Is blue light imaging without magnification satisfactory as screening for esophageal squamous cell carcinoma? Post-hoc analysis of multicenter randomized controlled trial.

OBJECTIVES: Narrow light observation is currently recommended as an alternative to Lugol chromoendoscopy (LCE) to detect esophageal squamous cell carcinoma (ESCC). Studies revealed little difference in sensitivity between the two modalities in expert settings; however, these included small numbers of cases. We aimed to determine whether blue light imaging (BLI) without magnification is satisfactory for preventing misses of ESCC. METHODS: This was a post-hoc analysis of a multicenter randomized controlled trial targeting patients at high risk of ESCC in expert settings. In this study, BLI without magnification followed by LCE was performed. The evaluation parameters included: (i) the diagnostic abilities of ESCC; (ii) the endoscopic characteristics of lesions with diagnostic differences between the two modalities; and (iii) the color difference between cancerous and noncancerous areas in BLI and LCE. RESULTS: This study identified ESCC in 49 of 699 cases. Of these cases, nine (18.4%) were missed by BLI but detected by LCE. In per-patient analysis, the sensitivity of BLI was lower than that of LCE following BLI (83.7% vs. 100.0%; P = 0.013), whereas the specificity and accuracy of BLI were higher (88.2% vs. 81.2%; P < 0.001 and 87.8% vs. 82.5%; P < 0.001, respectively). No significant endoscopic characteristics were identified, but the color difference was lower in BLI than in LCE (21.4 vs. 25.1; P = 0.003). CONCLUSION: LCE following BLI outperformed BLI in terms of sensitivity in patients with high-risk ESCC. Therefore, LCE, in addition to BLI, would still be required in screening esophagogastroduodenoscopy even by expert endoscopists.

Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice.

Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

Living-Donor Liver Transplantation for Erythropoietic Protoporphyria: A Case Report and Literature Review.

Erythropoietic protoporphyria (EPP) is a very rare disease with an estimated prevalence of 1 in 200,000 individuals. Decreased ferrochelatase activity causes the accumulation of protoporphyrin in the body, and light exposure results in the generation of active oxygen, causing photosensitivity. Liver damage has the greatest influence on the prognosis, and liver transplantation is the only treatment option for patients with decompensated liver cirrhosis. We report a case of living-donor liver transplantation for decompensated liver cirrhosis associated with EPP. The patient was a 52-year-old male who led a normal life except for mild photosensitivity. When the patient was 37-year-old, hepatic dysfunction was noticed. At 48-year-old, high erythrocyte protoporphyrin levels, skin biopsy, and genetic tests resulted in a diagnosis of EPP. The patient underwent living- donor liver transplantation because of decompensated liver cirrhosis. In the operating room and intensive care unit, a special light-shielding film was applied to all light sources to block light with harmful wavelengths during treatment. Due to the need for special measures, a lecture on patients with EPP was given before surgery to deepen understanding among all medical professionals involved in the treatment. As a result, no adverse events occurred during the perioperative period, and the patient was discharged on the 46th post-operative day. Currently, the transplanted liver is functioning extremely well, and the patient is alive 3 years post-transplant. Herein, we describe a case of living donor liver transplantation for EPP with a brief literature review.

Blue light imaging and linked color imaging as a screening mode for esophageal squamous cell carcinoma in high-risk patients: Multicenter randomized trial.

OBJECTIVES: Blue light imaging (BLI) and linked color imaging (LCI) are superior to conventional white light imaging for detecting esophageal squamous cell carcinoma (ESCC). Hence, we compared their diagnostic performances in ESCC screening. METHODS: This open-labeled, randomized controlled trial was performed at seven hospitals. Patients with a high risk of ESCC were randomly assigned to the BLI group (BLI followed by LCI) and LCI group (LCI followed by BLI). The primary end-point was the detection rate of ESCC in the primary mode. The main secondary end-point was its miss rate in the primary mode. RESULTS: In total, 699 patients were enrolled. The detection rate of ESCC did not significantly differ between the BLI and LCI groups (4.0% [14/351] vs. 4.9% [17/348]; P = 0.565); however, the number of patients with ESCC tended to be smaller in the BLI group (19 vs. 30). Notably, the miss rate of ESCC was lower in the BLI group (26.3% [5/19] vs. 63.3% [19/30]; P = 0.012) and LCI detected no ESCCs missed by BLI. The sensitivity was higher in BLI (75.0% vs. 47.6%; P = 0.042); on the other hand, the positive predictive value in BLI tended to be lower (28.8% vs. 45.5%; P = 0.092). CONCLUSIONS: The detection rates of ESCC did not significantly differ between BLI and LCI. Although BLI may have the potential to be advantageous over LCI for the diagnosis of ESCC, it is still unclear whether BLI is superior to LCI, and a further large-scale study is needed. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT1022190018-1).

