle layer of esophageal achalasia and EGJOO, in contrast to those of control specimens. In contrast, the correlation between TLR7 and clinical score was not significant. Immunohistochemical staining revealed increased numbers of TLR7-expressing macrophages between the muscle layers. CONCLUSIONS: TLR7-expressing macrophages are involved in the innate immune response underlying esophageal achalasia and EGJOO. This result will lead to the elucidation of new pathogenetic mechanisms and the development of novel therapeutic targets.

'IHPBA-APHPBA clinical practice guidelines': international Delphi consensus recommendations for gallbladder cancer.

BACKGROUND: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally. METHOD: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts. RESULTS: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC. CONCLUSIONS: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies.

Testicular teratomagenesis from primordial germ cells with overexpression of germinal center-associated nuclear protein.

Testicular teratomas are the major histologic type of testicular germ cell tumors and their incidence continues to grow. Moreover, teratomas can develop from undifferentiated cells in induced pluripotent stem (iPS) cell transplantation therapy, seriously hampering the progress of regenerative medicine. Germinal center-associated nuclear protein (GANP) is thought to be important to the biogenetic control of primordial germ cells and is among the genes susceptible to testicular germ cell tumors. Thus, we analyzed the expression of GANP in human testicular postpubertal-type teratomas and established a novel mouse model to reveal the association between GANP and teratomagenesis. We analyzed 31 cases of human testicular postpubertal-type teratomas and, in all cases, GANP was overexpressed. The aberrant expression was also detected in germ cell neoplasia in situ accompanied by the teratoma. GANP expression was particularly high in the epithelia of the epidermis, cutaneous appendages, and trachea-like ciliated epithelium. To further clarify the association between GANP and teratomagenesis, we established a novel teratomagenesis mouse model (CAG-ganpTg mice). In the GANP-teratoma mice, GANP-overexpressing teratomas were more frequent at the testes and the middle portion of the uterus than has been seen in the previously established mouse models. In conclusion, GANP is overexpressed in testicular postpubertal-type teratomas and is an essential teratomagenic factor. We also found that CAG-ganpTg mice are useful mouse models of teratomagenesis that mimics human midline teratomas and that teratomas may originate from the overexpression of GANP in primordial germ cells.

Exploration of Malignant Characteristics in Neoadjuvant Chemotherapy-Resistant Rectal Cancer, Focusing on Extramural Lesions.

BACKGROUND: Extramural vascular invasion (EMVI) and tumor deposits (TD) are poor prognostic factors in rectal cancer (RC), especially when resistant to neoadjuvant chemotherapy (NAC). We aimed to define differential expression in NAC responders and non-responders with concomitant EMVI and TD. METHODS: From 52 RC surgical patients, post-NAC resected specimens were extracted, comprising two groups: cases with residual EMVI and TD (NAC-resistant) and cases without (NAC-effective). Proteomic analysis was conducted to define differential protein expression in the two groups. To validate the findings, immunohistochemistry was performed in another cohort that included 58 RC surgical patients. Based on the findings, chemosensitivity and prognosis were compared. RESULTS: The NAC-resistant group was associated with a lower 3-year disease-free survival rate than the NAC-effective group (p = 0.041). Discriminative proteins in the NAC-resistant group were highly associated with the sulfur metabolism pathway. Among these pathway constituents, selenium-binding protein 1 (SELENBP1) expression in the NAC-resistant group decreased to less than one-third of that of the NAC-effective group. Immunohistochemistry in another RC cohort consistently validated the relationship between decreased SELENBP1 and poorer NAC sensitivity, in both pre-NAC biopsy and post-NAC surgery specimens. Furthermore, decrease in SELENBP1 was associated with a lower 3-year disease-free survival rate (p = 0.047). CONCLUSIONS: We defined one of the differentially expressed proteins in NAC responders and non-responders, concomitant with EMVI and TD. SELENBP1 was suspected to contribute to NAC resistance and poor prognosis in RC.

Effect of problem-based learning tutor seniority on medical students' emotions: an equivalence study.

