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The aim of this systematic review is to shed light on the role of tumor budding (TB) in the biology, behavior, and prognosis of head and neck squamous cell carcinoma (HNSCC). A search was run in PubMed, Scopus, and Embase databases following PRISMA guidelines. After full‐text screening and application of inclusion/exclusion criteria, 36 articles were included. Several investigations support the prognostic role of TB, which might play a role in selecting rational treatment strategies. To achieve this goal, further research is needed for greater standardization in TB quantification. Although TB is not included as a negative prognostic factor in the current management guidelines, it might be reasonable to consider a closer follow‐up for HNSCC cases with high histopathological evidence of TB. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignant tumor with neuroendocrine differentiation, with a rapidly growing incidence rate, high risk of recurrence, and aggressive behavior. The available therapeutic options for advanced disease are limited and there is a pressing need for new treatments. Tumors harboring fusions involving one of the neurotrophin receptor tyrosine kinase (NTRK) genes are now actionable with targeted inhibitors. NTRK-fused genes have been identified in neuroendocrine tumors of other sites; thus, a series of 76 MCCs were firstly analyzed with pan-TRK immunohistochemistry and the positive ones with real-time RT-PCR, RNA-based NGS, and FISH to detect the eventual underlying gene fusion. Despite 34 MCCs showing pan-TRK expression, NTRK fusions were not found in any cases. As in other tumors with neural differentiation, TRK expression seems to be physiological and not caused by gene fusions. [ABSTRACT FROM AUTHOR]

The incidence of cutaneous melanoma has been increasing in the last decades among the fair-skinned population. Despite its complex and multifactorial etiology, the exposure to ultraviolet radiation (UVR) is the most consistent modifiable risk factor for melanoma. Several factors influence the amount of UVR reaching the Earth's surface. Our study aimed to explore the relationship between melanoma and altitude in an area with mixed geographic morphology, such as the Veneto region (Italy). We included 2752 melanoma patients who were referred to our centers between 1998 and 2014. Demographics, histological and clinical data, and survival information were extracted from a prospectively maintained local database. Head/neck and acral melanoma were more common in patients from the hills and the mountains, while limb and trunk melanoma were more common in patients living in plain and coastal areas. Breslow thickness, ulceration and mitotic rate impaired with increased altitude. However, the geographical area of origin was not associated with overall or disease-free survival. The geographical area of origin of melanoma patients and the "coast-plain-hill gradient" could help to estimate the influence of different sun exposure and to explain the importance of vitamin D levels in skin-cancer control. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC. Methods: A retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens. Results: 143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor. Conclusions: Autoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient. [ABSTRACT FROM AUTHOR]

Malignant melanoma (MM) is the most lethal skin cancer. AXL is a tyrosine kinase receptor involved in several oncogenic processes and might play a role in blocking necroptosis (a regulated cell death mechanism) in MM through the downregulation of the necroptotic-related driver RIPK3. The aim of this study was to evaluate the clinical impact of the expression of AXL and RIPK3 in 108 primary cutaneous MMs. Association between AXL and RIPK3 immunoreactivity and clinical–pathological variables, sentinel lymph node status, and tumor-infiltrating lymphocytes (TILs) was assessed. Immunoreaction in tumor cells was detected in 30 cases (28%; range, 5%–80%) and in 17 cases (16%; range, 5%–50%) for AXL and RIPK3, respectively. Metastases in the sentinel lymph nodes were detected in 14 out of 61 patients, and these were associated with AXL-positive immunoreactivity in the primary tumor (p < 0.0001). No association between AXL and TILs was found. RIPK3 immunoreactivity was not associated with any variables. A final logistic regression analysis showed Breslow and AXL-positive immunoreactivity as the stronger predictor for positive sentinel node status [area under the receiver operating characteristic curve (AUC) of 0.96]. AXL could be a potential new biomarker for MM risk assessment, and it deserves to be further investigated in larger studies. [ABSTRACT FROM AUTHOR]