A case of synchronous double cancers consisting of maxillary gingival carcinoma and intraductal papillary mucinous carcinoma, invasive: case report.

BACKGROUND: The development of synchronous multiple primary cancers is one of the major causes of death in patients with head and neck cancer. Herein, we report a case of synchronous intraductal papillary mucinous carcinoma (IPMC), invasive in a patient with maxillary gingival carcinoma. CASE PRESENTATION: A 73-year-old female visited our hospital complaining of a mass on the left side of the maxillary gingiva. Intraorally, an exophytic tumor, 50 × 25 mm in size, was found on the gingiva of the left maxillary posterior, and a diagnosis of squamous cell carcinoma was revealed by cytology. Emission tomography/ computed tomography with 18 Fluorodeoxyglucose-Positron (18FDG- PET/ CT) showed increased accumulation in the left maxillary gingiva, the left side of cervical lymph nodes, and the main pancreatic duct. The pancreatic ductal tumor was performed the biopsy at esophagogastroduodenoscopy (EGD) and resulted in a pathological diagnosis of IPMC, invasive. The patient was diagnosed as synchronous double primary cancers consisting of maxillary gingival carcinoma cT4aN2bM0 and IPMC, invasive cT3N0M0. She refused radical treatment, and died 11 months later. CONCLUSION: 18FDG- PET/ CT, EGD and multidisciplinary approach is required for the detection and determining the treatment strategy of synchronous double primary cancers.

Establishment of a monoclonal antibody against glycosylated CD271 specific for cancer cells in immunohistochemistry.

Various proteins are highly expressed in cancer (e.g., epidermal growth factor receptor); however, the majority are also expressed in normal cells, although they may differ in expression intensity. Recently, we reported that CD271 (nerve growth factor receptor), a glycosylated protein, increases malignant behavior of cancer, particularly stemlike phenotypes in squamous cell carcinoma (SCC). CD271 is expressed in SCC and in normal epithelial basal cells. Glycosylation alterations generally occur in cancer cells; therefore, we attempted to establish a cancer-specific anti-glycosylated CD271 antibody. We purified recombinant glycosylated CD271 protein, immunized mice with the protein, and screened hybridomas using an ELISA assay with cancer cell lines. We established a clone G4B1 against CD271 which is glycosylated with O-glycan and sialic acid. The G4B1 antibody reacted with the CD271 protein expressed in esophageal cancer, but not in normal esophageal basal cells. This specificity was confirmed in hypopharyngeal and cervical cancers. G4B1 antibody recognized the fetal esophageal epithelium and Barrett's esophagus, which possess stem cell-like characteristics. In conclusion, G4B1 antibody could be useful for precise identification of dysplasia and cancer cells in SCC.

Cholesterol Granuloma of the Liver Mimicking Malignant Tumor: A Case Report.

Cholesterol granuloma is a benign, tumor-like lesion with an accumulation of cholesterol crystals in the tissue and is a consequence of a chronic inflammatory reaction. It commonly occurs in the middle ear but rarely in the liver. There is only one previous case report of cholesterol granuloma of the liver, which was caused by cholesterol hepatolithiasis. We report a case of cholesterol granuloma of the liver in a patient with no intrahepatic cholesterol stones; it was difficult to rule out malignant liver tumor preoperatively. The patient was a 79-year-old woman in whom a lesion in the liver was detected on abdominal ultrasonography. She was referred to our hospital for detailed examination and treatment. Abdominal contrast-enhanced computed tomography showed a 20 mm lesion with ring enhancement in the lateral segment of the liver during the arterial and delayed phases. Since a malignant tumor could not be ruled out radiologically, laparoscopic lateral segment hepatectomy was performed for definitive diagnosis and treatment. The resection specimen showed a yellowish-white lesion measuring 15 mm in diameter. Pathological examination showed a granulomatous lesion with cholesterol crystals surrounded by foreign body giant cells. The lesion was diagnosed as cholesterol granuloma of the liver. The postoperative course was good, and the patient was discharged on postoperative day 5. She was healthy, and no recurrence of the cholesterol granuloma was detected at the 5-month follow-up. This is the first case report of cholesterol granuloma of the liver mimicking a malignant liver tumor in a patient with no intrahepatic cholesterol stones.