BACKGROUND: The effectiveness of peer learning has been recognized and discussed by many scholars, and implemented in the formal curriculums of medical schools internationally. However, there is a general dearth of studies in measuring the objective outcomes in learning. METHODS: We investigated the objective effect of near-peer learning on tutee's emotions and its equivalence within the formal curriculum of a clinical reasoning Problem Based Learning session in a Japanese medical school. Fourth-year medical students were assigned to the group tutored by 6th-year students or by faculties. The positive activating emotion, positive deactivating emotion, negative activating emotion, negative deactivating emotion, Neutral emotion were measured using the Japanese version of the Medical Emotion Scale (J-MES), and self-efficacy scores were also assessed. We calculated the mean differences of these variables between the faculty and the peer tutor groups and were statistically analyzed the equivalence of these scores. The equivalence margin was defined as a score of 0.4 for J-MES and 10.0 for the self-efficacy score, respectively. RESULTS: Of the 143 eligible participant students, 90 were allocated to the peer tutor group and 53 were allocated to the faculty group. There was no significant difference between the groups. The 95% confidence interval of the mean score difference for positive activating emotions (-0.22 to 0.15), positive deactivating emotions (-0.35 to 0.18), negative activating emotions (-0.20 to 0.22), negative deactivating emotions (-0.20 to 0.23), and self-efficacy (-6.83 to 5.04) were withing the predetermined equivalence margins for emotion scores, meaning that equivalence was confirmed for these variables. CONCLUSIONS: Emotional outcomes were equivalent between near-peer PBL sessions and faculty-led sessions. This comparative measurement of the emotional outcomes in near-peer learning contributes to understanding PBL in the field of medical education.

An autopsy case of amyotrophic lateral sclerosis with striatonigral and pallidoluysian degeneration and cat's-eye-shaped neuronal nuclear inclusions.

We report the case of a Japanese woman with sporadic amyotrophic lateral sclerosis (ALS) of 28 months' duration who died at the age of 66 years. Postmortem examination revealed moderate loss of neurons and phosphorylated TDP-43 (p-TDP-43)-immunoreactive neuronal and glial cytoplasmic inclusions in the upper and lower motor neurons. Additionally, marked neuronal loss was observed in the neostriatum, globus pallidum, subthalamic nucleus, and substantia nigra. p-TDP-43-immunoreactive inclusions were frequently found in these areas. Neuronal loss and TDP-43 pathology in the motor, striatonigral, and pallidoluysian systems were predominant on the right side. Moreover, p-TDP-43-immunoreactive cat's-eye-shaped neuronal nuclear inclusions (NNIs) were observed in the affected lesions. NNIs in the striatonigral system were also positive for valosin-containing protein (VCP). We diagnosed the patient as having ALS with striatonigral and pallidoluysian degeneration. Patients with ALS rarely experience pallido-nigro-luysian degeneration. To our best knowledge, only one case of ALS combined with striatonigral and pallidoluysian degeneration has been reported. Neuronal loss in the striatonigral and/or pallidoluysian systems has also been reported in patients with ALS with multisystem degeneration accompanied by long-term use of an artificial respirator. Based on these findings, a possibility of an extremely rare subtype of ALS demonstrating selective loss of neurons in the striatonigral and pallidoluysian systems exists; another possibility is that this type could be an early stage or forme fruste of ALS with multisystem degeneration. Although VCP-positive cat's-eye-shaped NNIs have been reported in spinocerebellar ataxia type-2 cases, our case report presents VCP-positive NNIs in a patient with ALS for the first time.

The clinical and neuropathological picture of adult neuronal intranuclear inclusion disease with no radiological abnormality.

In typical adult neuronal intranuclear inclusion disease (NIID) with predilection for the basal ganglia or cerebral cortex, not only neurons but also glial cells harbor intranuclear inclusions. In addition, these inclusions are present in the peripheral autonomic nervous system, visceral organs and skin. In NIID cases with an expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of the Notch 2 N-terminal like C (NOTCH2NLC) gene, these repeats are located in an upstream open reading frame (uN2C) and result in the production of a polyglycine-containing protein called uN2CpolyG. Typically, patients with adult NIID show high-intensity signals at the corticomedullary junction on diffusion-weighted brain magnetic resonance imaging. We report a case of adult NIID in a 78-year-old Japanese male, who suffered from mild, non-progressive tremor during life but showed no radiographic abnormalities suggestive of adult NIID. Pathologically, ubiquitin-, p62- and uN2CpolyG-positive neuronal intranuclear inclusions were particularly frequent in the hippocampal formation, but were also seen in the enteric plexuses, kidney and cardiac muscles. By contrast, glial intranuclear inclusions were barely evident in the affected regions. The present case also had an immunohistochemical profile differing from that of typical adult NIID. The findings in this case suggest that adult NIID can show clinical, radiographic and pathological heterogeneity.

Gastric Focal Neutrophil Infiltration and Wide Duodenal Gastric Foveolar Metaplasia Are Histologic Discriminative Markers for Crohn's Disease and Behçet's Disease.