The "Veneto Cancer Registry" records melanoma as the most common cancer diagnosed in males and the third common cancer in females under 50 years of age in the Veneto Region (Italy). While melanoma is rare in children, it has greater incidence in adolescents and young adults (AYA), but literature offers only few studies specifically focused on AYA melanoma. The aim of this study was to describe the characteristics, surgical treatment, and prognosis of a cohort of AYA melanoma in order to contribute to the investigation of this malignancy and provide better patient care. This retrospective cohort study included 2,752 Caucasian patients (702 AYA and 2,050 non-AYA patients) from the Veneto Region who were over 15 years of age at diagnosis, and who received diagnosis and/or treatment from our institutions between 1998 and 2014. Patients were divided in adolescents and youth (15-25 years), young adults (26-39 years) and adults (more than 39 years) for the analysis. We found statistically significant differences in gender, primary site, Breslow thickness, ulceration, pathologic TNM classification (pTNM) stage and tumor subtype among the age groups. Disease-specific survival and disease-free survival were also different among the age groups. Our findings suggest that the biological behavior of melanoma in young people is different to that in adults, but not such as to represent a distinct pathological entity. Additional and larger prospective studies should be performed to better evaluate potential biological and cancer-specific differences between AYAs and the adult melanoma population. [ABSTRACT FROM AUTHOR]

Cytokine-Induced Killer (CIK) cells share several functional and phenotypical properties of both T and natural killer (NK) cells. They represent an attractive approach for cell-based immunotherapy, as they do not require antigen-specific priming for tumor cell recognition, and can be rapidly expanded in vitro. Their relevant expression of FcγRIIIa (CD16a) can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their lytic activity in an antigen-specific manner. Here, we report the efficacy of this combined approach against triple negative breast cancer (TNBC), an aggressive tumor that still requires therapeutic options. Different primitive and metastatic TNBC cancer mouse models were established in NSG mice, either by implanting patient-derived TNBC samples or injecting MDA-MB-231 cells orthotopically or intravenously. The combined treatment consisted in the repeated intratumoral or intravenous injection of CIK cells and cetuximab. Tumor growth and metastasis were monitored by bioluminescence or immunohistochemistry, and survival was recorded. CIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either in patient-derived tumor xenografts or MDA-MB-231 cell line models. Moreover, this approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and led to an enrichment of the CD16a+ subset. Data highlight the potentiality of this novel immunotherapy strategy where a nonspecific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells. ACT, Adoptive Cell Transfer; ADCC, Antibody-Dependent Cell-mediated Cytotoxicity; ADP, Adenosine diphosphate; BLI, Bioluminescence Imaging; CAR, Chimeric Antigen Receptor; CIK, Cytokine Induced Killer cells; CTX, Cetuximab; DMEM, Dulbecco's Modified Eagle Medium; EGFR, Human Epidermal Growth Factor 1; ER, Estrogen; FBS, Fetal Bovine Serum; FFPE, Formalin-Fixed Paraffin-Embedded; GMP, Good Manufacturing Practices; GVHD, Graft Versus Host Disease; HER2, Human Epidermal Growth Factor 2; HRP, Horseradish Peroxidase; IFN-γ, Interferon-γ; IHC, Immunohistochemistry; IL-2, Interleukin-2; ISO, Irrelevant antibody; i.t., intratumoral; i.v., intravenous, mAbs, Monoclonal Antibodies; mIHC, Multiplex Fluorescence Immunohistochemistry; MHC, Major Histocompatibility Complex; NK, Natural Killer; NKG2D, Natural-Killer group 2 member D; NSG, NOD/SCID common γ chain knockout; PARP, Poly ADP-ribose polymerase; PBMCs, Peripheral Blood Mononuclear Cells; PBS, Phosphate-buffered saline; PDX, Patient-derived xenograft; PR, Progesterone; rhIFN-γ, Recombinant Human Interferon-γ; RPMI, Roswell Park Memorial Institute; STR, Short tandem Repeat; TCR, T Cell Receptor; TNBC, Triple Negative Breast Cancer; TSA, Tyramide Signal Amplification [ABSTRACT FROM AUTHOR]