Advanced extramedullary hematopoiesis with a marked increase in reticulin fibers and hemorrhage on various organs: the first autopsy case report.

Myelofibrosis is characterized by stem cell-derived clonal proliferation potentially resulting in bone marrow fibrosis. As the disease progresses, extramedullary hematopoiesis is frequently detected in the spleen and the liver but rarely in other organs. We report a case of a 68-year-old woman with myelofibrosis with a JAK2 mutation, showing extramedullary hematopoiesis (EMH) in various organs with a marked increase in reticulin fibers, and myeloproliferative neoplasm (MPN)-related necrotizing crescent glomerulonephritis. She was admitted to our hospital owing to respiratory discomfort. Computed tomography revealed a mass in the anterior mediastinum. Ten days later, the patient died owing to respiratory distress. At autopsy, EMH were detected in the anterior mediastinum, heart, lung, spleen, and the kidney with a marked increase in reticulin fibers. We considered that respiratory distress was partially caused by EMH. In the kidney, necrotizing crescent glomerulonephritis was observed. Immunohistochemically, the glomerular basement and mesangial area were IgA- and C3d-positive. Ultrastructural examination revealed the presence of dense deposits in the subendothelial space and the mesangial and paramesangial areas. Thus, we suspected that MPN-related necrotizing crescentic glomerulonephritis harbored a pathogenesis similar to that of IgA-dominant post-infectious glomerulonephritis or IgA nephropathy. This case report could widen the spectrum of MPN- or EMH-related lesions.

Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation.

Biliary atresia (BA) is a cholestatic disease with extrahepatic bile duct obstruction that requires early surgical intervention and occasionally liver transplantation (LT). Accumulation of toxic bile acids induces oxidative stress that results in cell damage, such as cell senescence, mitochondrial dysfunction and others. However, details of their reciprocal association and clinical significance are unexplored. Therefore, we used immuno-localization of markers for cell senescence (p16 and p21), nuclear double-strand DNA damage (γH2AX), autophagy (p62), and mtDNA damage (mtDNA copy number) in patients with BA who underwent Kasai portoenterostomy (KP) and LT. We studied liver biopsy specimens from 54 patients with BA, 14 who underwent LT and 11 from the livers of neonates and infants obtained at autopsy. In hepatocytes, p21 expression was significantly increased in KP. In cholangiocytes, p16 expression was significantly increased in LT, and p21 expression was significantly increased in KP. p62 expression was significantly increased in the KP hepatocytes and LT cholangiocytes. Furthermore, mtDNA copy number significantly decreased in KP and LT compared with the control. Cell senescence and mitochondrial DNA damage progression were dependent on the BA clinical stages and could possibly serve as the markers of indication of LT.

Rapidly progressive glomerulonephritis in a patient with angioimmunoblastic T-cell lymphoma: a rare autopsy case showing IgA vasculitis and cylinder-like deposits.

Angioimmunoblastic T-cell lymphoma (AITL), a hematological malignancy, originates from follicular helper T cells. The primary site of AITL is the lymph nodes, but extranodal presentation is frequent in patients with advanced stages. Here, we report a rare case of a patient with AITL presenting with rapidly progressive glomerulonephritis (RPGN). The patient underwent computed tomography, which showed systemic lymph node swelling. RPGN was noted at the time of admission. Livedo was observed in the lower limbs with purpura on the foot. The patient was diagnosed with AITL based on lymph node biopsy. Skin biopsy revealed vasculitis with immunoglobulin A (IgA) deposits. Renal biopsy revealed endocapillary proliferative glomerulonephritis with massive subendothelial deposits and intraluminal thrombi. Immunofluorescence showed IgA, IgG, and complement component 3c-predominant granular staining pattern in the capillary and mesangial areas. Electron micrographs demonstrated dense cylindrical-like deposits in the subendothelial space. Chemotherapy drugs were administered, but the patient's respiratory distress increased until death. Upon autopsy, membranoproliferative glomerulonephritis and extensive necrotizing cellular crescent formation were observed in the glomeruli. Taken together, this case is a rare combination of AITL and RPGN showing both cylinder-like deposits suggestive of cryoglobulinemic glomerulonephritis (CN) and IgA vasculitis.