BACKGROUND/AIMS: Behçet's disease (BD) with intestinal lesions and Crohn's disease (CD) share clinical features. However, no report has compared the 2 diseases with regard to lesions of the upper gastrointestinal tract (UGT). We aimed to evaluate endoscopic and histologic findings of UGT in CD and BD. METHODS: We retrospectively assessed the endoscopic records and biopsy samples of 84 Helicobacter pylori-negative patients (50 CD, 34 BD). In duodenal samples, MUC5AC immunohistochemical analysis was performed to identify gastric foveolar metaplasia. RESULTS: In endoscopic findings, bamboo joint-like appearance (17/50 CD, 0/34 BD) and erosions (14/50 CD, 2/34 BD) were significantly more frequent in CD gastric lesions (p < 0.001, and p = 0.012). In histologic findings of stomach, focal neutrophil infiltration in lamina propria (15/48 CD, 1/34 BD) was significantly more frequent in CD (p < 0.001). In that of duodenum, wide gastric foveolar metaplasia (19/49 CD, 1/34 BD) was significantly more frequent in CD duodenal lesions (p = 0.013). The mean maximum width of the gastric foveolar metaplasia was 114.0 ± 10.6 and 29.5 ± 4.5 µm for CD and BD respectively (p = 0.003). CONCLUSIONS: In H. pylori-negative patients, gastric focal neutrophil infiltration and wide duodenal gastric foveolar metaplasia were important for distinguishing CD from BD.

Steroidogenesis in ovarian-like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms.

STEROIDOGENESIS IN HEPATIC MUCINOUS CYSTIC NEOPLASM: Aim Mucinous cystic neoplasms (MCNs) occur in the ovary, pancreas, and retroperitoneum but very rarely in the liver. Mucinous cystic neoplasms are known to harbor ovarian-like mesenchymal stroma (OLS) expressing progesterone and estrogen receptors. In this study we evaluated steroidogenesis in OLS of 25 hepatic MCNs and 24 pancreatic MCNs. Methods Both steroid receptors and steroidogenic factors were immunohistochemically evaluated using H-scores and results were compared with those in 15 ovarian MCNs and 10 normal ovaries. Results Androgen receptor (AR) H-scores in OLS were significantly higher in hepatic, pancreatic, and ovarian MCN than those in normal ovaries. H-scores of cytochrome P450 17α-hydroxylase/c17-20 lyase (P450c17) and 5α-reductase-1 (5αRED-1) in the stroma were significantly higher in OLS of hepatic and pancreatic MCN than in the stroma of ovarian MCN and normal ovary. In tumor epithelium, AR H-scores were significantly higher in hepatic and pancreatic MCN than in ovarian MCN. In both hepatic and pancreatic MCN, a significant positive correlation was detected between AR H-score in the epithelium and P450c17 H-score in OLS (hepatic MCN: Pearson's r = 0.446, P = 0.025; pancreatic MCN: r = 0.432, P = 0.035). In pancreatic MCN, a significantly positive correlation was detected between AR H-score in the tumor epithelium and 5αRED-1 H-score in OLS (Pearson's r = 0.458, P = 0.024). Conclusions These results indicated that locally produced androgens in OLS could be pivotal for tumorigenesis of both hepatic and pancreatic MCN and influence epithelial cells, possibly in a paracrine fashion, which could represent biological significance of OLS in these neoplasms.

Colocalization of Bunina bodies and TDP-43 inclusions in a case of sporadic amyotrophic lateral sclerosis with Lewy body-like hyaline inclusions.

Sporadic amyotrophic lateral sclerosis (sALS) is characterized pathologically by loss of upper and lower motor neurons with occurrence of transactivation response DNA-binding protein 43 kDa (TDP-43)-immunoreactive skein-like and round hyaline inclusions. Lewy body-like hyaline inclusions (LBHIs) are also found in a small proportion of sALS cases as well as in individuals with familial ALS with mutations in the Cu/Zu superoxide dismutase (SOD1) gene. LBHIs in sALS are immunopositive for TDP-43, but not for SOD1. The occurrence of Bunina bodies (BBs) is another key pathological feature of sALS. BBs are immunonegative for TDP-43 but immunopositive for cystatin C, transferrin, peripherin and sortilin-related receptor CNS expressed 2 (SorCS2). Despite differences between BBs and TDP-43 inclusions in terms of protein constituents and ultrastructure, the two inclusions are known to be linked. We recently encountered a case of sALS of 10 months duration in which many round hyaline inclusions, LBHIs and BBs were found in the anterior horn cells of the spinal cord. Our immunohistochemical and ultrastructural examinations revealed the presence of BBs within the skein-like and round hyaline inclusions, and in the LBHIs. Colocalization of BB-related proteins (cystatin C, transferrin and SorCS2) and TDP-43 was also confirmed in the halo of LBHIs as well as in the marginal portion of the skein-like and round hyaline inclusions. These findings suggest that there is some relationship between BBs and TDP-43-immunoreactive inclusions in terms of their formation processes.

