A novel classification of senile dermatochalasis: insights from clinical and histological analysis.

PURPOSE: Dermatochalasis is a common disorder of the elderly, often requiring upper blepharoplasty. Although it is mainly accepted as a process of aging, its clinical and histological findings vary among patients. The aim of this study was to classify types of dermatochalasis based on their clinical and histological findings. METHODS: This retrospective study included patients with dermatochalasis who had undergone senile blepharoplasty at a single center. Clinical parameters such as margin-to-reflex distance 1 (MRD1), eyelid contour, visual field, and pre-existing medical conditions were assessed. Histological analysis was conducted of eyelid tissues stained with hematoxylin and eosin (H&E) and D2-40 to evaluate dermal edema, inflammation, lymphatic changes, and stromal depth. RESULTS: This study included 67 eyes of 35 patients. The mean age of the patients was 69.0 ± 8.3 years, and the average MRD1 was 1.8 ± 1.3 mm. In correlation analysis, two distinct types of dermatochalasis based on the histological findings were identified: lymphangiectasia-dominant and stromal edema-dominant types. The difference between nasal and temporal side MRD1(NT-MRD1) showed the area under the ROC curve of 0.718 of for distinguishing the two histological types of dermatochalasis was 0.718. CONCLUSION: Our novel classification of senile dermatochalasis based on morphological and histological analysis provides insights into the underlying pathology and may help to predict surgical outcomes and complications.

miR-22-3p and miR-30e-5p Are Associated with Prognosis in Cervical Squamous Cell Carcinoma.

Alteration in expression of miRNAs can cause various malignant changes and the metastatic process. Our aim was to identify the miRNAs involved in cervical squamous cell carcinoma (SqCC) and metastasis, and to test their utility as indicators of metastasis and survival. Using microarray technology, we performed miRNA expression profiling on primary cervical SqCC tissue (n = 6) compared with normal control (NC) tissue and compared SqCC that had (SqC-M; n = 3) and had not (SqC-NM; n = 3) metastasized. Four miRNAs were selected for validation by qRT-PCR on 29 SqC-NM and 27 SqC-M samples, and nine metastatic lesions (ML-SqC), from a total of 56 patients. Correlation of miRNA expression and clinicopathological parameters was analyzed to evaluate the clinical impact of candidate miRNAs. We found 40 miRNAs differentially altered in cervical SqCC tissue: 21 miRNAs were upregulated and 19 were downregulated (≥2-fold, p < 0.05). Eight were differentially altered in SqC-M compared with SqC-NM samples: four were upregulated (miR-494, miR-92a-3p, miR-205-5p, and miR-221-3p), and four were downregulated (miR-574-3p, miR-4769-3p, miR-1281, and miR-1825) (≥1.5-fold, p < 0.05). MiR-22-3p might be a metastamiR, which was gradually further downregulated in SqC-NM > SqC-M > ML-SqC. Downregulation of miR-30e-5p significantly correlated with high stage, lymph node metastasis, and low survival rate, suggesting an independent poor prognostic factor.

The multistep process of vaginal cancer arising from deep infiltrating endometriosis: a case report.

BACKGROUND: Malignant transformation of endometriosis in extraovarian sites remains rare. Furthermore, the process is not definitely understood. CASE PRESENTATION: Herein, we report the case of a 40-year-old premenopausal nulligravida woman who presented with vaginal bleeding and who was finally diagnosed with a vaginal cancer originating from endometriosis and with a synchronous endometrial cancer. A gynecologic examination revealed a multiple polypoid mass on the posterior vaginal fornix. Magnetic Resonance Imaging of the pelvis showed two masses abutting respectively on the anterior uterine wall, and in the rectovaginal septum. The patient underwent a total laparoscopic excision of the rectovaginal mass, radical hysterectomy and low anterior resection of the rectum. The lesions were diagnosed as endometriosis, endometriosis-associated complex hyperplasia and endometrioid cancer. Furthermore, a synchronous endometrioid endometrial cancer was reported. CONCLUSIONS: This case revealed the multistep process of malignant transformation of deep infiltrating endometriosis. The progression was individualized between implantation sites and in the same organ.

Mechanical properties and degradation process of biliary self-expandable biodegradable stents.