[A case of abscess-associated hepatocellular carcinoma with massive lymphoid cell infiltration].

A 76-year-old Japanese man was admitted to our hospital with chills and fever. Computed tomography revealed a 10-cm cystic tumor with peripheral ring enhancement in the left lobe of the liver and several small low-density areas with early peripheral enhancement in both lobes. The large liver mass was diagnosed as a pyogenic abscess and treated with antibiotics. However, elevation of the tumor marker, PIVKA-II, raised the possibility of hepatocellular carcinoma. A fine-needle aspiration biopsy was performed, and malignant hepatic cells were identified. The patient underwent left hepatectomy. Histological analyses of the resected surgical specimen confirmed necrotic liver abscess and residual hepatocellular carcinoma with massive lymphoid cell infiltration. Immunohistochemical analyses revealed that the lymphoid cells were positive for CD3 and CD8. The PIVKA-II level returned to normal after surgery and the hepatic lesions disappeared within 10 months. These findings suggest that the liver abscess stimulated cancer immunity, resulting in the proliferation of cytotoxic T lymphocytes and, subsequently, tumor regression.

[Endoscopic mucosal resection of localized plasmablastic lymphoma with early rectal cancer:a rare case report and literature review].

A 79-year-old male with a positive fecal occult blood test result underwent total colonoscopy, which revealed a 15-mm-semipedunculated polyp in the rectum. The polyp appeared to be an adenoma using narrow-band imaging observation in magnifying endoscopy, although a 3mm reddish segment with a different surface structure was identified adjacent to the base of the polyp. En-bloc endoscopic mucosal resection (EMR) was performed. From the pathological evaluation using the specimen, the polyp was mainly a tubular adenoma with an adenocarcinoma component within the lesion. Additionally, a tiny plasmablastic lymphoma (PBL) component, which was positive for CD45, CD79a, CD30, CD38, MUM1, and lambda light chain;negative for CD3, CD5, CD20, CD56, CD138, cyclin D1, PAX5, IgG, IgA, IgM, IgE, HHV8, and kappa light chain, coexisted near the stalk. The proliferation index using Ki-67 immunohistochemistry was approximately 80%. Furthermore, Epstein-Barr virus-encoded RNAs were identified in in-situ hybridization, although the human immunodeficiency virus was not detected. The patient received contrast-enhanced computed tomography (CT) and positron emission tomography-CT (PET-CT) follow-ups after treatment without recurrence for two years. This is the first report of gastrointestinal PBL that could be treated using EMR.

Correlation between TXNRD1/HO-1 expression and response to neoadjuvant chemoradiation therapy in patients with esophageal squamous cell carcinoma.

BACKGROUND: Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are both involved in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and play key roles in antioxidant responses. In patients with esophageal squamous cell carcinoma (ESCC), the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), as well as the difference in their expression after chemoradiotherapy, remains unknown. METHODS: Proteins involved in the Nrf2 pathway were immunolocalized in carcinoma cells in ESCC patients on NACRT with 5-fluorouracil and cisplatin, followed by esophagectomy. The 8-hydroxydeoxyguanosine (8-OHdG) levels were used to quantify reactive oxygen species. The changes in immunoreactivity before and after NACRT (Δ) were assessed. RESULTS: Tumor reduction following NACRT was significantly attenuated in pre-therapeutic biopsy specimens associated with high HO-1 status. TXNRD1Δ, HO-1Δ, and 8-OHdGΔ were significantly different in the ineffective and effective groups. The overall survival was significantly lower in high Nrf2 and TXNRD1 groups. In addition, high TXNRD1 expression was an independent prognostic factor in the multivariate analysis of overall survival. CONCLUSIONS: The study findings indicate that HO-1 status in pre-therapeutic biopsy specimens could predict response to NACRT, and TXNRD1 status could predict overall survival of ESCC patients.

