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Leptomeningeal carcinomatosis is a rare but serious consequence of pre-existing tumors, such as breast, lung, and gastrointestinal carcinomas. Further, leptomeningeal carcinomatosis is more frequently diagnosed with breast cancers, if only because breast cancers are diagnosed far more often than any other carcinomas. In this paper, we present the case of a leptomeningeal carcinomatosis patient who experienced complete remission following therapy targeted at the Her-2 (human epidermal growth factor receptor 2-positive) receptor. This patient’s diagnosis was complicated by the fact that brain and column MRI imaging were clear, but analysis of the cerebrospinal fluid led to the conclusion of leptomeningeal carcinomatosis. The tests were requested because the patient, under chemotherapy for advanced breast cancer at the time, reported some neurological symptoms. Following the diagnosis of leptomeningeal carcinomatosis and subsequent T-DM1 Her-2 receptor therapy, the patient showed a complete response to leptomeningeal carcinomatosis within 30 days and survived for another 16 months. This case offers compelling evidence that the effect TDM1 Her-2 receptor therapy has on a patient’s remission and long-term survivability is considerably better than other therapies for similar pre-existing conditions diagnosed with leptomeningeal carcinomatosis. Further prospective studies should confirm these findings.

Summary Hepatoid tumors (HT) are rare neoplasms morphologically resembling hepatocellular carcinoma, which arise in several organs other than the liver. A comprehensive molecular profile of this group of neoplasms is still lacking. Genomic characterization of 19 HTs from different organs (three colon HTs, four esophagogastric HTs, four biliary HTs, six genitourinary HTs, two lung HTs) was performed using a multigene next-generation sequencing panel. NGS unraveled a composite molecular profile of HT. Their genetic alterations were clearly clustered by tumor site: (i) colorectal HT displayed microsatellite instability, high tumor mutational burden, mutations in ARID1A/B genes and NCOA4-RET gene fusion (2/3 cases); (ii) gastric HT had TP53 mutations (2/4); (iii) biliary HT displayed loss of CDKN2A (3/4) and loss of chromosome 18 (2/4); (iv) genital HT showed gain of chromosome 12 (3/6); (v) lung HT had STK11 somatic mutations (2/2). The only commonly mutated gene occurring in HT of different sites was TP53 (8/19 cases: colon 2, esophagogastric 2, biliary 2, genital 1, lungs 1). This study shows that most genetic alterations of HT were clustered by site, indicating that context matters. The novel potential targets for HT precision oncology are also clustered based on the anatomic origin. This study shed light on the biology of these rare cancers and may have important consequences for treatment decisions and clinical trial selection for HT patients.

The objective of the present study was to investigate the association between angiotensin-converting enzyme (ACE) inhibitor use and cancer incidence (overall, and breast, prostate, and colorectal cancers specifically) in a large representative sample of US adults. Cross-sectional data on cancer diagnosis, timing of cancer diagnosis, ACE inhibitor use, and other characteristics were extracted from 49 512 adults aged ≥ 20years participating in the National Health and Nutrition Examination Survey (1999–2016). Multivariable-logistic and propensity score matching (PSM) regressions examined the relationship between pre-diagnosis use of ACE inhibitors and diagnosis of all cancers, and breast, prostate, and colorectal cancers specifically. Overall, we observed an increased likelihood of cancer diagnosis [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.088–1.480] among those who used ACE inhibitors compared to non-ACE inhibitor use, and for prostate cancer diagnosis (OR 1.438, 95% CI 1.090–1.897), after adjusting for age, sex, body mass index, race/ethnicity, educational attainment, physical activity, alcohol drinking status, smoking status, and high blood pressure. PSM regression retrieved more conservative estimates such that the increased likelihood of cancer diagnosis was only observed when comparing ACE inhibitor users with non-drug users (OR 1.022, 95% CI 1.016–1.027). Compared with non-ACE inhibitor use, ACE inhibitor use was associated with an increased risk of prostate cancer. In conclusion, in this large representative sample of US adults, it was found that ACE inhibitor use may have a marginal influence on some cancers. © 2020, Springer Nature Switzerland AG.