OBJECTIVES: The clinical outcomes and prevalence of adverse events associated with biliary biodegradable stents (BS) can differ according to degradation process and time. The aim of this study was to observe the degradation process and time of different BS prototypes, and to evaluate sequential changes in their mechanical properties. METHODS: Using an in vitro bile flow phantom model, we compared degradation time, radial force changes, and morphologic changes among four different BS prototypes: polydioxanone (PDO) BS, polyglycolide (PGA) BS, polydioxanone/poly-l-lactic acid (PDO/PLLA) sheath-core BS, and polydioxaone/magnesium (PDO/Mg) sheath-core BS. Using an in vivo swine bile duct dilation model, we performed a direct peroral cholangioscopy (DPOC) examination to observe the biodegradation process and related adverse events at regular intervals. RESULTS: In the bile flow phantom model, the PGA BS and PDO/Mg BS prototypes showed rapid radial force reduction and morphological changes and complete degradation within six weeks. PDO/PLLA BS maintained high radial force and kept their original shape for longer than the PDO BS, up to 16 weeks. A total of 24 BS were inserted into the dilated bile ducts of 12 swine. In this animal model, DPOC examination revealed that PDO BS and PDO/PLLA BS maintained their original shapes for approximately 12 weeks, but PDO BS showed a greater degree of fragmentation and induced biliary stones and bile duct obstruction. CONCLUSION: Our results showed that PDO/PLLA BS maintained their original shape and radial force for a relatively long time and minimized adverse events.

Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.

Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.

Experimental study on the friction effect of plastic stents for biliary stone fragmentation (with video).

BACKGROUND AND AIM: In patients with irretrievable or intractable bile duct stone, temporary insertion of a plastic stent (PS) followed by further endoscopic retrograde cholangiopancreatography (ERCP) or surgery has been recommended as a 'bridge' therapy. However, the exact mechanism of stone fragmentation has not been discovered. The aim of the present study was to evaluate whether PS shape can facilitate stone fragmentation. METHODS: Using a new in vitro bile flow phantom model, we compared the friction effect among three different PS groups (straight PS group, double pigtail-shaped PS group, and screw-shaped PS group) and a control group. Each group had 10 silicon tube blocks that separately contained one stone and two PS. The control group had 10 blocks each with only a stone and no PS. We carried out analysis of the friction effect by stone weight and volume changes among the groups, excluding fragmented stones. RESULTS: After 8 weeks, complete fragmentation was noted in one out of 34 cholesterol stones (2.9%) and in four out of six pigmented stones (66.7%). Fragmentation tended to be more prominent in the screw-shaped PS group than in the straight PS group, double pigtail-shaped group, and control group (volume change: -11.33%, 7.94%, 4.43%, and 2.05%, respectively, P = 0.1390; weight change: -9.30%, 0.71%, -0.10%, and -1.23%, respectively, P = 0.3553). CONCLUSION: Stone fragmentation may be induced by PS friction effect. Also, screw-shaped plastic stents may improve friction effect. These results may help guide future PS development and clinical decisions.

Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts.

BACKGROUND: Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs). METHODS: HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-ß1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-ß1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent. RESULTS: Both PPAR-γ agonists reduced the TGF-ß1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-ß1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-ß1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-ß1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent. CONCLUSIONS: Troglitazone and rosiglitazone suppress TGF-ß1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.

The Stent Patency and Migration Rate of Different Shaped Plastic Stents in Bile Flow Phantom Model and In Vivo Animal Bile Duct Dilation Model.

BACKGROUND/AIM: In research and development of biliary plastic stents (PS), continuous efforts have been made to overcome short patency time and high rate of migration. The aim of this study was to evaluate the patency and migration rate of different PS shapes for a given period of time. METHODS: Using an in vitro bile phantom model, we compared the patency among different shapes of PS (three straight PS, four double-pigtail PS, and a new screw-shaped PS). We performed an analysis of the degree of luminal narrowing by light microscopic examination. Using an in vivo swine model, we compared the patency and migration rate among the three different types of PS. RESULTS: Eight weeks after the bile exposure in the bile flow phantom model, 80 PS were retrieved and analyzed. The straight PS showed less biofilm formation and luminal narrowing than other types of PS (p < 0.05). Forty-nine PS were inserted into the dilated bile ducts of 10 swine models, and 39 PS were successfully retrieved 8 weeks later. The stent migration occurred less frequently in the double-pigtail PS and the screw-shaped PS than it did in the straight PS (11.1, 10, and 27.3%, respectively). However, there was no statistical difference in stent patency among the different shapes. CONCLUSIONS: Stent patency may not be significantly different depending on the shape of PS for 8 weeks. The screw-shaped PS showed similar patency and migration rate to the double-pigtail PS. These results may help guiding future PS development and clinical decisions.

