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Table S2. Oncogenic/Likely-oncogenic structural variants in GBC

Purpose:Gallbladder carcinoma (GBC) is an uncommon and aggressive disease, which remains poorly defined at a molecular level. Here, we aimed to characterize the molecular landscape of GBC and identify markers with potential prognostic and therapeutic implications.Experimental Design:GBC samples were analyzed using the MSK-IMPACT (Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets) platform (targeted NGS assay that analyzes 505 cancer-associated genes). Variants with therapeutic implications were identified using OncoKB database. The associations between recurrent genetic alterations and clinicopathologic characteristics (Fisher exact tests) or overall survival (univariate Cox regression) were evaluated. P values were adjusted for multiple testing.Results:Overall, 244 samples (57% primary tumors and 43% metastases) from 233 patients were studied (85% adenocarcinomas, 10% carcinomas with squamous differentiation, and 5% neuroendocrine carcinomas). The most common oncogenic molecular alterations appeared in the cell cycle (TP53 63% and CDKN2A 21%) and RTK_RAS pathways (ERBB2 15% and KRAS 11%). No recurrent structural variants were identified. There were no differences in the molecular landscape of primary and metastasis samples. Variants in SMAD4 and STK11 independently associated with reduced survival in patients with metastatic disease. Alterations considered clinically actionable in GBC or other solid tumor types (e.g., NTRK1 fusions or oncogenic variants in ERBB2, PIK3CA, or BRCA1/2) were identified in 35% of patients; 18% of patients with metastatic disease were treated off-label or enrolled in a clinical trial based on molecular findings.Conclusions:GBC is a genetically diverse malignancy. This large-scale genomic analysis revealed alterations with potential prognostic and therapeutic implications and provides guidance for the development of targeted therapies.

Figure S1. Mutation signatures and altered canonical pathways in GBC.

Table S3. Therapy regimens

Table S1. Sample list (cBioPortal identifiers, ‘DMP_SAMPLE_ID’). Only the primary tumor (if available) or the earliest collected metastasis are included (n=233)

Detailed statistical results

Figure S2. Microbiome analysis in GBC.

Context.— Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. Objective.— To investigate their morphologic, immunohistochemical, and molecular features. Design.— Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. Results.— The mean age at diagnosis was 69 years (42–81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Conclusions.— Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.

Purpose: Gallbladder carcinoma (GBC) is an uncommon and aggressive disease, which remains poorly defined at a molecular level. Here, we aimed to characterize the molecular landscape of GBC and identify markers with potential prognostic and therapeutic implications. Experimental Design: GBC samples were analyzed using the MSK-IMPACT (Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets) platform (targeted NGS assay that analyzes 505 cancer-associated genes). Variants with therapeutic implications were identified using OncoKB database. The associations between recurrent genetic alterations and clinicopathologic characteristics (Fisher exact tests) or overall survival (univariate Cox regression) were evaluated. P values were adjusted for multiple testing. Results: Overall, 244 samples (57% primary tumors and 43% metastases) from 233 patients were studied (85% adenocarcinomas, 10% carcinomas with squamous differentiation, and 5% neuroendocrine carcinomas). The most common oncogenic molecular alterations appeared in the cell cycle (TP53 63% and CDKN2A 21%) and RTK_RAS pathways (ERBB2 15% and KRAS 11%). No recurrent structural variants were identified. There were no differences in the molecular landscape of primary and metastasis samples. Variants in SMAD4 and STK11 independently associated with reduced survival in patients with metastatic disease. Alterations considered clinically actionable in GBC or other solid tumor types (e.g., NTRK1 fusions or oncogenic variants in ERBB2, PIK3CA, or BRCA1/2) were identified in 35% of patients; 18% of patients with metastatic disease were treated off-label or enrolled in a clinical trial based on molecular findings. Conclusions: GBC is a genetically diverse malignancy. This large-scale genomic analysis revealed alterations with potential prognostic and therapeutic implications and provides guidance for the development of targeted therapies.

