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Background and aims: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC. Methods: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%. Results: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91–2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0–0.53%), PCC (95% CI 0–0.59%), or PD (95% CI 0–0.86%) histologic type. Conclusion: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type. [ABSTRACT FROM AUTHOR]

Background: Programmed death‐ligand 1 (PD‐L1) is an important screening biomarker to select patients with gastric cancer (GC) for optimized treatment, including immune checkpoint inhibitors (ICI). Methods: In this single‐institution retrospective cohort study, patients with metastatic GC with available PD‐L1 results between October 2019 and September 2021 were identified by reviewing their electronic medical records. Genomic data were obtained from the Samsung Medical Center Clinical Sequencing Platform. Results: Among the 399 patients, 276 (69%) had a PD‐L1 combined positive score (CPS) ≥1, 155 (39%) had a CPS between 1 and 5, and 121 (30%) had a CPS ≥5. Of the 121 patients with CPS ≥5, 28 (23%) had a known etiology for "inflamed tumor," with Epstein–Barr virus (EBV) positivity (N = 11) or high tumor mutational burden (TMB) (N = 17), which included microsatellite instability (MSI) (N = 9). PD‐L1 CPS ≥5 was observed in 11/11 (100%) patients with EBV positivity, 9/12 (75%) patients with MSI, and 17/33 (52%) patients with high TMB. For the 108 patients who received ICI therapy, CPS ≥5 was the only predictor significantly associated with survival in multivariable analyses, including TMB, MSI, or EBV. Objective response rate (ORR) was 49% in patients with CPS ≥5, 30% in patients with 1 ≤ CPS <5, and 19% in patients with CPS <1. Among the 31 responders to ICI therapy, 27 (87%) had a CPS of ≥1. Mutations in TET2, IRS2, DOT1L, PTPRT, and LRP1B were associated with a higher ORR (63%–100%), whereas MDC1 mutations were associated with a low ORR (22%). Conclusions: PD‐L1 expression is an independent and sensitive biomarker for ICI therapy. Considering its significant association with several gene alterations, including PIK3CA mutations and MET amplification, combining ICI therapy with other targeted agents may be a promising therapeutic strategy for GC. [ABSTRACT FROM AUTHOR]

Extremely well-differentiated gastric-type adenocarcinoma (EWDGA) is a rare type of gastric cancer composed of deceptively bland-looking malignant cells resembling normal foveolar or pyloric epithelium. The histological features of this tumor have not been recognized by many pathologists, and inter-observer variation studies are lacking. Here, we report seven EWDGAs and inter-observer variation of six preoperative biopsies was evaluated by 11 pathologists in a single institute. Based on the pathological diagnosis of the endoscopic biopsy slides, the average rate of definite malignancy diagnosis was 15.2 %, and the overall diagnostic concordance rate was 34.9 % among 11 pathologists. Microscopically, the surface epithelium was preserved and only a few atypical tumor glands were scattered in most endoscopic biopsies. Structural atypia was minimal, and the tumor glands were barely distinguishable from normal glands. Although nuclear atypia was minimal, enlarged nuclei, relatively large glands with irregular shapes, and abundant cytoplasmic mucin were observed in gastric pinch biopsies. In preoperative biopsies, no cases showed p53 overexpression, and Ki-67 labeling index ranged from 3 % to 35 % and was higher compared to non-neoplastic glands in 3 cases. After gastrectomy, four (57.1 %) patients had advanced gastric cancer and three (42.9 %) had lymph node metastasis. Genomic profiling of the four patients revealed mutations of TP53 , BRAF , KRAS , STK11 , and MDM2/CCND1 amplification. Immunohistochemistry for p53 was not helpful while Ki-67 may be helpful when staining pattern is distinct from the non-neoplastic mucosa. In conclusion, it is challenging to diagnose EWDGA using biopsy specimens. Recognizing and addressing this rare entity will increase diagnostic accuracy to ensure the early diagnosis of cancer. [ABSTRACT FROM AUTHOR]

Purpose: Homologous recombination deficiency (HRD) is related to tumorigenesis. Currently, the possibility of HRD as a prognostic biomarker to immune checkpoint inhibitors is unknown. We aimed to investigate whether HRD has potential as a biomarker for immunotherapy. Methods: The status of homologous recombination deficiency (HRD) was assessed with the next-generation sequencing (NGS) TruSight™ Oncology 500 assay in 501 patients with advanced solid tumor including gastrointestinal (GI), genitourinary (GU), or rare cancer. Results: among the 501 patients, HRD was observed as follows: 74.7% (347/501) patients; GU cancer (92.0%, 23 of 25), colorectal cancer (CRC) (86.1%, 130 of 151), hepatocellular carcinoma (HCC) (83.3%, 10 of 12), pancreatic cancer (PC) (76.2%, 32 of 42), biliary tract cancer (BTC) (75.0%, 36 of 48), sarcoma (65.0%, 39 of 60), melanoma (52.4%, 11 of 21), other GI cancers (50.0%, 11 of 22), and rare cancer (50.0%, 2 of 4). Sixty-five of the 501 patients had received immune checkpoint inhibitors (ICIs) during the course of the disease. Tumor types of 65 patients treated with ICIs are as follows: melanoma (95.2%, 20 of 21), HCC (33.3%, 4 of 12), rare cancer (25.0%, 1 of 4), GC (12.2%, 14 of 116), BTC (10.4%, 5 of 48), and sarcoma (5.0%, 3 of 60). The most frequently reported mutations were BRCA2 (n = 90), ARID1A (n = 77), ATM (n = 71), BARD1 (n = 67). Patients without HRD exhibited an objective response rate (ORR) of 33.3% (4 of 12), and patients with HRD exhibited an ORR of 34.0% (18 of 53). There was no significant difference in ORR between patients with and without HRD (P = 0.967). Progression-free survival (PFS) was 6.5 months (95% CI 0.000–16.175) in patients without HRD and 4.1 months (95% CI 2.062–6.138) in patients with HRD, revealing no statistical significance (P = 0.441). Conclusion: Herein, we reported the status of HRD using a cancer-panel for various solid tumor patients in routine clinical practice and demonstrated that HRD as a single biomarker was not sufficient to predict efficacy of ICIs in solid tumor patients. [ABSTRACT FROM AUTHOR]

Pembrolizumab appears promising for patients with programmed cell death ligand-1 (PD-L1)-positive solid tumors. However, data on immunotherapy for biliary tract cancers (BTC) are limited. We aimed to investigate the predictive value of PD-L1 expression as an immunotherapeutic biomarker in BTC. Patients with advanced BTC (n = 175) were screened for PD-L1 expression using PharmDx assay and microsatellite instability (MSI) status. Of the total of 175 patients, 125 (71%) showed tumoral PD-L1 positivity (≥ 1%) while only two (2/142, 1.4%) showed MSI-High. Among 175 patients, 26 patients were treated with pembrolizumab as a second-line therapy, and tumor response was evaluated. Separating these patients into two groups by PD-L1 expression (high [≥ 50%] vs. low [< 50%]), overall response rate was 23% (56% [5/9] in high PD-L1 group vs. 6% [1/17] in low PD-L1 group, P = 0.004). Disease control rate was also higher in high PD-L1 group (78% vs. 35%, P = 0.019). The six responders showed median progression-free survival of 5.8 months after starting pembrolizumab, and none of them was MSI-High. High PD-L1 expression was associated with a better response to pembrolizumab. PD-L1 expression can potentially serve as an alternative predictive biomarker for pembrolizumab therapy in advanced BTC. [ABSTRACT FROM AUTHOR]