The high morbidity and mortality of colorectal cancer (CRC) remain a worldwide challenge, despite the advances in prevention, diagnosis, and treatment. RAS alterations have a central role in the pathogenesis of CRC universally recognized both in the canonical mutation-based classification and in the recent transcriptome-based classification. About 40% of CRCs are KRAS mutated, 5% NRAS mutated, and only rare cases are HRAS mutated. Morphological and molecular correlations demonstrated the involvement of RAS in cellular plasticity, which is related to invasive and migration properties of neoplastic cells. RAS signaling has been involved in the initiation of epithelial to mesenchymal transition (EMT) in CRC leading to tumor spreading. Tumor budding is the morphological surrogate of EMT and features cellular plasticity. Tumor budding is clinically relevant for CRC patients in three different contexts: (i) in pT1 CRC the presence of tumor buds is associated with nodal metastasis, (ii) in stage II CRC identifies the cases with a prognosis similar to metastatic disease, and (iii) intratumoral budding could be useful in patient selection for neoadjuvant therapy. This review is focused on the current knowledge on RAS in CRC and its link with cellular plasticity and related clinicopathological features. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 2 (NF2) is an autosomal dominant, multiple neoplasia syndrome characterized by bilateral vestibular schwannomas (VSs). Endoglin is a proliferation‐associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate endoglin expression in a series of NF2‐associated VSs, as compared with a group of sporadic VSs. Methods: Using image analysis, vessel cross‐sectional area (AA) and density (VD) were calculated from CD105 expression in 7 NF2‐associated VSs and 14 size‐matched sporadic VSs. Results: There were no significant differences between NF2‐associated VSs and sporadic cases in terms of AA (P =.28), or VD (P =.39). A positive correlation emerged between tumor growth rate (measured on contrast‐enhanced MRI) and VD in the cohort of NF2‐associated VSs (rho = 0.95, P =.05). Conclusions: Further investigations are needed to ascertain the feasibility of (a) measuring circulating endoglin levels to monitor tumor growth rate and (b) targeting tumor neoangiogenesis with anti‐endoglin approaches in NF2‐associated VS. [ABSTRACT FROM AUTHOR]

The cytomorphologic evaluation of serous cavity specimens can quickly determine the cause of an effusion as well as the presence or absence of a neoplastic process. Ancillary tests such as immunohistochemistry and fluorescence in situ hybridization are frequently used to help to definitively identify malignant cells, determine a site of origin, and distinguish between malignant and reactive mesothelial proliferations. In recent years, microRNAs (miRNAs) have been increasingly evaluated in cytologic specimens, including those from serous cavities. The examination of miRNA is attractive because of the stability of miRNA in such specimens and data suggesting that miRNA can provide prognostic and therapeutic information in addition to its role in diagnosis. Furthermore, miRNAs exist within extracellular exosomes, and this allows for their analysis in specimens that contain only rare malignant cells, degenerated cells, or obscuring components. This review discusses the technical aspects of specimen processing for miRNA analysis, recent studies of miRNA expression in malignant serous cavity specimens, and the potential importance of miRNA expression analysis for serous cavity specimens in the near future. MicroRNAs are powerful markers: stable, easily quantifiable, and informative. In effusions, microRNAs can be used as diagnostic tools for several cancer histotypes. [ABSTRACT FROM AUTHOR]

Background: An example of aggressive eosinophilic polyposis can be found in eosinophilic granulomatosis with polyangiitis (EGPA). Intercellular adhesion molecule-1 (iCAM-1) and vascular cell adhesion molecule-1 (vCAM-1) play a part in mediating the recruitment and adhesion of leukocytes to the vessel wall, and their blood-to-tissue migration under inflammatory conditions. Objective: This prospective study compared 3 groups—patients with a definite diagnosis EGPA, non-EGPA patients with phenotypic features suggestive of EGPA, and patients with non-eosinophilic nasal polyposis (controls)—in terms of nasal tissue histology, iCAM-1 and vCAM-1 expression, and blood inflammatory cells. Methods: A total of 58 adults underwent sinus surgery (13 patients with EGPA, 23 suspected of having EGPA, and 22 controls). Results: Mean tissue eosinophil counts were significantly higher in EGPA patients and suspected cases of EGPA than in controls. Although iCAM-1 and vCAM-1 were diffusely expressed in sinonasal tissues, they did not differently stain EGPA, eosinophilic-type and non-eosinophilic polyposis. Blood basophil and eosinophil levels were high in both the EGPA and the suspected EGPA groups. Intergroup differences were found for eosinophils but not for basophils. Conclusions: We do not have yet blood or tissue markers able to differentiate the early phase of EGPA from chronic rhinosinusitis with nasal polyps. Further investigations are mandatory considering EGPA patients at their initial diagnosis and before any treatment, in terms of nasal histology and blood inflammatory cells, to identify markers characterizing sinonasal mucosa inflammation and useful for an early diagnosis of EGPA. [ABSTRACT FROM AUTHOR]