Utility of a new notation to visualize flow cytometry analysis results: first preliminary comparison with immunohistochemistry to detect CD30 expression on T-cell lymphoma cells.

BACKGROUND: It is important to confirm CD30 expression in T-cell lymphoma cases, but immunohistochemical staining for CD30 is not commonly performed and no comparison has been done between the results of flow cytometry (FCM) and immunohistochemical staining for CD30. Therefore, we devised a notation that we termed proportion of immunoreactivity/expression for FCM (PRIME-F notation), based on the cellular proportion showing different antigen-antibody reactivity. METHODS: We retrospectively compiled 211 cases of T-cell lymphoma, assessed via FCM, from major hospitals in Miyagi Prefecture from January 2012 to January 2019, and compared 52 of these cases with the immunohistochemical immunoreactive (IR) pattern of CD30 (PRIME-I notation). The PRIME-F notation was divided into five levels: notations starting with "-" followed by 3, 2, and 1 ">" correspond to level-I, level-II, or level-III; notations starting with "(dim)+" correspond to level-IV; and those starting with "+" or "(bright)+" correspond to level-V. RESULTS: The 52 cases of PRIME-F notation with "+" included 16 cases of peripheral T-cell lymphoma (PTCL/NOS), 3 of follicular T-cell lymphoma (FTL), 3 of angioimmunoblastic T-cell lymphoma (AITL), 6 of extranodal NK/T-cell lymphoma/nasal type (ENKL), 18 of adult T-cell lymphoma (ATL), and 6 cases of anaplastic large cell lymphoma (ALCL). Eight of the 52 cases were immunohistochemically CD30-negative. In the PRIME-F level-I to III group (excluding false-positive cases), 21.7% (5 out of 23 cases) were < 10% positive for CD30 upon immunohistochemistry (IHC). Contrarily, in the level-IV & -V group, no CD30 positivity rate of < 10% upon IHC was found (0%) (p = 0.0497). In level-IV, 42.9% of cases presented a CD30 negative rate > 1/3 upon IHC, while in level-V, only 7.1% (one out of 14 cases) did. The CD30 negative rate tended to be low (p = 0.0877) in level-V. CONCLUSIONS: To our knowledge, this is the first report describing the correspondence between FCM and immunohistochemistry findings for CD30 through newly proposed notations. The PRIME-F and PRIME-I notations for CD30 showed a minor positive correlation. The PRIME notation is considered universally applicable to antibodies, and notations of both FCM and IHC show great potential for big data.

Increased neutrophil-lymphocyte ratio predicts recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

BACKGROUND: The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms. METHODS: Circulating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan-Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals. RESULTS: Univariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR = 3.49 95% CI 1.05-11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46-168.2; P = 0.015) were independent recurrence predictors. CONCLUSIONS: The circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

Necroptosis in biliary atresia of the liver.

Biliary atresia (BA) is characterized by the occlusion of extrahepatic bile ducts due to sclerosing inflammation. Necroptosis is a recently characterized form of programmed cell death but has not been examined in BA. We, therefore, explored the potential involvement of necroptosis in the pathogenesis of BA by evaluating the correlation between necroptosis-related factors and clinicopathological features of BA patients. We studied liver biopsy specimens of 59 patients with BA and 30 with congenital biliary dilatation (CBD). We also evaluated 14 surgical BA cases, who eventually underwent liver transplantation and 9 normal liver from neonates and infants obtained at autopsy. Necroptosis-related factors including toll-like receptor 3 (TLR3), receptor-interacting protein kinase1 (RIP1), receptor-interacting protein kinase3 (RIP3), mixed lineage kinase domain-like (MLKL), and phosphorylated mixed lineage kinase domain-like (pMLKL) in these liver specimens were immunolocalized. TLR3, RIP1, MLKL in the intrahepatic cholangiocytes was significantly higher in BA than CBD. pMLKL immunoreactivity was significantly greater at an earlier age of BA patients. The native liver survival period was significantly prolonged in the high RIP3 group. The low RIP3 status could serve as an adverse clinical prognostic factor for the native liver survival among the necroptosis-related factors examined in this study.