Acute hepatitis E virus (HEV) infection could lead to acute liver failure (ALF), which requires liver transplantation (LT). HEV infection could progress to chronic infection in an immunosuppressed host. De novo autoimmune hepatitis (AIH) is a rare occurrence of AIH during post‐LT immunosuppressive therapy in patients who underwent LT due to not AIH but some other etiology. Here, we report the first case of ALF due to HEV infection, the recurrence of HEV after LT that responded to ribavirin therapy, and then the development of de novo AIH showing a complete response to glucocorticoid therapy but multiple relapses after steroid withdrawal. This peculiar case suggests that HEV could have a pathogenic role in the development of the de novo AIH; additionally, this case report could help clinicians make therapeutic decisions in the post‐LT condition. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating lymphocyte (TIL) levels have prognostic and predictive values in treatment-naïve breast cancers. However, there have been controversies regarding TIL subset changes and their clinical implications in post-treatment breast cancers. This study aimed to explore change and prognostic significance of TIL subset infiltration after primary systemic therapy (PST) in breast cancer. One-hundred-fifty-five patients who had residual disease after anthracycline- or anthracycline plus taxane-based PST were included. The quantities of intratumoral and stromal TIL subsets (CD8+, CD4+, and FOXP3+ TILs) in pre- and post-PST breast cancer samples, as well as changes between them, were analyzed along with their correlations with clinicopathologic features and outcome of patients. As a whole, intratumoral CD8+ and CD4+ TILs increased after PST while stromal TILs decreased. Both intratumoral and stromal FOXP3+ TILs decreased after PST. The chemo-sensitive group [residual cancer burden (RCB) class I and II] showed the same pattern of change in intratumoral CD8+ TILs as the whole group, whereas the chemo-resistant group (RCB class III) showed no significant change in intratumoral CD8+ TIL infiltration after PST. Survival analyses for each TIL subset as well as their ratios revealed that high levels of intratumoral, stromal, and total CD8+ TIL infiltration after PST were independent predictors of longer patient survival. In subgroup analyses, CD8+ TIL infiltration after PST revealed prognostic significance in the chemo-resistant group but not in the chemo-sensitive group. In conclusion, infiltration of CD8+, CD4+, and FOXP3+ TIL changed after PST in the intratumoral and stromal compartments. Especially, increase of intratumoral CD8+ TILs was associated with chemo-responsiveness. Moreover, CD8+ TIL status in residual tumors after PST may be used as a potential prognostic marker in breast cancer patients who receive PST and provide additional prognostic information to chemo-resistant group. [ABSTRACT FROM AUTHOR]

Background: Multiplicity in breast cancer is common. Studies on multiple breast cancers have revealed high concordance in biomarker status among individual lesions. However, genomic differences among multiple lesions are not well-established. We aimed to investigate the potential genomic heterogeneity of multiple breast cancer.Methods: Twenty-one patients with radiologically and histologically evident multiple breast cancer with similar histology were included. Two lesions from each of the 21 patients were selected, and biomarker status was evaluated for each lesion. Capture-based targeted next-generation sequencing was performed using a cancer gene panel consisting of 170 genes.Results: We identified discordance in intrinsic subtype in 2 (10%) of the 21 patients. Pathogenic mutations were detected in 13 of the 21 patients, of whom 11 shared oncogenic variants in the two lesions. The remaining two patients yielded different mutation results for TP53, ATM, and PIK3CA. Difference in copy number alteration was observed in 7 (33%) of the 21 patients including ERBB2 (n = 2), FGFR1 (n = 2), and FGFR2 (n = 1) genes.Conclusion: Despite similar histologic features of the individual lesions, inter-lesional genomic difference was identified in more than one-third of the patients. Inter-lesional genomic heterogeneity needs to be considered when performing a genomic test in multiple breast cancers. [ABSTRACT FROM AUTHOR]

Aims: Pembrolizumab has shown promising results for patients with programmed cell death ligand‐1 (PD‐L1)‐positive advanced biliary tract cancer in an ongoing clinical trial. However, data on PD‐L1 expression in bile duct cancers is limited, and the frequency of PD‐L1 positivity varies, which may be partly due to the assay used. The aim of this study was to evaluate PD‐L1 expression status in bile duct cancers by using 22C3, SP263 and E1L3N antibodies. Methods and results: We evaluated PD‐L1 expression in tissue microarrays of 183 extrahepatic bile duct cancers, including 89 perihilar and 94 distal bile duct cancers, by using 22C3, SP263 and E1L3N. When the 22C3 assay was used, tumoral PD‐L1 was shown to be expressed in 16.9% of cases at a 1% threshold. When the SP263 and E1L3N assays were used, tumoral PD‐L1 was shown to be expressed in 26% and 7.1% of cases, respectively. When whole tissue sections were examined, 59.6% of PD‐L1‐positive cases showed a low percentage (<10%) of positive tumour cells. Tumoral PD‐L1 positivity was associated with poor histological differentiation (P = 0.017) and the biliary epithelial phenotype (P = 0.041). High tumoral PD‐L1 expression (≥10%) was associated with worse overall survival (OS) and disease‐free survival (DFS) (OS, P = 0.012; DFS, P = 0.042). Conclusions: PD‐L1 was expressed in a small subset of patients with bile duct cancer, and the percentage of positive tumour cells was low in PD‐L1‐positive cases. The SP263 assay showed the highest PD‐L1 positivity in both tumour cells and immune cells, followed by the 22C3 and E1L3N assays. High PD‐L1 expression was associated with a poor prognosis in extrahepatic bile duct cancer patients. [ABSTRACT FROM AUTHOR]

Type 2 autoimmune pancreatitis (AIP) typically presents with diffuse or focal enlargement of the pancreas; however, its diverse clinical presentation has not yet been clarified. We herein described a 46‐year‐old man with a 1‐month history of ulcerative colitis who presented with imaging features of a mass‐like lesion in the pancreatic body with upstream duct dilatation and serum CA19‐9 elevation. He underwent laparoscopic distal pancreatectomy with splenectomy for suspected malignancy. Histologically, the area radiologically suspected to be duct dilatation consisted of necrotic tissue, in which the disrupted main pancreatic duct was involved. The area radiologically suspected to be the mass lesion showed features of pancreatitis without discrete mass. In addition, several ducts showed neutrophilic duct injury similar to granulocytic epithelial lesions observed in type 2 AIP. Immunohistochemistry revealed the aberrant expression of IL‐8 in the pancreatic ductules and infiltrating CD3‐positive T‐lymphocytes, findings recently identified in type 2 AIP. The present case is not typical for either type 2 AIP or other known conditions, but extreme examples of type 2 AIP may present with ductal obstruction because of severe neutrophilic duct injury. IL‐8 immunostaining may also assist in establishing a diagnosis of type 2 AIP with an atypical presentation. [ABSTRACT FROM AUTHOR]

Aims Clear cell meningioma ( CCM) is a rare subtype of meningioma and shows not only unusual histology, but also unique clinical features. Recently, SMARCE1 mutations have been shown to cause spinal and cranial CCMs. We present 12 cases which were diagnosed with CCM in a single institution between 1997 and 2014, and investigate their SMARCE1 mutation status. Methods and results To investigate the SMARCE1 mutation status of these tumours, we used a combination of Sanger sequencing and multiplex ligation-dependent probe amplification analysis and also performed SMARCE1 immunohistochemical staining. We found both SMARCE1 mutational hits, including novel SMARCE1 mutations, in six of eight tested patients. Immunohistochemical analysis showed loss of SMARCE1 protein staining in all but two cases. Two individuals who were diagnosed originally with CCM were negative for SMARCE1 mutations, but tested positive for NF2 mutations. As a result, these two tumours were re-analysed and eventually reclassified, as a microcystic and a mixed pattern of meningothelial meningioma with focal clear cell areas, respectively. Conclusions These results expand the spectrum of pathogenic variants in SMARCE1 and show that mutation screening can help to facilitate meningioma classification. This may have implications for prognosis and future clinical management of patients, as CCMs are classed as grade II tumours, while microcystic and meningothelial meningiomas are classed as grade I. [ABSTRACT FROM AUTHOR]