Background: Sinonasal inverted (schneiderian) papilloma (IP) is histologically benign but shows a propensity for malignant transformation. Survivin, a member of the inhibitor of the apoptosis family of proteins that controls cell division, apoptosis, metastasis, and, probably, also neoangiogenesis, is overexpressed in essentially all human cancers. Overexpression of the multidomain protein cortactin has also been associated with increased cell migration, invasion, and metastatic potential in several malignancies. Objective: The aim of the present study was to preliminarily investigate survivin and cortactin expression in a consecutive series of sinonasal IPs, and IP-associated squamous cell carcinomas (SCC). Methods: Immunohistochemical expression of nuclear survivin and cortactin was measured in 19 consecutive sinonasal IPs and 3 IP-associated SCCs. Results: The mean ± standard deviation nuclear survivin expression was 9.4 ± 9.2% and 31.7% ± 15.4% in sinonasal IPs and SCCs, respectively (p < 0.0001). Results of cortactin immunostaining was strongly positive in the cytoplasm of both sinonasal IPs and SCCs: no significant difference emerged between the IP and SCC epithelial components. Conclusion: Nuclear survivin expression was significantly higher in SCCs than in IPs. Prospective, multi-institutional prognostic studies, preferably on an international scale (given the few cases treated at single institutions), are needed to confirm the role of survivin in IP malignant transformation. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural mesothelioma is a rare tumor with a dismal prognosis, usually presenting with recurrent effusions. However, the majority of malignant pleural effusions are due to lung adenocarcinoma (AdC). The distinction between these tumors has considerable therapeutic and medicolegal implications and can be very challenging both histologically and cytologically. Appropriate immunohistochemistry (IHC) is required to support the diagnosis. MicroRNA (miRNA) expression analysis could be a viable diagnostic tool for distinguishing between these tumors. The purpose of the current study was to assess the reliability of miRNAs as diagnostic markers to differentiate epithelioid malignant mesothelioma (MM) from lung AdC.Methods: Bioinformatic analysis of publicly searchable data sets regarding miRNA expression profiling was performed to select the most significant differentially expressed miRNAs. These were analyzed by quantitative polymerase chain reaction on histologic (41 MM cases and 40 lung AdC cases) and cytological (26 MM cases and 27 lung AdC cases) specimens and the diagnostic performances were assessed.Results: miR-130a, miR-193a, miR-675, miR-141, miR-205, and miR-375 were found to be the best distinguishing markers. Of these, only miR-130a was significantly overexpressed in MM compared with lung AdC (P =.029 in histologic and P =.014 in cytological samples). miR-130a demonstrated a sensitivity of 77%, a specificity of 67%, a positive predictive value of 69%, a negative predictive value of 75%, and an accuracy of 72% in identifying MM.Conclusions: The diagnostic performances of miR-130a expression analysis and IHC appear to be similar. miR-130a quantification could be used reliably as second-level diagnostic tool to differentiate MM from lung AdC in pleural effusion cytology, mainly in those cases with ambiguous or negative IHC. Further validation is needed. Cancer Cytopathol 2017;125:635-43. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Cytopathology is a noninvasive and cost-effective method for detecting cancer cells in pleural effusions (PEs), although in many cases, the diagnostic performance is hindered by the paucity of significant cells or the lack of clear morphological criteria. This study presents the results of an omics approach to improving the diagnostic performance of PE cytology.Methods: Metabolic profiling with proton nuclear magnetic resonance (1 H-NMR) was performed for 92 PEs (44 malignant cases of 8 different cancers and 48 benign cases of 7 nonneoplastic conditions). Light's criteria were used to further classify PEs as transudates or exudates, and 1 H-NMR spectroscopy was used to differentiate malignant pleural effusions (mPEs) from benign pleural effusions (bPEs).Results: 1 H-NMR metabolic analysis showed clearly different spectra for mPEs and bPEs in the regions of the signals due to lipids, branched amino acids, and lactate, which were increased in mPEs. Transudates and exudates in bPEs were differentiated as well on the basis of the 1 H-NMR signals from lipids and lipoproteins, which were increased in exudates.Conclusions: Subject to validation in further larger studies, 1 H-NMR metabonomics could be an effective and reliable ancillary tool for PE investigations and diagnoses. Cancer Cytopathol 2017;125:341-348. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Keywords: melanoma; skin cancer; AYA; adolescent and young adult oncology; adolescent and young adult melanoma; survival; incidence; melanoma surgical treatment EN melanoma skin cancer AYA adolescent and young adult oncology adolescent and young adult melanoma survival incidence melanoma surgical treatment 1 2 2 10/29/21 20211027 NES 211027 In the published article, there was an error in B affiliation 1 b . Melanoma, skin cancer, AYA, survival, incidence, melanoma surgical treatment, adolescent and young adult oncology, adolescent and young adult melanoma. [Extracted from the article]