Notch3-specific inhibition using siRNA knockdown or GSI sensitizes paclitaxel-resistant ovarian cancer cells.

Notch signaling plays an important role in ovarian cancer chemoresistance, which is responsible for recurrence. Gamma-secretase inhibitor (GSI) is a broad-spectrum Notch inhibitor, but it has serious side effects. The efficacy of Notch3-specific inhibition in paclitaxel-resistant ovarian cancers was assessed in this study, which has not yet been evaluated relative to GSI. To analyze the effect of Notch3-specific inhibition on paclitaxel-resistant ovarian cancers, we compared cell viability, apoptosis, cell migration, angiogenesis, cell cycle, and spheroid formation after treatment with either Notch3 siRNA or GSI in paclitaxel-resistant SKpac cells and parental SKOV3 cells. Expression levels of survival, cell cycle, and apoptosis-related proteins were measured and compared between groups. Notch3 was significantly overexpressed in chemoresistant cancer tissues and cell lines relative to chemosensitive group. In paclitaxel-resistant cancer cells, Notch inhibition significantly reduced viability, migration, and angiogenesis and increased apoptosis, thereby boosting sensitivity to paclitaxel. Spheroid formation was also significantly reduced. Both Notch3 siRNA-treated cells and GSI-treated cells arrested in the G2/M phase of the cell cycle. Proteins of cell survival, cyclin D1 and cyclin D3 were reduced, whereas p21 and p27 were elevated. Both GSI and Notch3 siRNA treatment reduced expression of anti-apoptotic proteins (BCL-W, BCL2, and BCL-XL) and increased expression of pro-apoptotic proteins (Bad, Bak, Bim, Bid, and Bax). These results indicate that Notch3-specific inhibition sensitizes paclitaxel-resistant cancer cells to paclitaxel treatment, with an efficacy comparable to that of GSI. This approach would be likely to avoid the side effects of broad-spectrum GSI treatment. © 2015 Wiley Periodicals, Inc.

Bio-sheet graft therapy for artificial gastric ulcer after endoscopic submucosal dissection: an animal feasibility study.

BACKGROUND: Various bio-sheet grafts have been attempted either to accelerate healing of artificial ulcers or to prevent adverse events after endoscopic submucosal dissection (ESD), but neither prospective nor mechanistic studies were available. OBJECTIVE: To evaluate the substantial effect of a bio-sheet graft on artificial ulcer healing and its feasibility as an endoscopic treatment modality. DESIGN: Preclinical, in vivo animal experiment and proof-of-concept study. SETTING: Animal laboratory. SUBJECTS: Three mini-pigs, Sus scrofa, mean age 14 months. INTERVENTION: Multiple ulcers sized 2.5 cm in diameter were generated by ESD in 3 mini-pigs and were assigned randomly into the following 3 groups; control group, bio-sheet group, or combination (bio-sheet plus drug) group. Bio-sheet grafts or bio-sheet plus drug combinations were applied on the artificial ulcers immediately after the ESD. MAIN OUTCOME MEASUREMENTS: Feasibility and efficacy of endoscopic bio-sheet graft therapy for the management of artificial ulcers and the evaluation of healing conditions based on histology changes in the remaining gastric bed tissues harvested from the stomachs. RESULTS: Thirty-three ESD specimens were obtained. On an image analysis of the ratio of healed area in the remaining gastric bed tissue compared with the matched dissected gastric mucosa, the control group showed the most significant improvement in healing activity among the 3 groups (P < .05), whereas the severity of inflammation in the remaining ulcer tissue was significantly attenuated in bio-sheet and combination groups (P < .05). LIMITATIONS: Animal model. CONCLUSION: Although the bio-sheet grafts provided physical protection from gastric acid attack as reflected in the attenuated inflammation on the ulcer beds, unexpected delayed ulcer healing was noted in the bio-sheet graft group because of its physical hindrance of the healing process.

Anti-fibrotic and anti-stricture effects of biodegradable biliary stents braided with dexamethasone-impregnated sheath/core structured monofilaments.