Gastrointestinal neurofibroma usually develops as diffuse gastrointestinal involvement in neurofibromatosis type 1 patients. Only 4 cases of sporadic colonic neurofibroma in a patient without neurofibromatosis type 1 have been reported in the English literature. A 26-year-old female patient underwent colonoscopy, and a 4-cm-sized polypoid mass was identified in the sigmoid colon. Wedge resection of the mass showed a yellowish, hard submucosal tumor. Microscopically, the tumor was composed of wavy spindle cells, fibroblasts, and strands of collagen; the stroma showed scattered myxoid areas. The differential diagnoses included gastrointestinal stromal tumor, schwannoma, and neurofibroma. Immunohistochemistry for c-Kit, DOG (discovered on gastrointestinal stromal tumors)-1, smooth muscle actin, S-100 protein, and CD34 was performed. The tumor cells were diffusely positive for CD34 and S-100 protein, while they were completely negative for c-Kit, DOG-1, and smooth muscle actin. The final diagnosis was neurofibroma. Sporadic colonic neurofibroma is very rare. Given the diffuse positivity for CD34 and its rarity, colonic neurofibroma can be easily misdiagnosed as gastrointestinal stromal tumor. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis and unnecessary treatment. [ABSTRACT FROM AUTHOR]

Aim: Screening amplified genes for targeted therapy with high-throughput technology is very important. The NanoString nCounter system allows multiplexed digital quantification of target molecules through the use of color-coded barcodes with the great advantage that formalin-fixed, paraffin-embedded (FFPE) tissue can be utilized. Methods: We tested nCounter custom copy number variation (CNV) panels in 220 gastric cancer samples and evaluated the utility of this method as a screening tool for the detection of CNV using HER2. For the validation of results, we compared the nCounter results with immunohistochemistry (IHC), and we further performed in situ hybridization (ISH) in discrepant cases. Results: The average HER2 gene copy numbers (CNs) by nCounter were 17.25, 2.0 and 2.61 for the HER2 IHC positive (3+), equivocal (2+), and negative cases, respectively. Out of the 16 IHC 3+ cases, 13 (81.3 %) were reported as HER2 CN gain (≥4). Gastric cancers with homogeneous HER2 overexpression or high tumor purity showed HER2 CN ≥10. Among the 192 cases with HER2 IHC negative and without HER2 gene amplification, 29 showed a HER2 CN ≥4 with the nCounter assay. The nCounter assay had a concordance rate of 83.4 % (kappa value, 0.35), a sensitivity of 66.7 %, a specificity of 85.2 %, a negative predictive value of 96 %, and a positive predictive value of 32.6 % compared with HER2 IHC/ISH results. Fresh frozen (FF) samples revealed a higher concordance rate (91.5 %, kappa value, 0.59) than FFPE samples (78.5 %, kappa value 0.27) and showed a high specificity (97.2 %). Conclusion: The nCounter CNV assay is a reliable and practical method to detect high CN variations. Given the intra-tumoral HER2 heterogeneity and normal cell contamination, additional IHC and/or FISH is necessary and needs caution in interpretation, especially in FFPE tissue samples. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin). Methods: We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8 %). Results: Among 54 patients, the median age was 51.5 years (range 23-72 years). Male patients were 59.3 %. Seven patients (13.5 %) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among seven patients with tumors with FGFR2 expression, six achieved partial response (PR) with a 85.7 % response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5 %). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, P = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS. Conclusions: FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P = 0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles. [ABSTRACT FROM AUTHOR]

Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is a subtype of renal cell carcinoma (RCC) with unique morphologic features found exclusively in the background of end-stage renal disease. We analyzed the clinicopathologic features and immumoreactive profiles of 12 cases of ACD-RCC to further characterize this recently recognized entity. Review of histologic slides was performed in conjunction with immunohistochemical staining directed to the contemporary diagnostic antibodies and the putative target therapy-related markers. Histologically, the tumors showed characteristic inter-or intracellular microlumens and eosinophilic tumor cells. Intratumoral hemosiderin deposition and degenerating foamy tumor cells were consistent findings which were not previously described. Immunohistochemically, all the tumors were positive for alpha-methylacyl-CoA-racemase, CD10, pan-cytokeratin, PTEN (phosphatase and tensin homolog deleted on chromosome 10) and c-met, while negative for carbonic anhydrase-9, CD57, CD68, c-kit, pax-2, platelet-derived growth factor receptor (PDGFR)-α or vascular endothelial growth factor receptor (VEGFR)-2. Heterogenous staining was found for CK7 and kidney-specific cadherin. Positive reaction to c-met suggests its utility as a plausible therapeutic target in ACD-RCC. Thus, we present the unique morphologic and immunopathologic features of ACD-RCC, which may be helpful in both diagnostic and therapeutic aspects. [ABSTRACT FROM AUTHOR]