The purpose of the study was to analyze the expression of nucleophosmin (NPM1), CCAT/enhancer-binding protein alpha (CEBPA), and FMS-like tyrosine kinase 3 (FLT3) with immunohistochemistry and evaluate the relationship with clinicopathologic data with special emphasis on prognosis in bone marrow biopsy specimens diagnosed with acute myeloid leukemia (AML).Bone marrow biopsies of 104 patients who were diagnosed with AML were re-evaluated for diagnosis and subclassification. Immunohistochemically, anti-NPM1, anti-CEBPA, and anti-FLT3 antibodies were applied to slides prepared from formalin-fixed paraffin-embedded tissues. Sixty-three of these patients had their follow-up in our institutional hematology clinic and these patients' clinical, biochemical, and radiological data were obtained and analyzed from patient files. These data were analyzed with survival times statistically.Except for age, no significant effect of clinical data on prognosis was detected. Immunohistochemical results were also statistically compared with clinical data. No correlation was found between overall survival and disease-free survival with the expression of anti-CEBPA or anti-NPM1 antibodies. However, immunohistochemical reactivity for anti-FLT3 antibody was found to be a poor prognostic factor and statistically significant. Also, when the expression of FLT3 was analyzed with that of NPM1 or CEBPA, a correlation (dependent on the expression of FLT3) was found with disease-free survival.FLT3 is an independent prognostic factor for AML. CEBPA and NPM1 should be considered as good prognostic factors only in the absence of FLT3 abnormalities.

Pancreatic neoplasms are heterogenous and have traditionally been classified by assessing their lines of cellular differentiation using histopathologic methods, particularly morphologic and immunohistochemical evaluation. These methods frequently identify overlapping differentiation along ductal, acinar, and neuroendocrine lines, raising diagnostic challenges as well as questions regarding the relationship of these neoplasms. Neoplasms with acinar differentiation, in particular, frequently show more than one line of differentiation based on immunolabeling. Genome methylation signatures, in contrast, are better conserved within cellular lineages, and are increasingly used to support the classification of neoplasms. We characterized the epigenetic relationships between pancreatoblastomas, acinar cell carcinomas (including mixed variants), pancreatic neuroendocrine tumors, solid pseudopapillary neoplasms, and pancreatic ductal adenocarcinomas using a genome-wide array platform. Using unsupervised learning approaches, pancreatic neuroendocrine tumors, solid pseudopapillary neoplasms, ductal adenocarcinomas, and normal pancreatic tissue samples all localized to distinct clusters based on their methylation profiles, whereas all neoplasms with acinar differentiation occupied a broad overlapping region located between the predominantly acinar normal pancreatic tissue and ductal adenocarcinoma clusters. Our data provide evidence to suggest that acinar cell carcinomas and pancreatoblastomas are similar at the epigenetic level. These findings are consistent with genomic and clinical observations that mixed acinar neoplasms are closely related to pure acinar cell carcinomas rather than to neuroendocrine tumors or ductal adenocarcinomas.

Context.— Although most pancreatic and bile duct neoplasms are solid, mucinous cystic neoplasms and intraductal neoplasms have been increasingly recognized even when clinically silent, thanks to the increased use of sensitive imaging techniques. Cystic and intraductal neoplasms of the pancreas are often resectable and curable and constitute about 5% of all pancreatic neoplasms. Owing to their preinvasive nature and different biology, recognition of these entities remains a major priority. Mucinous cystic neoplasms are histologically and clinically distinct from other cystic pancreatic neoplasms. Pancreatic intraductal neoplasms encompass 3 major entities: intraductal papillary mucinous neoplasm, intraductal oncocytic papillary neoplasm, and intraductal tubulopapillary neoplasm. Intraductal papillary neoplasms of bile ducts are also preinvasive mass-forming neoplasms with both similarities and differences with their pancreatic counterparts. All of these pancreatobiliary neoplasms have diverse and distinctive clinicopathologic, genetic, and prognostic variations. Objective.— To review the clinical, pathologic, and molecular features of mucinous cystic and intraductal neoplasms of the pancreatobiliary tract. Data Sources.— Literature review, diagnostic manuals, and guidelines. Conclusions.— This review will briefly describe well-known clinical and pathologic features and will focus on selected recently described aspects of morphology, grading, classification, and genomic alterations of cystic and intraductal neoplasms of the pancreatobiliary tract.