Endoscopic biliary stent insertion has been widely used for the treatment of benign biliary stricture (BBS). Thus, the development of stent materials in the perspectives of structure, mechanical properties, and biocompatibility has been also studied. However, conventional metal and plastic stents have several disadvantages, such as repeated procedures to remove or exchange them, dislodgment, restenosis, biocompatibility, and poor mechanical properties. Sustainable effectiveness, attenuation and prevention of fibrosis, and biocompatibility are key factors for the clinical application of stents to BBS treatment. In addition, loading drugs could show synergistic effects with stents' own performance. We developed a dexamethasone-eluting biodegradable stent (DBS) consisting of a sheath/core structure with outstanding mechanical properties and sustained release of dexamethasone, which maintained its functions in a BBS duct over 12 weeks in a swine model. The insertion of our DBS not only expanded BBS areas but also healed secondary ulcers as a result of the attenuation of fibrosis. After 16 weeks from the insertion, BBS areas were totally improved, and the DBS was degraded and thoroughly disappeared without re-intervention for stent removal. Our DBS would be an effective clinical tool for non-vascular diseases. STATEMENT OF SIGNIFICANCE: This study describes the insertion of a drug-eluting biodegradable stent (DBS) into the bile duct. The sheath/core structure of DBS confers substantial durability and a sustained drug release profile. Drug released from the DBS exhibited anti-fibrotic effects without inflammatory responses in both in vitro and in vivo experiments. The DBS maintained its function over 12 weeks after insertion into the common bile duct, expanding benign biliary stricture (BBS) and reducing inflammation to heal secondary ulcers in a swine BBS model. After 16 weeks from the DBS insertion, the DBS thoroughly disappeared without re-intervention for stent removal, resulting in totally improved BBS areas. Our findings not only spotlight the understanding of the sheath/core structure of the biodegradable stent, but also pave the way for the further application for non-vascular diseases.

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway.

Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven-nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK-extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

Loss of S100A14 expression is associated with the progression of adenocarcinomas of the small intestine.

OBJECTIVES: Small intestinal adenocarcinoma (SIAC) is an exceedingly rare human malignant tumor, and its association with the S100A14 gene is not known yet. We aimed to investigate the clinicopathological correlations between S100A14 expression and SIAC. METHODS: Immunohistochemical analyses of S100A14, p21 and p53 were performed using tissue microarray analysis of 175 surgically resected SIACs. RESULTS: Of 175 SIACs, loss of S100A14 expression was observed in 128 cases (73.1%). Loss of S100A14 expression was associated with lymph node metastasis (p = 0.009) and advanced disease stage (p = 0.013), and was more frequently observed in distal than duodenal tumors (p = 0.043). The majority of SIACs lost p21 expression (93.7%), and significant loss of p21 expression was observed in cancers with high pT stages (pT(3) and pT(4); p = 0.011), lymph node metastasis (p = 0.029) and advanced cancer stage defined by the American Joint Committee on Cancer (p = 0.005). Overexpression of p53 was found in 23.4% of cases. Positive expression of p53 was associated with distally located SIACs (jejunum or ileum; p = 0.006). There was no association between the expression of S100A14 and p21 or p53. CONCLUSION: Loss of S100A14 in SIAC is common and is associated with higher metastatic potential and advanced clinical stage.

Dramatic Response to Cabozantinib in a Patient with Refractory Hepatocellular Carcinoma with c-MET Amplification.

We report a case of a patient with c-MET amplified hepatocellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previously received regorafenib plus nivolumab as first-line treatment, lenvatinib as second-line, sorafenib as third-line, and ipilimumab plus nivolumab as fourth-line treatment in sequence. However, all regimens showed early progression within 2 months. The patient's HCC was well-controlled, with a partial response (PR) of over 9 months after beginning cabozantinib treatment. Although there were mild adverse events such as diarrhea and elevated liver enzymes, they were tolerable. Next-generation sequencing (NGS) of the patient's previous surgical specimen indicated amplification of c-MET genes. Although it is well known that cabozantinib has excellent effectiveness for inhibiting c-MET at the preclinical level, to the best of our knowledge this is the first case of dramatic response to cabozantinib in a patient with advanced HCC with c-MET amplification.

Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma.