Background: Little is known about the histopathology and prognosis of persistent pure ground-glass opacity nodules (GGNs) of ≥ 10 mm in diameter. We aimed to compare the morphologic features of persistent pure GGNs of ≥ 10 mm in diameter at thin-section CT (TSCT) scan with histopathology and patient prognosis.Methods: A total of 46 resected GGNs that were evaluated with TSCT scan and followed up for ≥ 3 years were included in this study. Correlations between histopathology (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma) and CT scan characteristics were examined. CT scan and clinicodemographic data were investigated by univariate and multivariate analyses to identify features that helped distinguish invasive adenocarcinoma from AIS or MIA. Disease recurrence was also evaluated.Results: The nodules included 19 AISs (41%), nine MIAs (20%), and 18 invasive adenocarcinomas (39%). On univariate analysis, the presence of air bronchogram (P = .012), size of nodule (P = .032, cutoff = 16.4 mm in diameter), and mass of nodule (P = .040, cutoff = 0.472 g) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA. On multivariate analysis, size (P = .010) and mass of nodule (P = .016) were significant determinants for invasive adenocarcinoma. There were no cases of recurrence during a follow-up period of ≥ 3 years after surgical resection.Conclusions: In persistent pure GGNs of ≥ 10 mm in diameter, the size and mass of the nodule are determinants of invasive adenocarcinoma, for which surgical resection leads to excellent prognosis. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor 19 (FGF19)-mediated activation of mitogen-activated protein kinase and the β-catenin pathway may be involved in the development and progression of hepatocellular carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients. Methods: By immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6 months. Results: FGF19 protein expression was observed in 135 (48.0 %) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size ( P < 0.001), and higher BCLC stage ( P = 0.001). FGF19 expression was correlated with the early recurrence ( P < 0.001), but not with the late recurrence ( P = 0.582). FGF19 expression ( P = 0.002), viral etiology ( P = 0.028), and intrahepatic metastasis ( P < 0.001) were independent predictors of early recurrence. Multivariate analyses of survival revealed that FGF19 expression ( P < 0.001), intrahepatic metastasis ( P < 0.001), and liver cirrhosis ( P = 0.019) were independent predictors of shorter disease-free survival. FGF19 expression ( P = 0.005), larger tumor size ( P = 0.038), major portal vein invasion ( P = 0.048), intrahepatic metastasis ( P < 0.001), lower albumin level ( P = 0.024), and liver cirrhosis ( P = 0.031) were independent predictors of shorter disease-specific survival. Conclusions: FGF19 protein expression might be an effective predictor of early recurrence and a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy, indicating that FGF19 might be a potential preventive target in hepatocellular carcinoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: We compared the prognosis of patients with cardia or subcardia cancer using a gastric cancer staging system and identified a significant difference in overall survival according to invasion of the esophagogastric junction. In addition, esophagogastric junction invasion was a significant independent factor reflecting a poor prognosis. Esophagogastric junction invasion should be considered for staging, and additional research is needed to apply it to gastric and esophageal cancer classification. Background: There has been no comparison of the prognoses of Korean patients who underwent curative surgery for cancer located at the cardia or subcardia of the stomach. We performed this comparison and further investigated the prognostic significance of esophagogastric junction (EGJ) invasion in patients. Methods: The medical records of patients (n = 511) who were diagnosed with cardia or subcardia cancer and underwent surgery between January 2010 and May 2019 were retrospectively reviewed. Patients were further categorized into four groups for analysis: subcardia gastric cancer (sGC; subcardia cancer without EGJ invasion; n = 97), AEG (adenocarcinoma of the esophagogastric junction) type III (subcardia cancer with EGJ invasion, n = 54), AEG type II without EGJ invasion (n = 158), and AEG type II with EGJ invasion (n = 202). We compared the overall survival of the four groups using a gastric cancer staging system and evaluated the prognostic significance of EGJ invasion with multivariate analysis. Results: The median follow-up of patients was 46.0 months (range: 0–124 months). There was significant difference in overall survival curves among the four groups (p < 0.001). Subgroup analysis showed a significant difference in overall survival between the groups with and without EGJ invasion (p < 0.001). Cancers with EGJ invasion were more frequently in the cardia (p < 0.001), had a larger size (p < 0.001), and showed a more advanced pathologic stage (stages II and III; 67.6% versus 33.7%, p < 0.001) than those without EGJ invasion. EGJ invasion and the pathologic stage were significant independent prognostic factors of overall survival in cardia and subcardia cancer patients (hazard ratio 2.24, 95% confidence interval 1.32–3.81, p = 0.003). Conclusion: The overall survival between patients with cardia or subcardia cancer was significantly different according to EGJ invasion. EGJ invasion was an independent prognostic factor and should be considered for staging. Additional research is needed to apply this feature to gastric and esophageal cancer classification. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Rapamycin-insensitive companion of mTOR (RICTOR) is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2), and promotes cellular proliferation and survival through the activation of downstream AGC kinase family members. The amplification of RICTOR has been proposed as a therapeutically relevant genomic alteration. However, other than next-generation sequencing, precise diagnostic methods to detect RICTOR amplification in advanced solid cancers have not been fully explored. We performed immunohistochemistry (IHC) analysis on solid tumor tissues from 435 cancer patients. Overexpression of RICTOR was found in 213 cases (49.0 %: 1+, 29.4 %; 2+, 15.2 %; 3+, 4.4 %) consisting of 111 colorectal cancers, 42 gastric cancers, 16 renal cell carcinomas, 8 soft tissue sarcomas, 6 hepatocellular carcinomas, 6 cholangiocarcinomas, 4 lung cancers, and 37 other tumors. RICTOR overexpression was heterogeneous (stained < 50 % of the tumor volume) in 32.4 % (12/37) of IHC-positive cases. We performed fluorescence in situ hybridization (FISH) in 37 RICTOR-overexpressed IHC-positive cases (1+, 12; 2+, 11; 3+, 14) and 13 IHC-negative solid tumors. FISH enabled us to detect RICTOR amplification in 7/12 (58.3 %) IHC 1+, 10/11 (90.9 %) IHC 2+, and 11/14 (78.6 %) IHC 3+ cases. In total, there was amplification in 75.7 % (n = 28) of the RICTOR-overexpressed cases, according to FISH. There was RICTOR amplification in only 7.7 % of the RICTOR IHC-negative cases. RICTOR amplification was significantly more common in IHC-positive cases than in IHC-negative cases (p < 0.0001). The IHC results correlated well with those of FISH (r = 0.60). RICTOR overexpression is more common in solid tumors than previously reported in cases detected by next-generation sequencing. This discrepancy may be caused by intratumoral heterogeneity. In conclusion, heterogeneous RICTOR overexpression is common in solid tumors and RICTOR IHC can be used as a screening tool to detect RICTOR amplification. [ABSTRACT FROM AUTHOR]

Prognostic implications of therapeutic response of metastatic lymph nodes (LNs) to neoadjuvant chemotherapy (NAC) remain unclear in patients with breast cancer. We aimed to evaluate the prognostic value of axillary LN regression after NAC in locally-advanced breast cancer patients. Therapeutic response of the LNs was evaluated in 563 breast cancer patients and classified into four grades according to the regression pattern. Initial pathologic N stage was estimated from the sum of the metastatic LNs and those with complete regression. In survival analyses, LN regression grade, pathologic N stage after NAC, and presumed initial pathologic N stage stratified clinical outcome of the patients in the whole group, in both ER-positive and ER-negative subgroups, and in those with residual breast disease. On multivariate analysis, LN regression grade and presumed initial pathologic N stage were revealed as independent prognostic factors. The number of completely-responsive LNs and the ratio of non-responsive LNs also revealed a prognostic value. In conclusion, regression grade of axillary LNs and presumed initial pathologic N stage have prognostic values in breast cancer patients who receive NAC. Thus, regression of axillary LNs should be evaluated and included in pathologic reporting of post-NAC resection specimens. [ABSTRACT FROM AUTHOR]

Simple Summary: We developed an attention-based whole slide image (WSI)-level classification deep learning model employing surgically and endoscopically resected specimens to predict LNM in T1 CRC. Our AI model with H&E-stained WSIs and without annotations showed good performance power with the validation of an independent cohort in a single center. The area under the curve of our model was 0.781–0.824, higher than that of previous artificial intelligence (AI) studies with only WSIs. Our AI model, which showed the highest sensitivity (92.9%), reduced unnecessary additional surgery by 14.2% more than using the current JSCCR guidelines (68.3% vs. 82.5%). This revealed the feasibility of using an AI model with only H&E-stained WSIs to predict LNM in T1 CRC. According to the current guidelines, additional surgery is performed for endoscopically resected specimens of early colorectal cancer (CRC) with a high risk of lymph node metastasis (LNM). However, the rate of LNM is 2.1–25.0% in cases treated endoscopically followed by surgery, indicating a high rate of unnecessary surgeries. Therefore, this study aimed to develop an artificial intelligence (AI) model using H&E-stained whole slide images (WSIs) without handcrafted features employing surgically and endoscopically resected specimens to predict LNM in T1 CRC. To validate with an independent cohort, we developed a model with four versions comprising various combinations of training and test sets using H&E-stained WSIs from endoscopically (400 patients) and surgically resected specimens (881 patients): Version 1, Train and Test: surgical specimens; Version 2, Train and Test: endoscopic and surgically resected specimens; Version 3, Train: endoscopic and surgical specimens and Test: surgical specimens; Version 4, Train: endoscopic and surgical specimens and Test: endoscopic specimens. The area under the curve (AUC) of the receiver operating characteristic curve was used to determine the accuracy of the AI model for predicting LNM with a 5-fold cross-validation in the training set. Our AI model with H&E-stained WSIs and without annotations showed good performance power with the validation of an independent cohort in a single center. The AUC of our model was 0.758–0.830 in the training set and 0.781–0.824 in the test set, higher than that of previous AI studies with only WSI. Moreover, the AI model with Version 4, which showed the highest sensitivity (92.9%), reduced unnecessary additional surgery by 14.2% more than using the current guidelines (68.3% vs. 82.5%). This revealed the feasibility of using an AI model with only H&E-stained WSIs to predict LNM in T1 CRC. [ABSTRACT FROM AUTHOR]