Calcifying nested stromal epithelial tumor of the liver in a patient with Klinefelter syndrome: a case report and review of the literature.

BACKGROUND: Calcifying nested stromal epithelial tumor (CNSET) is a primary neoplasm of the liver, characterized by well-demarcated nests consisting of spindle and epithelioid cells with calcification and bone formation. An association of Cushing syndrome with CNSET has drawn attention, but the origin of CNSET has not been clarified. CASE PRESENTATION: We report here the case of a 20-year-old male with Klinefelter syndrome who underwent liver resection for an increasing liver tumor that was pathologically diagnosed with CNSET. He was postoperatively followed up and received several examinations, and recurrences and extrahepatic lymph node metastases were detected on the 64th day after surgery. Chemoembolization and chemotherapy were not effective, leading to tumor progression with development of progressive liver failure, and the patient finally died 164 days after hepatectomy. CONCLUSIONS: This case suggests that an imbalance of hormones affects the genesis and progression of CNSET, and indicates the importance of closely following patients with CNSET by imaging with attention to hepatic recurrence and extrahepatic metastases.

[A Case of Primary Neuroendocrine Carcinoma of the Duodenal Bulb].

A 82-year-old man with anemia underwent upper endoscopy, and a hemorrhagic type 1 tumor was detected on the posterior wall of the duodenal bulb. This patient was diagnosed with neuroendocrine carcinoma(NEC)using biopsy. Distant metastasis was not found on imaging. He was referred to our department for the purpose of surgical therapy and underwent pancreaticoduodenectomy. Based on pathological findings, we diagnosed this patient as having NEC. No postoperative adjuvant chemotherapy was administered, but outpatient clinical follow-up was performed. The patient achieved 16 relapse-free months after surgery. Among the cases of NEC with a primary tumor arising from the digestive tract, cases of NEC of the duodenum that are not papillary carcinoma are rare. We report this case in along with a literature review.

Evaluation of the usefulness of the indocyanine green clearance test for chemotherapy-associated liver injury in patients with colorectal cancer liver metastasis.

BACKGROUND: The indocyanine green (ICG) clearance test is reported to be useful for the preoperative evaluation of hepatic functional reserve. However, the ICG clearance test has not been sufficiently investigated in patients with colorectal liver metastasis after chemotherapy. The aim of the present study was to evaluate whether the ICG clearance test is a useful parameter for the preoperative detection of chemotherapy-associated liver injury. METHODS: Ninety-four patients undergoing liver resection for colorectal liver metastasis after chemotherapy were studied. The medical records for each case were retrospectively reviewed. They underwent pathological assessment to clarify the degree of histopathological liver injury of the nontumoral liver parenchyma. In addition, the correlation between the pathological score and the ICG retention rate at 15 min (ICG-R15) was analyzed. RESULTS: Sinusoidal injury was observed in the 31 of 94 patients. Steatohepatitis was observed in the 40 of 94 patients. There was no strong correlation between the preoperative ICG-R15 value and the sinusoidal pathological score (r = 0.117, P = 0.261). There was no strong correlation between the ICG-R15 and the nonalcoholic fatty liver disease activity score (r = 0.215, P = 0.037). CONCLUSIONS: It was difficult to predict the degree of chemotherapy-associated liver injury by the preoperative ICG-R15 value. It is necessary to estimate the hepatic functional reserve based on a combination of several clinical indicators without relying on the ICG test, in order to perform a safe radical liver resection.

Follicular dendritic cell sarcoma arising from the lymph node of the pancreatic head: a case report with literature review.

A 72-year-old man was referred to our hospital for the examination of a pancreatic head mass. Abdominal computed tomography revealed a contrasted 8-cm-diameter tumor extending from the dorsal pancreatic head to the porta hepatis. The preoperative diagnosis was challenging due to the absence of specific imaging findings and the inability to perform a biopsy. Positron emission tomography/computed tomography and diffusion-weighted imaging suggested a malignant tumor originating from the organs surrounding the pancreatic head. Subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection was performed, as dissection from the pancreatic head proved unfeasible. Pathological examination identified the tumor as an enlarged lymph node consisting of pleomorphic large cells forming clusters, positive for follicular dendritic cell markers cluster of differentiation (CD) 21 and CD23. No evidence of tumor capsule infiltration, other organ infiltration, or metastasis to other lymph nodes was observed. The final diagnosis was nodal follicular dendritic cell sarcoma (FDCS) originating from the pancreatic head lymph nodes. No recurrence occurred at 3 years postoperatively with no postoperative treatment. Intraperitoneal nodal FDCS is extremely rare, and occasionally, it can lead to postoperative recurrence and progression. It is crucial to differentiate neoplastic lymph node enlargement around the pancreatic head from nodal FDCS.