The Spalt-Like Transcription Factor 4 (SALL4) oncogene plays a central function in embryo-fetal development and is absent in differentiated tissues. Evidence suggests that it can be reactivated in several cancers worsening the prognosis. We aimed at investigating the risk associated with SALL4 reactivation for all-cause mortality and recurrence in cancer using the current literature. A PubMed and SCOPUS search until 1st September 2016 was performed, focusing on perspective studies reporting prognostic parameters in cancer data. In addition, 17 datasets of different cancer types from The Cancer Genome Atlas were considered. A total of 9,947 participants across 40 cohorts, followed-up for about 5 years on average, were analyzed comparing patients showing SALL4 presence (SALL4+, n = 1,811) or absence (SALL4-, n = 8,136). All data were summarised using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) for the time-dependent risk related to SALL4+, adjusted for potential confounders. SALL4+ significantly increased overall mortality (RR = 1.34, 95% confidence intervals (CI)=1.21-1.48, p<0.0001, I2=66%; HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%) and recurrence of disease (RR = 1.25, 95% CI = 1.1-1.42, p=0.0006, I2=62%); HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%) compared to SALL4-. Moreover, SALL4 remained significantly associated with poor prognosis even using HRs adjusted for potential confounders (overall mortality: HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%; recurrence of disease: HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%). These results suggest that SALL4 expression increases both mortality and recurrence of cancer, confirming this gene as an important prognostic marker and a potential target for personalized medicine.

Simple summary: The mechanism of epithelial–mesenchymal transition is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, resulting in cellular junction degradation and increased cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. This study aimed to investigate a potential interplay between epithelial–mesenchymal transition and angiogenesis in laryngeal carcinoma. In our study, univariate Cox regression identified pN+ status and Slug expression as predictive of disease-free survival, while a trend toward significance emerged for CD105-assessed microvessel density and N-cadherin expression. In the multivariate Cox regression model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting disease-free survival. Data from our study support the hypothesis of a mutual concurrence of epithelial–mesenchymal transition and angiogenesis in the development of an aggressive phenotype in laryngeal squamous cell carcinoma. The mechanism of epithelial–mesenchymal transition (EMT) is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, comprising important events, such as cellular junction degradation, downregulation of epithelial phenotype markers, overexpression of mesenchymal markers, and increase in cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. The aim of this exploratory study was to investigate a potential interplay between EMT and angiogenesis (quantified through CD105 expression) in laryngeal carcinoma (LSCC). CD105-assessed microvessel density (MVD) and EMT markers (E-cadherin, N-cadherin, Snail, Slug, Zeb1, and Zeb2) were assessed on 37 consecutive LSCC cases. The univariate Cox regression model identified pN+ status (p = 0.0343) and Slug expression (p = 0.0268) as predictive of disease-free survival (DFS). A trend toward significance emerged for CD105-assessed MVD (p = 0.0869) and N-cadherin expression (p = 0.0911). In the multivariate Cox model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting DFS (p = 0.0346, p = 0.0430, and p = 0.0214, respectively). Our data support the hypothesis of a mutual concurrence of EMT and angiogenesis in driving LSCC cells toward an aggressive phenotype. To better characterize the predictive performance of prognostic models based on EMT and angiogenesis, further large-scale prospective studies are required. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that play a pivotal role in many aspects of cell biology, including cancer development. Within esophageal cancer, miRNAs have been proved to be involved in all phases of carcinogenesis, from initiation to metastatic spread. Several miRNAs have been found to be dysregulated in esophageal premalignant lesions, namely Barrett's esophagus, Barrett's dysplasia, and squamous dysplasia. Furthermore, numerous studies have investigated the alteration in the expression levels of many oncomiRNAs and tumor suppressor miRNAs in esophageal squamous cell carcinoma and esophageal adenocarcinoma, thus proving how miRNAs are able modulate crucial regulatory pathways of cancer development. Considering these findings, miRNAs may have a role not only as a diagnostic and prognostic tool, but also as predictive biomarker of response to anti-cancer therapies and as potential therapeutic targets. This review aims to summarize several studies on the matter, focusing on the possible diagnostic–therapeutic implications. [ABSTRACT FROM AUTHOR]