Combined hepatocellular‐cholangiocarcinoma (cHCC‐CC) is a rare type of liver tumour that exhibits both hepatocytic and biliary differentiation within the same tumour. The histology and genomic alterations of recurrent/metastatic cHCC‐CC are poorly understood. We selected six patients with cHCC‐CC whose recurrent or metastatic tumours were histologically confirmed. Four patients with classic cHCC‐CCs and two with intermediate cell carcinomas (ICs) were included. The clinicopathological features were evaluated, and next‐generation sequencing was performed in 17 multiregional and longitudinal tumour samples. The histology of recurrent/metastatic lesions of classic cHCC‐CCs was variable: hepatocellular carcinoma (HCC) was observed in one (25.0%) patient, cHCC‐CC in one (25.0%) patient, and cholangiocarcinoma (CC) in two (50.0%) patients. Among 13 samples from four classic cHCC‐CC patients, the most frequent pathological variants were TP53 (46.2%), TERT promoter (38.5%), ARID1A mutations (23.1%), and MET amplification (30.8%). In the sequencing analysis of each HCC and CC component, three (75.0%) of the four classic cHCC‐CCs shared pathogenic variants. A large proportion of mutations, both pathogenic and those of undetermined significance, were shared by each HCC and CC component. Regarding ICs, the ATM mutation was detected in one patient. In conclusion, the histology of recurrent/metastatic cHCC‐CCs was heterogeneous. Genomic profiling of classic cHCC‐CCs revealed similar genomic alterations to those of HCC. Considerable overlapping genomic alterations in each HCC and CC component were observed, suggesting a monoclonal origin. Genetic alterations in ICs were different from those in either HCC or CC, suggesting the distinct nature of this tumour. [ABSTRACT FROM AUTHOR]

The ataxia telangiectasia mutated (ATM) gene is involved in the repair of double-stranded DNA breaks and a component of the DNA damage repair pathway. Tumors with mutations or low expression of both ARID1A and ATM exhibit increased numbers of tumor-infiltrating lymphocytes and a favorable prognosis. However, the relationship between ATM and ARID1A in gastric carcinoma (GC) is unclear. We used the mRNA expression data from the Asian Cancer Research Group to construct tissue microarrays (N = 249). Next-generation sequencing (NGS) databases of Samsung Medical Center (SMC) (N = 813) were used to compare genetic alterations. Tissue microarrays were used for ATM and ARID1A immunohistochemistry, and expressions were categorized as "low" and "high." NGS data from TCGA-STAD (N = 431) were used as independent cohorts for genetic alterations validation. In GCs, 32.1 % (80/249) of the cases showed low ATM protein expression (ATMlow) and 20.9 % (52/249) showed low ARID1A expression (ARID1Alow). ATMlow was significantly associated with older age (P <.01), gross type of tumor (P =.02), histology (P <. 01), lower incidence of perineural invasion (P =.04), lower disease stage (P <.01), microsatellite instability-high (P <.01), and ARID1Alow (P <.01). Furthermore, GCs in the SMC NGS database showed that ATM mutations were significantly correlated with ARID1A mutations (P <.01), and this finding remained significant in TCGA-STAD validation cohort (P <.01). ATMlow in GCs shows a characteristic clinicopathological feature that correlates strongly with ARID1Alow. ATM mutation was also associated with ARID1A mutations, highlighting the interactions between ATM and ARID1A in GC and suggesting a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor-2 (FGFR2) gene alterations have been identified in solid tumors. FGFR2 amplification is found in 2–9% of gastric carcinomas. We hypothesized that FGFR2 could be associated with peritoneal seeding and studied 360 advanced gastric carcinoma patients; 222 (61.7%) were male, 246 (73.7%) had poorly differentiated histology, and 175 (48.6%) presented with peritoneal seeding. High tumor mutation burden (TMB) was observed in 44 (12.2%) patients, high microsatellite instability (MSI) was observed in 12 (3.33%) patients, ERBB2 amplification was observed in 44 (12.2%) patients, EBV positivity was observed in 10 (10/278; 3.6%) patients, and PD-L1 positivity was observed in 186 (186/264; 70.5%) cases. We found FGFR2 amplification in 26 (7.2%) patients, of which 12 (46.2%) were female and 22 (84.6%) had poorly differentiated histology. In these 26 cases, the copy number of FGFR2 amplification ranged from 3.7 to 274. Eighteen of them showed seeding, and this association was statistically significant (18/26, 69.2%; 157/334, 47%; p = 0.023). In addition, high TMB was significantly associated with seeding (p = 0.028; OR = 1.83). Poorly differentiated histology was significantly associated with seeding (p = 0.04) but not with FGFR2 amplification (p > 0.1). Seeding was frequent in gastric carcinoma patients with FGFR2 amplification, in patients with high TMB, or in those who were female. The subgroup of patients with FGFR2 amplification could be potential candidates for targeted therapeutic agents. [ABSTRACT FROM AUTHOR]

Aims To improve the characterization of intraductal papillary neoplasm of the bile duct ( IPNB) and mucinous cystic neoplasm of the liver ( MCN-L). Methods and results A retrospective review of pathology archives (1999-2011) in our three institutions identified cases of IPNB ( n = 138) and MCN- L ( n = 54). The IPNB/ MCN- L ratio was 5.7:1 at Samsung Medical Centre in Seoul, which was significantly higher than those at the University of Washington Medical Center in Seattle (1:3.0) and King's College Hospital in London (1:6.3). This difference was mainly attributable to the considerably larger number of patients with IPNB in Seoul ( n = 131) than in Seattle and London ( n = 7). Western patients with IPNB were all non- Asian in ancestry. IPNB differed from pancreatic intraductal papillary neoplasm in its higher histological grade, more advanced stage of an associated invasive cancer, and worse prognosis. In contrast, MCN- L showed significantly lower histological grade than its pancreatic counterpart ( P = 0.022). Unlike in pancreatic mucinous cystic neoplasm, malignant transformation was very rare in MCN- L (10% versus 2%). Conclusions This study demonstrated demographic differences in IPNB and MCN- L among regions. IPNB and MCN- L differ from their pancreatic counterparts in the risk of malignant transformation and patients' prognosis. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitor approval for microsatellite instability-high (MSI-H) tumours has made MSI as a therapeutically important biomarker. Next-generation sequencing (NGS)-based MSI detection is being widely used for assessing MSI. However, MSI tumours detected using NGS and their relevance to MSI-polymerase chain reaction (PCR) and mismatch repair deficiency (dMMR) are unclear. In 1942 solid cancer cases tested using NGS-based comprehensive cancer panel with 523 genes (1.94 mb), the MSI score, tumour mutation burden (TMB; ≥ 10 mutations/mb), and frameshift mutations were analysed. GeneScan analyses of five mononucleotide markers (MSI-PCR) and MMR protein immunohistochemistry (IHC) were compared with the NGS-MSI results. With a ≥ 12% MSI score as a cut-off for MSI-H, two MSS cases were classified as MSI-H. With a ≥ 20% cut-off, 10 cases categorised as MSS by NGS were MSI-H/dMMR by MSI-PCR and MMR IHC. To avoid discrepant cases, we adopted a high MSI cut-off and a borderline MSI category. Finally, MSI-H (≥ 20%), borderline MSI (≥ 7% and < 20%), and MSS (< 7%) were found in 35 (1.8%), 24 (1.2%), and 1883 (97%) cases, respectively. All MSI-H cases by NGS were MSI-H/dMMR by MSI-PCR and MMR IHC. Of the 24 borderline MSI cases by NGS, MSI-H/dMMR was 9 (37.5%) cases, MSS/dMMR was 1 (4.2%) case, and 11 (45.8%) of them had high TMB. All MSS cases by NGS were MSS/pMMR by MSI-PCR/IHC, and 257 (13.6%) had high TMB. With those arbitrary cut-off points, 10 (0.5%) MSS cases using NGS were discrepant with MSI-PCR or MMR IHC, and all were borderline MSI cases. The mean number of frameshift mutations was significantly higher in the MSI-H group (28.3) than in the borderline MSI (7.7) or MSS (1.3) groups (p < 0.001). In conclusion, to facilitate therapeutic decision-making for NGS, cut-off points for MSI can be defined based on MSI-PCR/dMMR confirmation. [ABSTRACT FROM AUTHOR]