In the last two decades, there has been marked development in virtual slide technology as well as its application in various subspecialties of pathology. In particular, there have been several studies examining the utility of whole slide imaging (WSI) in breast and gynecological pathology. The aim of this systematic review is to analyse published evidence regarding validation studies of WSI applied specifically to the female genital tract and breast pathology.A systematic search was carried out in Pubmed and Embase databases and studies dealing with the validation of a WSI system for breast and gynaecological pathology. The topics evaluated concerned expertise of engaged pathologists, varied specimens, scanners, washout period, experience viewing WSI, and diagnostic concordance of WSI to traditional light microscopic diagnoses.Of 1467 publications retrieved, 23 studies were included. Most of these studies concerned breast pathology. Validation guidelines recommended by the College of American Pathologists pertaining to a dataset of at least 60 cases, washout period, and recording intra-observer variability were followed by most studies. Major challenges encountered with WSI included difficulty identifying high-grade nuclear atypia and mitotic count for borderline ovarian tumors, interpretation of squamous intraepithelial lesions in liquid-based cervical cytology, and grading breast cancer.Published data demonstrates the value of utilizing WSI in breast and gynecological pathology. Key issues reported with WSI systems were problems related to focus, resolution and the contrast and brightness of immunohistochemical staining patterns. Grading breast cancer and mitotic count remained challenging in WSI as in conventional microscopy.

Juvenile polyposis (JP) is a rare familial syndrome characterized by the development of numerous hamartomatous polyps of the gastrointestinal tract and by an increased risk of developing gastrointestinal cancers. It follows a pattern of autosomal dominant inheritance and is associated with germline variants of SMAD4 or BMPR1A genes. Differential diagnosis may be difficult based on histology alone, due to morphological similarities to other familial syndromes. Here we report a case of familial JP diagnosed in a 50-years woman with a familial history positive for gastrointestinal cancers and other tumor types. The patient presented with severe iron deficiency anemia and showed numerous polyps in the stomach and jejunum according to endoscopy and imaging. She underwent an intra-gastric laparoscopic removal of the major gastric polyp, followed by jejunal exploration and resection of a segment with multiple neoformations. Histological examination revealed the presence of hamartomatous polyposis. Gastric and intestinal samples were analyzed with next-generation sequencing. Molecular analysis showed that the patient harbored a germline splicing site variant of SMAD4, c.1139 + 3A > G, which was complemented by different somatic variants of the same gene in the different polyps. Immunohistochemistry for SMAD4 confirmed loss of protein expression in the polyps, with regular expression in normal cells. cDNA sequencing further confirmed the findings. We thus definitively diagnosed the woman as having JP thanks to an integrated approach based on histology, immunohistochemistry and molecular analysis. The identified variants, all previously reported as variants of unknown significance, were classified as pathogenic as they complemented each other leading to SMAD4 loss.

Contains fulltext : 215605.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. METHODS: To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. RESULTS: The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. CONCLUSIONS: This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.

Objective Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. Methods Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic. Results Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). Conclusions Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior. © Wolters Kluwer Health, Inc. All rights reserved.

Introduction High fidelity between non–small cell lung cancer (NSCLC) primary tumours and patient-derived tumour xenografts (PDTXs) is of paramount relevance to spur their application. Extensive proteomic and kinomic analysis of these preclinical models are missing and may inform about their functional status, in terms of phosphopeptides and hyperactive signalling pathways. Methods We investigated tumour xenografts derived from patients with NSCLC to identify hyperactive signalling pathways. Fresh tumour fragments from 81 NSCLC surgical samples were implanted in Nod/Scid/Gamma mice, and engrafted tumours were compared with primary specimens by morphology, immunohistochemistry, gene mutation analyses, and kinase activity profiling. Four different tyrosine and serine/threonine kinase inhibitors were tested against primary tumour and PDTX lysates using the PamGene peptide microarray platform. Results The engraftment rate was 33%, with successful engraftment being more associated with poor clinical outcomes. Genomic profiles led to the recognition of hotspot mutations, some of which were initially undetected in donor samples. Kinomic analyses showed that characteristics of primary tumours were retained in PDTXs, and tyrosine kinase inhibitors (TKIs) responses of individual PDTX lines were either expected, based on the genetic status, or alternatively defined suitable targets unpredictable by single-genome fingerprints. Conclusions Collectively, PDTXs mostly resembled their parental NSCLC. Combining genomic and kinomic analyses of tumour xenografts derived from patients with NSCLC, we identified patients' specific targetable pathways, confirming PDTXs as a preclinical tool for biomarker identification and therapeutic algorithm'' improvement.