[Local recurrence of pheochromocytoma associated with von Hippel-Lindau disease 26 years after bilateral adrenalectomy : a case report].

A 60-year-old man who had undergone left adrenalectomy and right partial adrenalectomy for bilateral pheochromocytoma 26 years ago was found to have an elevated serum noradrenaline (NA) and dopamine (DA) during a long-term follow-up. At the time of right partial adrenalectomy, the normal part of the right adrenal gland was preserved. His cousin and second cousin had pheochromocytoma associated with von Hippel-Lindau (VHL) disease. His eldest daughter had cerebellar hemangioblastoma. Computed tomography and magnetic resonance imaging revealed a tumor which was 17 mm in diameter with contrast enhancement in the vicinity of the S6 region in the liver. 123 I-metaiodobenzylguanidine (MIBG) scintigraphy showed an abnormal accumulation in the same area. The tumor was surgically removed under the diagnosis of recurrence of pheochromocytoma. Histopathological examination revealed findings consistent with recurrent pheochromocytoma. After operation, serum NA and DA returned to normal range and the abnormal up-take on 123I-MIBG scintigraphy disappeared. Genetic testing revealed that the patient and his daughter had VHL disease. An extensive genetic examination and long-term follow-up should be considered for the present family.

[Testicular tumor arising in intra-abdominal testis which was not detected at prior orchidopexy : a case report].

A 35-year-old man with an intra-abdominal testicular tumor arising from the right unresolved intraabdominal testis is reported. At 10 years old, left orchidopexy was successfully performed for bilateral undescended testes. However, the right testis was not detected during the operation, and it was diagnosed as vanishing testis. Twenty-five years later, he was referred to our hospital with the complaint of right lower abdominal pain. Computed tomography revealed huge pelvic tumors and bulky para-aortic lymph node swellings. Histopathologic examination of the needle biopsy specimen obtained from the pelvic tumor revealed seminomatous germ cell tumor. Taking the results with a tumor marker study into consideration, the patient was tentatively diagnosed with non-seminomatous germ cell tumor NSGCT (stage IIB) arising from the unresolved intra-abdominal testis or extragonadal germ cell tumor. He received 3 courses of bleomycin, etoposide, cisplatin (BEP), and 4 courses of VP-16, ifosfamide, cisplatin (VIP). After chemotherapy, we performed tumorectomy and retroperitoneal lymphadenectomy because tumor markers were normalized and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)-CT revealed normalization. We identified the pelvic tumor as an intra-abdominal testicular tumor arising from right unresolved intra-abdominal testis. Pathological examination revealed no residual tumor cells. There has been no recurrence 17 months after surgery.

Adapting the Motivated Strategies for Learning Questionnaire to the Japanese Problem-Based Learning Context: A Validation Study.

The COVID-19 pandemic has greatly changed medical education, and medical trainees' self-regulation has become more emphasized. In Japan, the concept of self-regulated learning has not been fully applied in health profession education due to a lack of effective measurement tools. We aimed to validate the translated Japanese version of the Motivated Strategies for Learning Questionnaire in the context of Problem-Based Learning (J-MSLQ-PBL). The questionnaire employs a seven-point Likert-type scale with 81 items and is categorized into two sections: motivation and learning strategies. An exploratory factor analysis (EFA) was conducted by using Promax rotation to examine the factor structure of the scale, using the collected data from 112 Japanese medical students. Factor extraction was based on a scree plot investigation, and an item was accepted when the factor loading was ≥0.40. In the motivation section, the extracted factors from the EFA were well aligned with the subscales of the original MSLQ, including "Self-Efficacy for Learning and Performance", "Task Value", "Self-Efficacy for Learning and Performance", "Test Anxiety", "Extrinsic Goal Orientation", and "Intrinsic Goal Orientation". In the learning strategies, the extracted factors poorly matched the structure of the original subscales. This discrepancy could be explained by insufficient translation, the limited sample size from a single medical school, or cross-cultural differences in learning strategies between Western and Japanese medical students. Only the motivation part of the J-MSLQ-PBL should be implemented to measure the competency elements of self-regulated learning in Japan.