Background: The transforming growth factor-β/Smads signaling pathway plays an important role in tumorigenesis and progression in cancer, and may closely be related to the biological behaviors of some malignant tumors, such as gastric carcinoma. In this study, we investigated the roles of Smad3 and Smad3 phosphoisoforms in the prognosis of gastric carcinoma. Methods: We investigated the expressions of Smad3, pSmad3C(S423/425), pSmad3L(T179), pSmad3L(S204), and pSmad3L(S213) in tumor tissue microarrays of 442 gastric carcinoma patients who underwent curative surgery using immunohistochemistry and assessed their correlation with clinical outcome. Results: Positive Smad3 expression was observed in 33.5 % of gastric carcinoma. The rates of positive Smad3 phosphoisoforms expression varied according to the location of phosphorylation within Smad3: pSmad3C(S423/425) 28.5 %, pSmad3L(T179) 5.9 %, pSmad3L(S204) 1.8 %, and pSmad3L(S213) 20.8 %. Positive Smad3 expression was associated with diffuse type ( p = 0.003), poorer histologic differentiation ( p = 0.005), more frequent lymph node metastasis ( p = 0.001), and higher AJCC stage ( p = 0.006). Multivariate analyses revealed that Smad3 expression ( p = 0.041), pSmad3L(T179) expression ( p = 0.011), pSmad3L(S213) expression ( p = 0.003), and American Joint Committee on Cancer (AJCC) stage were independent predictors of shorter disease-free survival. Smad3 expression ( p = 0.033), pSmad3L(T179) expression ( p = 0.012), pSmad3L(S213) expression ( p = 0.005), and AJCC stage were also independent predictors of shorter overall survival. pSmad3C(S423/425) expression tended to show favorable influences on both disease-free survival ( p = 0.134) and overall survival ( p = 0.232). Conclusions: Smad3, pSmad3L(T179), and pSmad3L(S213) expression might be independent predictors of both shorter disease-free survival and shorter overall survival in gastric carcinoma patients after curative surgery, and might help clinicians identify patients at high risk of recurrence. [ABSTRACT FROM AUTHOR]

The tumor–stroma ratio (TSR) determined by pathologists is subject to intra- and inter-observer variability. We aimed to develop a computational quantification method of TSR using deep learning-based virtual cytokeratin staining algorithms. Patients with 373 advanced (stage III [n = 171] and IV [n = 202]) gastric cancers were analyzed for TSR. Moderate agreement was observed, with a kappa value of 0.623, between deep learning metrics (dTSR) and visual measurement by pathologists (vTSR) and the area under the curve of receiver operating characteristic of 0.907. Moreover, dTSR was significantly associated with the overall survival of the patients (P = 0.0024). In conclusion, we developed a virtual cytokeratin staining and deep learning-based TSR measurement, which may aid in the diagnosis of TSR in gastric cancer. [ABSTRACT FROM AUTHOR]

The ARID1A gene is pivotal in chromatin remodeling and genomic integrity and is frequently mutated in various cancer types. ARID1A mutation is the second most frequently mutated tumor suppressor gene and has been suggested as a predictor of immunotherapeutic responsiveness in gastric carcinoma (GC). Despite its significance, the relationship among ARID1A somatic mutations, RNA expression levels, and protein expression remains unclear, particularly in GC. For this purpose, we performed comparative study in two cohorts. Cohort 1 used next-generation sequencing (NGS) to identify 112 GC cases with ARID1A mutations. These cases were compared with ARID1A immunohistochemistry (IHC) results. Cohort 2 employed microarray gene expression data to assess ARID1A RNA levels and compare them with ARID1A IHC results. In Cohort 1, 38.4% of ARID1A -mutated GC exhibited a complete loss of ARID1A protein when assessed by IHC, whereas the remaining 61.6% displayed intact ARID1A. Discordance between NGS and IHC results was not associated with specific mutation sites, variant classifications, or variant allele frequencies. In Cohort 2, 24.1% of the patients demonstrated a loss of ARID1A protein, and there was no significant difference in mRNA levels between the ARID1A protein-intact and -loss groups. Our study revealed a substantial discrepancy between ARID1A mutations detected using NGS and protein expression assessed using IHC in GC. Moreover, ARID1A mRNA expression levels did not correlate well with protein expression. These findings highlighted the complexity of ARID1A expression in GC. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor progression through both immunologic and non-immunologic mechanisms. This study was conducted to evaluate the expression of S100A8, a well-known MDSC marker, and the significance of its expression in pre-invasive and invasive breast cancers. S100A8 expression in tumor cells (TCs) and immune cells (ICs) was assessed by immunohistochemistry, and its association with clinicopathologic features and infiltration of other IC subsets including CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs) and PD-L1+ ICs was evaluated. S100A8 expression in TCs and ICs showed a positive correlation in pre-invasive carcinoma and invasive carcinoma. S100A8+ ICs, but not S100A8+ TCs, were significantly higher in number in invasive carcinoma than in pre-invasive carcinoma. Infiltration of S100A8+ ICs was revealed as a poor prognostic indicator in pre-invasive and invasive carcinomas, especially in hormone receptor-positive subgroup. Infiltration of CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ ICs was significantly higher in S100A8+ IC (+) group than in S100A8+ IC (−) group. Combined analyses of IC subset infiltration revealed that infiltration of S100A8+ ICs was associated with poor clinical outcome in the PD-L1+ IC (−), CD8+ TIL-low, and FOXP3+ TIL-low subgroups. In conclusion, S100A8+ ICs seem to undergo a dynamic change during breast cancer progression in association with other IC subset infiltration. The prognostic impact of S100A8+ IC infiltration was greater in less immunogenic tumors. [ABSTRACT FROM AUTHOR]

Fast and accurate confirmation of metastasis on the frozen tissue section of intraoperative sentinel lymph node biopsy is an essential tool for critical surgical decisions. However, accurate diagnosis by pathologists is difficult within the time limitations. Training a robust and accurate deep learning model is also difficult owing to the limited number of frozen datasets with high quality labels. To overcome these issues, we validated the effectiveness of transfer learning from CAMELYON16 to improve performance of the convolutional neural network (CNN)-based classification model on our frozen dataset (N = 297) from Asan Medical Center (AMC). Among the 297 whole slide images (WSIs), 157 and 40 WSIs were used to train deep learning models with different dataset ratios at 2, 4, 8, 20, 40, and 100%. The remaining, i.e., 100 WSIs, were used to validate model performance in terms of patch- and slide-level classification. An additional 228 WSIs from Seoul National University Bundang Hospital (SNUBH) were used as an external validation. Three initial weights, i.e., scratch-based (random initialization), ImageNet-based, and CAMELYON16-based models were used to validate their effectiveness in external validation. In the patch-level classification results on the AMC dataset, CAMELYON16-based models trained with a small dataset (up to 40%, i.e., 62 WSIs) showed a significantly higher area under the curve (AUC) of 0.929 than those of the scratch- and ImageNet-based models at 0.897 and 0.919, respectively, while CAMELYON16-based and ImageNet-based models trained with 100% of the training dataset showed comparable AUCs at 0.944 and 0.943, respectively. For the external validation, CAMELYON16-based models showed higher AUCs than those of the scratch- and ImageNet-based models. Model performance for slide feasibility of the transfer learning to enhance model performance was validated in the case of frozen section datasets with limited numbers. [ABSTRACT FROM AUTHOR]