To assess efficacy and safety of trastuzumab biosimilars in comparison to the reference drug through a systematic review and meta-analysis of randomized controlled trials (RCTs). A comprehensive search was conducted using PubMed, Web of Science, Cochrane library, Open Grey and ClinicalTrials.gov databases. Dichotomous data for efficacy and safety outcomes were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs). Meta-analysis was performed with the Mantel–Haenszel method using Revman 5.3 software. Eight phase III RCTs including a total of 3913 patients with HER2 + breast cancer were identified that met the inclusion criteria. The pooled results for the comparison of trastuzumab biosimilars to the reference drug showed no differences of objective response rate (ORR) (RR 1.05, 95% CI 0.98–1.12, P = 0.20) or overall survival (RR 0.82, 95% CI 0.61–1.09, P = 0.17) in the intention-to-treat population, as well as no difference of ORR (RR 1.03, 95% CI 0.97–1.10, P = 0.30) in the per-protocol population. Similarly, no significant difference was detected in any type of adverse event reported in at least three RCTs, including any serious treatment-emergent adverse effects (RR 0.97, 95% CI 0.76–1.25, P = 0.83), heart failure (RR 1.47, 95% CI 0.69–3.14, P = 0.32), neutropenia (RR 1.05, 95% CI 0.96–1.15, P = 0.26), and infusion-related reaction (RR 1.10, 95% CI 0.89–1.36, P = 0.38). This meta-analysis provides compelling evidence of clinical comparability between trastuzumab biosimilars and the originator product in terms of both efficacy and safety for the treatment of HER2 + breast cancer.

Strong prognostic markers able to stratify lung adenocarcinoma (ADC) patients are lacking. We evaluated whether a six-immunohistochemical markers panel (TTF1, SP-A, Napsin A, MUC5AC, CDX2 and CK5), defining the putative neoplastic “cell of origin,” allows to identify prognostic subgroups among lung ADC. We screened a large cohort of ADC specimens (2003–2013) from Torino Institutional Repository identifying: (i) marker positivity by immunohistochemistry, (ii) main morphological appearance by light microscopy, (iii) presence of “hotspot” mutations of candidate genes by Sequenom technology. To evaluate possible predictors of survival and time to recurrence, uni- and multivariable-adjusted comparisons were performed. We identified 4 different subgroups: “alveolar,” “bronchiolar,” “mixed” and “null type." Alveolar-differentiated ADC were more common in young (P =.065), female (P =.083) patients, frequently harboring EGFR-mutated (P =.003) tumors with acinar pattern (P

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The aim of the present study was to map and grade evidence for the relationships between telomere length with a diverse range of health outcomes, using an umbrella review of systematic reviews with meta-analyses. We searched for meta-analyses of observational studies reporting on the association of telomere length with any health outcome (clinical disease outcomes and intermediate traits). For each association, random-effects summary effect size, 95% confidence interval (CI), and 95% prediction interval were calculated. To evaluate the credibility of the identified evidence, we assessed also heterogeneity, evidence for small-study effect and evidence for excess significance bias. Twenty-one relevant meta-analyses were identified reporting on 50 different outcomes and including a total of 326 observational studies. The level of evidence was high only for the association of short telomeres with higher risk of gastric cancer in the general population (relative risk, RR=1.95, 95%CI: 1.68-2.26), and moderate for the association of shorter telomeres with diabetes or with Alzheimer’s disease, even if limited to meta-analyses of case-control studies. There was weak evidence for twenty outcomes and not significant association for 27 health outcomes. The present umbrella review demonstrates that shorter telomere length may have an important role in incidence gastric cancer and, probably, diabetes and Alzheimer’s disease. At the same time, conversely to general assumptions, it does not find strong evidence supporting the notion that shorter telomere length plays an important role in many health outcomes that have been studied thus far.