Superficial CD34 positive fibroblastic tumor (SCPFT) is a recently recognized, unique neoplasm with distinctive histomorphological features such as high pleomorphism, low mitotic rate, and diffuse CD34 reactivity. Hereby we present three cases of our experience with clinicopathological, morphological, and immunohistochemical characteristics. The patients were a 31-year-old female, 53-year-old female, and 33-year-old male. The tumors were all superficially located; left forearm, medial aspect of the left ankle, and left thigh, respectively. Histomorphologically they had expansile and focal infiltrative growth pattern consisting of highly pleomorphic spindle cells with intranuclear inclusions, yet low mitotic rate. Tumoral cells showed strong and diffuse reactivity for CD34. One of our cases showed focal and weak reactivity for pancytokeratin. Unlike the other two tumors, one case was positive for desmin. During the clinical follow-up, one case showed local recurrence four times. SCPFT is a newly recognized, borderline mesenchymal neoplasm of soft tissues that can show local recurrence or even rarely metastasize. To the best of our knowledge, this three case series is the first to be reported from Turkey. Our aim to report these three cases was to make contribution to the literature about this rare entity and increase awareness.

To evaluate the potential value of machine learning (ML)-based histogram analysis (or first-order texture analysis) on T2-weighted magnetic resonance imaging (MRI) for predicting consistency of pituitary macroadenomas (PMA) and to compare it with that of signal intensity ratio (SIR) evaluation. Fifty-five patients with 13 hard and 42 soft PMAs were included in this retrospective study. Histogram features were extracted from coronal T2-weighted original, filtered and transformed MRI images by manual segmentation. To achieve balanced classes (38 hard vs 42 soft), multiple samples were obtained from different slices of the PMAs with hard consistency. Dimension reduction was done with reproducibility analysis, collinearity analysis and feature selection. ML classifier was artificial neural network (ANN). Reference standard for the classifications was based on surgical and histopathological findings. Predictive performance of histogram analysis was compared with that of SIR evaluation. The main metric for comparisons was the area under the receiver operating characteristic curve (AUC). Only 137 of 162 features had excellent reproducibility. Collinearity analysis yielded 20 features. Feature selection algorithm provided six texture features. For histogram analysis, the ANN correctly classified 72.5% of the PMAs regarding consistency with an AUC value of 0.710. For SIR evaluation, accuracy and AUC values were 74.5% and 0.551, respectively. Considering AUC values, ML-based histogram analysis performed better than SIR evaluation (z = 2.312, p = 0.021). ML-based T2-weighted MRI histogram analysis might be a useful technique in predicting the consistency of PMAs, with a better predictive performance than that of SIR evaluation.

Ergonomics education has been a stable element of undergraduate industrial design programs in Turkey; however, it is mainly for introductory purposes, in an effort to reflect the multidisciplinary nature of human and ergonomicfactorss. In this research, the effectiveness of ergonomics education given in industrial design departments in Turkey and possible improvement areas are investigated. The aim was to identify how students utilise ergonomics methods during their design projects and to examine the effectiveness of their ergonomics education. The students' points of view on the ergonomics modules they took were also sought. An online questionnaire survey was conducted with 79 undergraduate industrial design students from various universities in Turkey. The results are presented and discussed, and directions for further studies are suggested.

Targeted responder model is a recent approach in providing initial treatment to cardiac arrest patients. In this model, a group of trained responders are dispatched via mobile devices to nearby cardiac arrests. While prior work shows that targeted responder programs are successful in reducing average response time, less than a quarter of the responders who receive the notification of a nearby cardiac arrest travel to the scene of event. This study is an attempt to better understand barriers to respond in targeted responder programs. We conducted a weeklong diary study and focus groups with 12 participants. We identified four categories of barriers that emerge and we discussed the design implications of our findings within the broader context of location-based crowdsourcing.

In this paper, we describe Papetto, a lightweight robotic arm that moves according to face detection techniques in order to mirror facial movements such as head shaking, leaning and tilting. Using this system we examine the role of the "frame" in video chat and how embodied co-presence is defined and bounded through light-weight robotic mirroring to enable new forms of engagement in remote communication.