Background & aims: Elastography point quantification is a convenient method for measuring liver stiffness. It can be performed simultaneously with conventional ultrasonography. This study aimed to evaluate its diagnostic performance for assessing hepatic fibrosis in patients with autoimmune liver disease (AILD), including autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Methods: The diagnostic performance of elastography point quantification (ElastPQ) was evaluated and compared with that of serum fibrosis markers, including the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4), using the receiver operating characteristics analysis with histologic evaluation as the reference standard. Results: In 49 AIH patients, sensitivity and specificity of ElastPQ were 93.6% and 44.4%, respectively, for significant fibrosis (≥ F2, cutoff 4.47 kPa), and 63.6% and 86.8% for cirrhosis (F4, cutoff 9.28 kPa). In 41 PBC patients, they were 81.8% and 73.3%, respectively, for significant fibrosis (≥ F2, cutoff 5.56 kPa), and 100% and 81.6%, respectively, for advanced fibrosis (≥ F3, cutoff 6.04 kPa). The areas under the receiver operating characteristic curves of ElastPQ for significant fibrosis (0.77, 95% CI 0.67–0.86) and cirrhosis (0.81, 95% CI 0.65–0.96) were higher than those of APRI and FIB-4 in AILD patients. According to the multivariable analysis, histological activity, steatosis, and body max index (BMI) were not significant factors that influenced the result of ElastPQ. Conclusions: ElastPQ exhibited better diagnostic performance–without the influence of confounding factors–for assessing hepatic fibrosis in AILD patients than serum fibrosis markers. [ABSTRACT FROM AUTHOR]

Pathology archives with linked clinical data are an invaluable resource for translational research, with the limitation that most cancer samples are formalin-fixed paraffin-embedded (FFPE) tissues. Therefore, FFPE tissues are an important resource for genomic profiling studies but are under-utilised due to the low amount and quality of extracted nucleic acids. We profiled the copy number landscape of 356 breast cancer patients using DNA extracted FFPE tissues by shallow whole genome sequencing. We generated a total of 491 sequencing libraries from 2 kits and obtained data from 98.4% of libraries with 86.4% being of good quality. We generated libraries from as low as 3.8 ng of input DNA and found that the success was independent of input DNA amount and quality, processing site and age of the fixed tissues. Since copy number alterations (CNA) play a major role in breast cancer, it is imperative that we are able to use FFPE archives and we have shown in this study that sWGS is a robust method to do such profiling. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung.Methods: Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off. The primary endpoint was overall response. Secondary endpoints were progression-free survival, overall survival, and toxicity.Results: All 26 patients were men with a median age of 68 years (range, 52-80 years). The majority of patients were ever-smokers. The median duration of dovitinib administration (28 days per cycle) was 2.5 months (range, 0.7-8.6 months). The overall response rate was 11.5% (95% confidence interval [95% CI], 0.8%-23.8%) and the disease control rate was 50% (95% CI, 30.8%-69.2%), with 3 patients achieving partial responses. Response durations for the patients with partial responses were ≥4.5 months, ≥ 5.1 months, and 6.1 months, respectively. After a median follow-up of 15.7 months (range, 1.2-25.6 months), the median overall survival was 5.0 months (95% CI, 3.6-6.4 months) and the median progression-free survival was 2.9 months (95% CI, 1.5-4.3 months). The most common grade 3 or higher adverse events were fatigue (19.2%), anorexia (11.5%), and hyponatremia (11.5%) (event severity was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]).Conclusions: Treatment with dovitinib demonstrated modest efficacy in patients with advanced SCC with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in patients with SCC are warranted. Cancer 2016;122:3024-3031. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Introduction: Meningioangiomatosis (MA) is a rare benign cerebral lesion. We aimed to evaluate the CT and MR features of sporadic MA, with a focus on the correlation between imaging and histopathologic findings. Methods: CT ( n = 7) and MR ( n = 8) images of eight patients (6 men and 2 women; mean age, 12.8 years; range, 4–22 years) with pathologically proven MA were retrospectively reviewed. After dividing the MA lesions according to their distribution into cortical and subcortical white matter components, the morphologic characteristics were analyzed and correlated with histopathologic findings in seven patients. Results: CT and MR images showed cortical ( n = 4, 50 %) and subcortical white matter ( n = 7, 88 %) components of MA. All four cortical components revealed hyperattenuation on CT scan and T1 isointensity/T2 hypointensity on MR images, whereas subcortical white matter components showed hypoattenuation on CT scan and T1 hypointensity/T2 hyperintensity on MR images. Two cortical components (25 %) demonstrated enhancement and one subcortical white matter component demonstrated cystic change. Seven cases were available for imaging-histopathologic correlation. In all seven cases, the cortex was involved by MA and six patients (86 %) showed subcortical white matter involvement by MA. There were excellent correlations between the imaging and histopathologic findings in subcortical white matter components, and the accuracy was 100 % (seven of seven); whereas there were poor correlations in cortical components, and the accuracy was 43 % (three of seven). Conclusions: The cerebral cortex and subcortical white matter were concomitantly involved by MA. Subcortical white matter components of MA were more apparent than cortical components on CT and MR imaging. [ABSTRACT FROM AUTHOR]

Studies on gastrointestinal stromal tumors ( GISTs) in young patients are limited due to their rarity, and none have been conducted in Asian populations. GISTs from patients under the age of 30 were retrospectively reviewed and were analyzed for clinicopathologic features, immunohistochemistry for SDHB (succinate dehydrogenase subunit B), and mutations for exon 9, 11, 13, and 17 of KIT gene and exon 12, 14, and 18 of PDGFRA gene. We found two pediatric (<18 years old) and 20 young adult (18-30 years old) GIST cases. Pediatric GISTs occurred in two girls, both as solitary masses with epithelioid histology in the stomach. Both GISTs were wild type for KIT and PDGFRA genes, were negative for SDHB, and there was no recurrence during follow-up. Of the 20 GISTs in young adults, 12 (60%) were from extra-gastric locations (six duodenum, five jejunum, and one esophagus), and 16 (80%) showed a spindle cell morphology. Mutations of KIT or PDGFRA genes were identified in 14 (78%) of the 18 cases. One patient with multiple gastric GISTs with perigastric lymph node metastases at presentation developed multiple distant metastases and died of the disease 7.3 years after diagnosis. Of the 19 R0-resected young adult patients, one patient with small intestinal GIST harboring KIT exon 11 deletion mutation developed recurrence and showed partial responses for imatinib. In summary, compared with pediatric GIST cases, young adult GISTs are heterogeneous and share the characteristics of both pediatric and adult GISTs. When a mesenchymal tumor is clinically suspected in the small intestine of young adults, a GIST should be included in the differential diagnoses. Further mutation studies and extensive treatments are recommended for these cases. [ABSTRACT FROM AUTHOR]