Biallelic inactivation of the tumor suppressor gene BRCA1-associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1- were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to BAP1- adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1-: n = 697; BAP1+: n = 2,750), with a median follow-up over 60 months, were meta-analyzed. Compared to BAP1+, BAP1- significantly increased all-cause mortality, cancer-specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high-tumor grading (P

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P =.04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1–positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1–negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P =.034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P =.035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC. © 2018 Elsevier Inc.

Background and Objectives Lymph node involvement is common in thyroid cancer, but the system of staging does not consider the histological features of lymph node metastases. We conducted a meta-analysis to investigate the prognostic role of extranodal extension (ENE) in thyroid cancer patients. Methods We ran PubMed and SCOPUS searches without language restrictions. Prospective studies reporting data on overall mortality, cancer-specific mortality, or disease recurrence including thyroid cancer patients, in which cases with ENE (ENE+) were compared with those with only intranodal disease (ENE−) were eligible. Data were summarized using risk ratios (RR) for number of deaths/recurrences, and hazard ratios (HR) for time-dependent risks related to ENE+ status, adjusted for potential confounders. Results Of 414 hits, 23 studies were eligible and included. Compared to ENE−, patients who were ENE+ had significantly higher rates of all-cause mortality (studies = 8; RR = 3.25; 95%CI: 1.35–2.64, I2 = 83%) and recurrence (studies = 17; RR = 2.64, 95%CI: 1.93–3.60, I2 = 73%). Using HRs adjusted for potential confounders, ENE+ status carried a significantly higher risk of all-cause and cancer-specific mortality and disease recurrence. Conclusion It becomes mandatory to consider ENE in the histopathological examination of surgical samples in thyroid cancer patients, and this factor should be included in future oncological staging systems. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.

The extranodal extension (ENE) of nodal metastasis involves the extension of neoplastic cells through the lymph node capsule into the perinodal adipose tissue. This morphological feature has recently been indicated as an important prognostic factor in various cancer types, but its role in prostate cancer is still unclear. We aimed to clarify it, performing the first meta-analysis on this issue, comparing prognostic parameters in surgically treated, node-positive prostate cancer patients with (ENE+) vs. without (ENE−) ENE. Data were summarized using risk ratios (RRs) for number of deaths/recurrences and hazard ratios (HRs), with 95% confidence intervals (CI), for the time-dependent risk related to ENE positivity. Six studies followed-up 1,113 patients with N1 prostate cancer (658 ENE+ vs. 455 ENE−) for a median of 83 months. The presence of ENE was associated with a significantly higher risk of biochemical recurrence (RR = 1.15; 95%CI: 1.03–1.28; I2 = 0%; HR = 1.40, 95%CI: 1.12–1.74; I2 = 0%) and “global” (biochemical recurrence and distant metastasis) recurrence (RR = 1.15; 95%CI: 1.04–1.28; I2 = 0%; HR = 1.41, 95%CI: 1.14–1.74; I2 = 0%). ENE emerged as a potential prognostic moderator, earmarking a subgroup of patients at higher risk of recurrence. It may be considered for the prognostic stratification of metastatic patients. New possible therapeutic approaches may explore more in depth this prognostic parameter.

BACKGROUND Gains of a gene due to DNA polyploidy versus amplification of the specific locus are distinct molecular alterations in tumors. OBJECTIVE We quantified copy number gains of ALK gene due to unspecific polyploidy versus amplifications of the specific locus in a series of non-small cell lung cancers. METHODS The locus specific ALK copy (LSI) number status was evaluated in 205 cases by FISH. Ratio LSI ALK copy number corrected for control probes CEP2, CEP3 and CEP17 (CEPs) was scored. Amplification of the specific ALK locus was defined when ratio set to ≥ 2 while polyploidy was interpreted when the increase in gene copy resulted < 2 in ratio (LSI/control CEPs). RESULTS Twenty one cases (10.2%) showed ≥ 8 ALK signals, 68 cases (33.2%) 3-7 signals and 116 cases (56.6%) a mean of 2 signals. Only 2/21 cases of the cohort harboring ≥ 8 signals showed a ratio ≥ 2 after CEPs correction interpretable as amplified, showing numerous doubled fluorescent spots. All the remaining cases showed a mirrored number of fluorescent spots per each CEPs, interpretable as polyploidy. CONCLUSION We detected a high prevalence of ALK gene copy number usually due to polyploidy rather than ALK locus amplification, the latter visible prevalently as double minutes.