The advent of precision therapies against specific gene alterations characterizing different neoplasms is revolutionizing the oncology field, opening novel treatment scenarios. However, the onset of resistance mechanisms put in place by the tumor is increasingly emerging, making the use of these drugs ineffective over time. Therefore, the search for indicators that can monitor the development of resistance mechanisms and above all ways to overcome it, is increasingly important. In this scenario, microRNAs are ideal candidate biomarkers, being crucial post-transcriptional regulators of gene expression with a well-known role in mediating mechanisms of drug resistance. Moreover, as microRNAs are stable molecules, easily detectable in tissues and biofluids, they are the ideal candidate biomarker to identify patients with primary resistance to a specific targeted therapy and those who have developed acquired resistance. The aim of this review is to summarize the major studies that have investigated the role of microRNAs as mediators of resistance to targeted therapies currently in use in gastro-intestinal neoplasms, namely anti-EGFR, anti-HER2 and anti-VEGF antibodies, small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors. For every microRNA and microRNA signature analyzed, the putative mechanisms underlying drug resistance were outlined and the potential to be translated in clinical practice was evaluated. [ABSTRACT FROM AUTHOR]

The population screening campaigns have resulted in increasing the prevalence of endoscopically resected colorectal cancers (CRCs) invading the submucosa (pT1). Synchronous nodal involvement occurs in less than 15 % of these tumors. Histologic criteria currently used for selecting patients needing resection are imprecise and most patients could have been simply followed-up. Tumor infiltrating lymphocytes (TILs) and mismatch repair (MMR) status impact on CRC prognosis. To identify patients requiring completion surgery, the value of histologic variables, TILs and MMR status as risk factors of nodal metastasis was investigated in screening detected and endoscopically removed pT1 CRCs. In 102 endoscopically resected pT1 CRCs, the cancer phenotype, CD3+ and CD8+ TILs, and MMR status were assessed. Univariate and multivariate analyses were used to evaluate the correlation with nodal metastasis. Positive resection margin, evidence of vascular invasion and tumor budding, wide area of submucosal invasion, and high number of CD3+ TILs were associated with nodal metastasis in univariate analyses. Vascular invasion was statistically independent in multivariate analysis. Evidence of neoplastic cells in the vessels and/or at the excision border featured 5 out of 5 metastatic tumors and 13 out of 97 non-metastatic ones. Completion surgery should be recommended only in pT1 CRC with vascular invasion or with tumor cells reaching the margin. In all other cases, the treatment choice should result from a multidisciplinary discussion on the patient-centered evaluation of the risk-benefit ratio. [ABSTRACT FROM AUTHOR]

Although the diagnosis and treatment of sporadic vestibular schwannoma has improved in recent years, no factors capable of predicting its growth have been identified as yet. Endoglin (CD105) is a proliferation-associated protein expressed in angiogenic endothelial cells, and a potential prognostic indicator for several solid tumors. The aim of the present study was primarily to investigate the expression and role of CD105 in a series of sporadic vestibular nerve schwannomas. In 71 consecutive cases of vestibular schwannoma, vessel cross-sectional area and density were calculated from immunohistochemically assessed CD105 expression using image analysis to correlate them with: (i) tumor dimensions; and (ii) tumor growth rate measured on high-resolution contrast-enhanced MRI (ceMRI). Based on assessments of CD105 expression, a significant positive correlation was identified between vessel cross-sectional area and tumor size at the time of surgery (p = 0.0024), and between vessel density and tumor size (p = 0.013). Vessel cross-sectional area (p = 0.0006) and vessel density (p = 0.003) were significantly greater in tumors measuring ≥10 mm in size than in those <10 mm. Conversely, when tumor growth rate could be calculated from two or more ceMRI (38 cases), there was no significant correlation between tumor growth rate and cross-sectional vessel area or vessel density as assessed with CD105. Further investigations are needed to ascertain the feasibility of: (i) using circulating endoglin assay to monitor tumor growth; and (ii) targeting neoangiogenesis with anti-endoglin antibodies in sporadic vestibular schwannoma. [ABSTRACT FROM AUTHOR]