Simple Summary: Para-aortic lymph node (PALN) metastasis in pancreatic cancer (PC) is regarded as a contraindication to surgical resection. Nevertheless, the prognostic impact of unexpected intraoperative PALN metastasis is not firmly established. This retrospective study aims to analyze the prognostic impact of unexpected PALN metastasis and give insight on what surgeons should consider for patients with unexpected intraoperative PALN metastasis. Radiologically identified para-aortic lymph node (PALN) metastasis is contraindicated for pancreatic cancer (PC) surgery. There is no clinical consensus for unexpected intraoperative PALN enlargement. To analyze the prognostic role of unexpected PALN enlargement in resectable PC, we retrospectively reviewed data of 1953 PC patients in a single tertiary center. Patients with unexpected intraoperative PALN enlargement (group A1, negative pathology, n = 59; group A2, positive pathology, n = 13) showed median overall survival (OS) of 24.6 (95% CI: 15.2–33.2) and 13.0 (95% CI: 4.9–19.7) months, respectively. Patients with radiological PALN metastasis without other metastases (group B, n = 91) showed median OS of 8.6 months (95% CI: 7.4–11.6). Compared with group A1, groups A2 and B had hazard ratios (HRs) of 2.79 (95% CI, 1.4–5.7) and 2.67 (95% CI: 1.8–4.0), respectively. Compared with group A2, group B had HR of 0.96 (95% CI: 0.5–1.9). Multivariable analysis also showed positive PALN as a negative prognostic factor (HR 2.57, 95% CI: 1.2–5.3), whereas positive regional lymph node did not (HR 1.32 95% CI: 0.8–2.3). Thus, unexpected malignant PALN has a negative prognostic impact comparable to radiological PALN metastasis. This results suggests prompt pathologic evaluation for unexpected PALN enlargements is needed and on-site modification of surgical strategy would be considered. [ABSTRACT FROM AUTHOR]

Nuclear factor E2-related factor2 (Nrf2) activation is associated with both cytoprotective effects and malignant behavior of cancer cells. This study aimed to evaluate the clinicopathological implications of the expression of Nrf2, pNrf2, and its regulator Keap1 in human hepatocellular carcinomas (HCCs). Tissue microarrays consisting of 285 surgically resected HCCs were immunohistochemically stained with pNrf2, Nrf2, Keap1, stemness-related markers (keratin 19 (K19), epithelial cell adhesion molecule (EpCAM)), carbonic anhydrase IX (CAIX), epithelial–mesenchymal transition (EMT)-related markers (ezrin, uPAR, E-cadherin), and p53, and the results were correlated with the clinicopathological features. pNrf2 expression was significantly associated with increased proliferative activity, as well as EpCAM, ezrin, p53, and CAIX expression and E-cadherin loss (p < 0.05, all). Strong cytoplasmic Nrf2 expression was associated with CAIX and ezrin expression (p < 0.05, both). Keap1 was associated with increased proliferative activity, portal vein invasion, EMT-related markers, and p53 expression in CAIX-negative HCCs (p < 0.05, all). Both pNrf2 and cytoplasmic Nrf2 expression were associated with decreased overall survival (p < 0.05, both), and cytoplasmic Nrf2 expression was an independent predictor of decreased overall survival on multivariate analysis (hazard ratio 4.15, p < 0.001). Both pNrf2 and cytoplasmic Nrf2 expression were associated with poor survival and aggressive behavior of HCC. In addition, Keap1 expression was also associated with aggressive HCC behavior in CAIX-negative HCCs, suggesting that Keap1 expression should be interpreted in the context of hypoxia status. [ABSTRACT FROM AUTHOR]

B Introduction: b The prognostic significance of R1 resection for pancreatic ductal adenocarcinoma (PDAC) has varied in the literature due to a lack of consensus on the definition of various resection margin/surfaces. The safety margins for all circumferential margin/surfaces (anterior, posterior, SMV/PV groove, SMA) were recorded in millimeters. In contrast, involvement of the SMA margin and SMV/PV groove by both 0mm and 1mm rules was correlated with significantly decreased OS and DFS. [Extracted from the article]

Chromosomal instability (CIN) is known to be associated with prognosis and treatment response in breast cancer. This study was conducted to determine whether copy number gain of centromere 17 (CEP17) reflects CIN, and to evaluate the prognostic and predictive value of CIN in breast cancer. CIN status was determined by summing copy number gains of four centromeric probes (CEP1, CEP8, CEP11, and CEP16) based on fluorescence in situ hybridization and CIN scores were calculated using next generation sequencing data. High CIN was associated with adverse clinicopatholgical parameters of breast cancer. Among them, positive HER2 status, high Ki-67 index and CEP17 copy number gain were found to be independent predictors of high CIN. High CIN was associated with poor clinical outcome of the patients in the whole group, as well as in luminal/HER2-negative and HER2-positive subtypes. CEP17 copy number was significantly higher in the high-CIN-score group than in the low-CIN-score group. A positive linear correlation between the mean CEP17 copy number and the CIN score was found. In conclusion, CEP17 copy number was confirmed as a useful predictor for CIN in breast cancer, and high CIN was revealed as an indicator of poor prognosis in breast cancer. [ABSTRACT FROM AUTHOR]

Background: The antibody-dependent cellular cytotoxicity (ADCC) is a cell-mediated immune defense mechanism in which effector immune cells actively lyse antibody-coated target cells. The ADCC of tumor cells is employed in the treatment of various cancers overexpressing unique antigens, and only natural killer (NK) cells are known to be major effectors of antibody mediated ADCC activity. Canine NK cells are still defined as non-B, non-T large granular lymphocytes because of the lack of information regarding the NK cell-restricted specific marker in dogs, and it has never been demonstrated that canine NK cells have ADCC ability against tumor cells. In the present study, we investigated whether canine non-B, non-T NK cells have ADCC ability against target antibody-coated tumor cells, using cetuximab and trastuzumab, the only human antibodies reported binding to canine cancer cells. Results: Activated canine non-B, non-T NK cells (CD3−CD21−CD5−TCRαβ−TCRγδ−) for 13~17 days ex vivo showed ADCC ability against trastuzumab- or cetuximab-coated target tumor cells expressing various levels of human epidermal growth factor receptor 2 (HER-2) and epidermal growth factor receptor (EGFR). Trastuzumab and cetuximab induced significant ADCC responses of canine NK cells even in CMT-U334 and CF41.Mg cells expressing low levels of HER-2 and/or EGFR, as well as in SKBR3 and DU145 cells overexpressing HER-2 and/or EGFR. The trastuzumab-mediated ADCC activity of NK cells was significantly enhanced by treatment with rcIL-21. Conclusions: The results of this study suggest that canine non-B, non-T NK lymphocytes have a potential ADCC function and that combinational strategies of monoclonal antibodies with either cytokines, which activate NK cells in vivo, or adoptive transfer of NK cells may be a feasible method for amplifying the efficacy of immunotherapy against malignant cancers even with very low expression of target molecules in dogs. [ABSTRACT FROM AUTHOR]

Chemotherapy can alter the makeup of a tumor cell population by exerting selection pressure. We examined the change in Shannon index, a mathematical diversity measure used in ecology, for c-MYC copy number variation (CNV) after neoadjuvant chemotherapy and evaluated its clinical significance in breast cancer. Associations between Shannon indices for c-MYC CNV in pre- and post-neoadjuvant chemotherapy breast cancer samples and clinicopathologic features of tumors as well as patient survival were analyzed in 144 patients. A change in c-MYC amplification and copy number gain status was found in 14.3% and 33.6% with most cases showing positive to negative conversion. The chemo-sensitive group showed a significant decrease in Shannon index after neoadjuvant chemotherapy. However, there was no difference in diversity indices between pre- and post-neoadjuvant chemotherapy specimens in the chemo-resistant group. In survival analyses, high Shannon indices for c-MYC CNV in post-neoadjuvant chemotherapy samples as well as those in pre-neoadjuvant chemotherapy samples were revealed as independent prognostic factors for poor disease-free survival not only in the whole group but also in the chemo-resistant subgroup. These findings suggest that a change in Shannon index for c-MYC CNV after neoadjuvant chemotherapy reflects chemo-responsiveness and that Shannon indices after neoadjuvant chemotherapy have a prognostic value in breast cancer patients who receive neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]