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I2 = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I2 = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13-1.88, p = 0.004; HR, 2.65; 95% CI, 1.79-3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05-2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Background Pulmonary Adenocarcinoma with Enteric Differentiation (PAED) is a rare subtype of adenocarcinoma of emerging interest, recently introduced in the 2015 WHO classification. However, little is known about major molecular signatures of this class of adenocarcinomas and information about new biomarkers totally lack. Methods We examined the NRAS, PIK3CA, EGFR, KRAS and BRAF status through mass spectrometry sequencing and ALK rearrangement by FISH in a series of 8 PAEDs. Results 1/8 (12.5%) case had a simultaneous PIK3CA mutation (E545K) and an EML4-ALK translocation. KRAS gene showed a mutation in the codon 12 in 4/8 of PAED (50%), NRAS, BRAF and EGFR genes were wild type in all tumor samples. Conclusions We concluded that PIK3CA mutations and ALK rearrangement occur also in PAEDs, while NRAS mutations might be a very rare event similarly to pulmonary adenocarcinomas of conventional type. KRAS is the prevailing gene mutated in this class of adenocarcinoma.

Introduction: The extranodal extension (ENE) of nodal metastases (the extension of neoplastic cells through the nodal capsule into the perinodal soft tissue) is a histological feature that has been considered a prognostic factor in several cancers, but the role in gastric cancer was not yet investigated. We aimed to investigate the prognostic role of ENE in patients affected by gastric cancer through a systematic review and meta-analysis. Material and Methods: Two independent authors searched major databases until 09/30/2015 to identify studies providing data on gastric cancer patients’ prognostic parameters and comparing patients with ENE (ENE+) vs intra-nodal extension (ENE−). The data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) with 95% confidence intervals (CI), adjusted for potential confounders. Results: Nine studies followed up 3250 patients with gastric cancer (1064 ENE+ and 2186 ENE−). ENE+ was associated with a significantly higher risk of all-cause mortality (RR = 1.70; 95% CI: 1.43–2.03, I2 = 66%; HR = 2.14; 95% CI: 1.66–2.75, I2 = 0%), cancer-specific mortality (RR = 1.59; 95% CI: 1.42–1.79; HR = 1.52; 95% CI: 1.19–1.96), and disease recurrence (RR = 3.43, 95% CI: 1.80–6.54, I2 = 0%). Discussion: Judging from our results, ENE in gastric cancer patients should be considered for prognostic purposes from the gross sample to the pathology report. © 2016, The Society for Surgery of the Alimentary Tract.

Brunello E, Brunelli M, Manfrin E, Nottegar A, Bersani S, Vergine M, Molino A, Fiorio E, Chilosi M, Gobbo S, Martignoni G & Bonetti F (2012) Histopathology 60, 482–488 Classical lobular breast carcinoma consistently lacks topoisomerase-IIα gene amplification: implications for the tailored use of anthracycline-based chemotherapies [Correction added after online publication, 17 January 2012: Title amended to match main article title.] Aims: There is consistent lack of data focusing the topoisomerase-IIα gene status in lobular breast carcinoma, a subtype that usually shows poor responsiveness to chemotherapies including those using anthracycline drugs. Methods and results: Forty-six infiltrative lobular carcinomas, 13 with matched metastases, were used. Topoisomerase-IIα gene amplification was evaluated by chromogenic in situ hybridization (CISH) and fluorescence in situ hybridization (FISH). We also assessed Her2/neu status by CISH, FISH and silver in situ hybridization (SISH). HER2 immunoexpression was assessed by the HercepTest. Forty-four of 46 (95%) cases revealed no topoisomerase-IIα amplification, whereas two of 46 (5%) cases were amplified by all three techniques. Eleven of the 13 metastatic sites showed no amplification either in the primary or in the metastases (85%); the remaining two were amplified (15%). Her2/neu was not amplified in 44 of 46 (95%) cases nor was it amplified in 11 of 13 (95%) metastatic tissues. The two cases showing Her2/neu and topoisomerase-IIα amplification scored 3+; the remaining non-amplified cases scored 0 or 1+ in 40 and 2+ in four cases. Conclusions: In the era of personalized and tailored therapies, we suggest that patients affected by the classical lobular subtype of breast carcinoma constantly lack the ad hoc predictive rationale for receiving common chemotherapy that includes anthracyclines.