BACKGROUND: This study was conducted to evaluate the clinical feasibility of nab-paclitaxel plus gemcitabine-cisplatin triplet chemotherapy in patients with locally advanced cholangiocarcinoma in real-world practice. METHODS: We retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with nab-paclitaxel plus gemcitabine-cisplatin between October 2019 and August 2021 at a single institution. The initial diagnosis of cholangiocarcinoma was histologically confirmed. RESULTS: One hundred twenty-nine patients were included in this study. Among the patients with a measurable lesion (57.4%), the objective response rate and disease control were 60.8% and 91.9%, respectively. Seventy-seven patients (59.7%) were determined as resectable after triplet chemotherapy, but 73 (56.6%) underwent subsequent curative surgery. The major postoperative complication rate was 15.1%, and there were 2 postoperative mortalities (2.7%). There were 6 complete remission cases (8.2%) in the final pathology. The R0 resection was achieved in 67 patients (91.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 67 patients (91.8%). Fifty-two patients (71.2%) had no lymph node metastasis. Patients who underwent surgery after triplet chemotherapy had significantly higher 12-month overall survival (95.9% vs 76.8%; P < .001) than those treated with chemotherapy alone. CONCLUSION: Nab-paclitaxel plus gemcitabine-cisplatin chemotherapy demonstrated a down-staging effect through a high response rate, indicating that this triplet chemotherapy is feasible as induction therapy in patients with locally advanced cholangiocarcinoma.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma.

Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Notch3 and Jagged2 contribute to gastric cancer development and to glandular differentiation associated with MUC2 and MUC5AC expression.

AIMS: Notch signalling plays diverse roles in malignant tumours as well as in normal tissue development. In this study we investigated the expression of Notch signalling pathway genes and their clinicopathological significance in gastric carcinomas. METHODS AND RESULTS: Notch1, Notch3, Jagged1, Jagged2 and Hes1 expression were analysed by quantitative real-time polymerase chain reaction (qRT-PCR) (n = 81) and immunohistochemistry (n = 103) in gastric carcinomas. MUC2 and MUC5AC expression were also assessed, using immunohistochemistry only. With qRT-PCR, Notch1, Notch3, Jagged1 and Jagged2 expression were increased significantly in tumour compared to normal tissue (P < 0.001, P = 0.002, P = 0.008 and P < 0.001, respectively). Overexpression of Notch3 and Jagged2 was associated with intestinal-type carcinomas (P = 0.024) and better histological differentiation (P = 0.047), respectively. Immunohistochemistry showed a reverse correlation between MUC2 and Notch3 or Jagged1 (P = 0.033 and P = 0.005, respectively) and between MUC5AC and Jagged1 or Hes1 (P = 0.004 and P = 0.002, respectively). Notch3 and Jagged2 gene overexpression related to a favourable outcome on univariate (P = 0.046 and P = 0.042, respectively) and multivariate (P = 0.045, Notch3) analysis. CONCLUSION: The expression of Notch3 and Jagged2 is associated not only with gastric cancer development but also with the intestinal/glandular differentiation of gastric carcinoma cells, suggesting a role as a possible favourable prognostic indicator.

Development of quality assurance program for digital pathology by the Korean Society of Pathologists.

BACKGROUND: Digital pathology (DP) using whole slide imaging is a recently emerging game changer technology that can fundamentally change the way of working in pathology. The Digital Pathology Study Group (DPSG) of the Korean Society of Pathologists (KSP) published a consensus report on the recommendations for pathologic practice using DP. Accordingly, the need for the development and implementation of a quality assurance program (QAP) for DP has been raised. METHODS: To provide a standard baseline reference for internal and external QAP for DP, the members of the Committee of Quality Assurance of the KSP developed a checklist for the Redbook and a QAP trial for DP based on the prior DPSG consensus report. Four leading institutes participated in the QAP trial in the first year, and we gathered feedback from these institutes afterwards. RESULTS: The newly developed checklists of QAP for DP contain 39 items (216 score): eight items for quality control of DP systems; three for DP personnel; nine for hardware and software requirements for DP systems; 15 for validation, operation, and management of DP systems; and four for data security and personal information protection. Most participants in the QAP trial replied that continuous education on unfamiliar terminology and more practical experience is demanding. CONCLUSIONS: The QAP for DP is essential for the safe implementation of DP in pathologic practice. Each laboratory should prepare an institutional QAP according to this checklist, and consecutive revision of the checklist with feedback from the QAP trial for DP needs to follow.