Quantitative digital image analysis of somatostatin receptor 2 immunohistochemistry in pancreatic neuroendocrine tumors.

Immunohistochemical analysis of somatostatin receptor 2 (SSTR2) provides important information regarding the potential therapeutic efficacy of somatostatin analogues (SSAs) in patients with neuroendocrine tumors. HER2 scoring has been proposed to interpret SSTR2 immunoreactivity but their reproducibility was relatively low because of its intrinsic subjective nature. Digital image analysis (DIA) has recently been proposed as an objective and more precise method of evaluating immunoreactivity. Therefore, in this study, we used DIA for analyzing SSTR2 immunoreactivity in pancreatic neuroendocrine tumors (PanNETs) to obtain its H score and "(%) strong positive cells" and compared the results with those of manually obtained HER2 scores. Membranous SSTR2 immunoreactivity evaluated by DIA was calculated by two scales as: "Membrane Optical Density" and "Minimum Membrane Completeness". PanNETs with HER2 score of > 2 demonstrated the highest concordance with results of "(%) strong positive cells" obtained by DIA when "Minimum Membrane Completeness" was tentatively set at 80%. The SSTR2 immunoreactivity, evaluated based on all scoring systems, was different between grades G1 and G2 in insulinoma but not in non-functional PanNETs. DIA provided reproducible results of SSTR2 immunoreactivity in PanNETs and yielded important information as to the potential application of SSAs.

[Complete Response to Neoadjuvant Chemotherapy with Imatinib of a Large Gastric GIST-A Case Report].

A 54-year-old woman was presented with the intraabdominal mass to our hospital. Abdominal CT showed 22 cm tumor of the stomach with invasion to the pancreas and the spleen. Upper GI endoscopy showed submucosal tumor at the stomach body, and endoscopic US showed low echoic tumor. The tumor was diagnosed as gastric GIST by biopsy with c-kit positive cells. After 4 months of neoadjuvant therapy with imatinib, she underwent total gastrectomy, distal pancreatectomy and splenectomy. Histopathologically, there were no viable tumor cells in the resected specimen. The patient has no evidence of recurrence at 8 months post operation.

GR, Sgk1, and NDRG1 in esophageal squamous cell carcinoma: their correlation with therapeutic outcome of neoadjuvant chemotherapy.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. The glucocorticoid (GC)-glucocorticoid receptor (GR) pathway plays pivotal roles in cellular response to various stresses of tumor cells, including chemotherapy. However, the status of the GC-GR pathway in ESCC, including its correlation with chemotherapeutic responses, is largely unknown. METHODS: GR, serum-and glucocorticoid-regulated kinase 1 (Sgk1), and N-myc down regulation gene 1 (NDRG1) were immunolocalized in 98 patients with ESCC who had undergone esophagectomy following neoadjuvant chemotherapy (NAC) with 2 courses of 5-fluorouracil + cisplatin. We also examined biopsy specimens before NAC in 42 cases and compared the results between those before and after NAC. RESULTS: Overall survival (OS) of the patients treated with surgery following NAC was significantly shorter in the group with high GR than that with low GR status (P = 0.0473). Both OS and disease-free survival (DFS) were significantly shorter in both Sgk1- and NDRG1-high groups than in the low groups (OS: Sgk1, P = 0.0055; NDRG1, P = 0.0021; DFS: Sgk1, P = 0.0240; NDRG1, P = 0.0086). Biopsy specimens before NAC showed significantly shorter DFS in the high Sgk1 group (P = 0.0095), while both OS and DFS were shorter in the high NDRG1 group (OS, P = 0.0233; DFS, P = 0.0006) than in the respective low groups. In the high NDRG1 group of biopsy specimens before NAC, the tumor reduction rate by NAC was significantly attenuated (P = 0.021). CONCLUSIONS: High GR, Sgk1, and NDRG1 statuses in ESCC after NAC was significantly associated with an overall worse prognosis, with no significant changes in their expression levels before and after NAC. Therefore, increased activity of the GC-GR pathway with enhanced induction of Sgk1 and NDRG1 in carcinoma cells play pivotal roles in tumor progression and development of chemo-resistance in patients with ESCC undergoing NAC.