Introduction The epithelial to mesenchymal transition, a well-known and re-emerging model in pathology, has not been completely investigated in the field of gestational pathology. This study aims at improving the comprehension of this process in molar disease, even looking for new possible immunohistochemical markers. Materials and methods We have analysed the immunohistochemical expression of Twist1 and Snai2, two of the most important transcription factors involved in epithelial to mesenchymal transition, in formalin-fixed paraffin-embedded samples of 23 spontaneous abortive pregnancies, 22 molar pregnancies (10 partial and 12 complete) and 7 term placentas. Results Twist1 and Snai2 were highly expressed in stromal villi cells of molar disease. Particularly, Twist1 was highly expressed in complete moles compared to both abortive pregnancies (p < 0.001) and partial moles (p < 0.05). Also Snai2 was more expressed by complete moles, differentiating them from non-molar abortions (p < 0.05). Discussion On the basis of the known cadherins and claudins expression in these pathologies, our new findings reinforce the hypothesis of the involvement of epithelial to mesenchymal transition in early molar pregnancies and above all in complete moles. Furthermore, we highlighted that in molar disease not only the trophoblast, but even the villi stromal cells, are involved. Thanks to their specificity, furthermore, these Twist1 and Snai2 could be used as additional immunohistochemical tool in the diagnosis of complete molar disease, with Twist1 as the first choice. © 2015 Elsevier Ltd. All rights reserved.

Transferrin receptor/CD71 is a membrane protein expressed on nucleated red blood cells (NRBCs) and trophoblasts. Here, we propose the first study to evaluate the usefulness of CD71 immunolabeling in the main fields of gestational pathology. To this aim, formalin-fixed, paraffin-embedded samples of 45 orthotopic (23 spontaneous abortive and 22 molar pregnancies) and 11 ectopic pregnancies were immunostained for CD71. NRBCs were morphologically evident in 23 cases: 12/23 abortive, 4/11 ectopic, and 7/10 partial molar pregnancies. CD71 immunolabeling detected NRBCs in all 23 previous cases and in 8 new cases: 2 partial moles and 6 spontaneous abortive pregnancies. No NRBCs were detected in complete moles by means of either morphology or immunohistochemistry (IHC). In 4 cases with extensive necrotic changes, CD71 marked NRBCs and a few ghost villi, which were not certainly identifiable with standard histological evaluation. Furthermore, there was an inversely proportional relationship between total percentage of CD71-positive NRBCs and gestational age (R=0.69; P

Introduction: The report of cases of lung squamous cell cancers harboring anaplastic lymphoma kinase ( ALK ) gene rearrangements raises the question whether this histologic subtype should be also evaluated for such molecular predictive test. Methods: A consecutive series of 40 lung pure squamous cell carcinomas were analyzed for ALK gene status by fluorescence in situ hybridization. Squamous differentiation was validated using an immunohistochemical panel including n-p63 (p40), cytokeratin (CK) 5/6, sex-determining region Y (SRY)-Box2 (SOX2), thyroid transcription factor 1, CK7, and Napsin-A. Results: Squamous differentiation was confirmed in all tumors as they stained positive for n-p63 and CK5/6 and negative for thyroid transcription factor 1 and Napsin-A. One of 40 cases (2.5%) showed an ALK rearrangement on fluorescence in situ hybridization analysis. Conclusions: ALK translocation may be found in lung pure squamous cell carcinomas. Our data suggest the opportunity to test ALK rearrangements on biopsy samples harboring squamous cell cancer differentiation.

The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer.Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders.Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P0.0001, I(2) = 48%).Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.