The metastatic spread of breast carcinoma to the stomach is a rare event and often represents a diagnostic challenge. In the present study, 23 cases of gastric metastases from breast cancer were retrospectively identified dating back until 2007. Primitive histotype, localization, gross appearance, microscopic architecture were analyzed. Cytokeratins 7 and 20, sex hormones, HER2 and Ki67 expression was evaluated. According to the results, the series was characterized by an enrichment of lobular primitive histotype (43.7%). In most cases gastric metastases were described as parietal nodules, polypoid masses or ulcerated lesions, mainly involving the antro-angular region. In a relatively high rate (10.5%) of cases, endoscopic examinations resulted negative for macroscopic lesions. More than half of the cases (52.2%) microscopically resembled primitive poorly cohesive gastric cancer. Because gross and histological findings can be deceiving, immunohistochemistry may be essential for the diagnosis of gastric metastases from breast cancer. Accordingly with the results of our analysis and literature review, an immunohistochemical panel composed of cytokeratins 7 and 20, Estrogen and Progesteron Receptors would drastically improve diagnostic accuracy. Interaction among the clinician, endoscopist and the pathologist is also essential to provide the patient the best therapeutic option. [ABSTRACT FROM AUTHOR]

Background: The cut-off of < 1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1-9%) BC, comparing them to ER-negative (ER < 1%) and ER-intermediate (ER 10-50%) tumors., Patients and Methods: Among 921 patients with early-stage I-III, ER ≤ 50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at < 0.05 significance level., Results: ER-low and ER-negative tumors exhibited similar median TILs, significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in Basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank p = .033, hazard ratio (HR) 0.37 [95% CI 0.15-0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank p < .001, HR 0.41 [95% CI 0.27-0.60])., Conclusions: ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Lung cancer is still the main cause of cancer death. In the last decades, significant innovations were introduced in non-small cell lung cancer (NSCLC) treatment and management improving patient outcomes. The discovery of immune checkpoint inhibitors and the detection of an increasing list of actionable genetic alterations are enabling a tailored approach. Herein, we assessed in a pragmatic retrospective study the rate of biomarker tests within a large pulmonary pathology-based unit (PPU) network of the Veneto region (Northern Italy)., Methods: Each PPU of 7 hubs and spoke centers implemented a biomarker database with pathologic and clinical data of patients with NSCLC diagnosis over 24 months., Results: Out of 1,817 NSCLC cases, 51% were advanced and 49% early stage, with 72% being adenocarcinomas. Programmed death ligand 1 expression and epidermal growth factor receptor mutations were available in most samples, 91% and 78%, respectively. Only 36% of advanced stages received all 5 biomarker tests with an increased rate over time. Co-occurring molecular alterations were detected in 42 cases (2%): the prevalence was (n=17) 41% and (n=25) 59% in early and late-stage adenocarcinomas, respectively., Conclusions: In this real-world study, while most patients received at least one biomarker test, less than 50% had all 5 biomarkers. The screening appeared to increase over time especially with the progressive use of next generation sequencing. Our results confirm the importance of systematic biomarker testing including all NSCLCs based on the evidence of several genomic alterations also in early-stage disease whose analysis may become relevant as neo-adjuvant targeted therapies are available., Keywords: Non-small cell lung cancer (NSCLC); biomarkers; actionable targets; lung cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-107/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

The introduction of deep learning caused a significant breakthrough in digital pathology. Thanks to its capability of mining hidden data patterns in digitised histological slides to resolve diagnostic tasks and extract prognostic and predictive information. However, the high performance achieved in classification tasks depends on the availability of large datasets, whose collection and preprocessing are still time-consuming processes. Therefore, strategies to make these steps more efficient are worth investigation. This work introduces SlideTiler, an open-source software with a user-friendly graphical interface. SlideTiler can manage several image preprocessing phases through an intuitive workflow that does not require specific coding skills. The software was designed to provide direct access to virtual slides, allowing custom tiling of specific regions of interest drawn by the user, tile labelling, quality assessment, and direct export to dataset directories. To illustrate the functions and the scalability of SlideTiler, a deep learning-based classifier was implemented to classify 4 different tumour histotypes available in the TCGA repository. The results demonstrate the effectiveness of SlideTiler in facilitating data preprocessing and promoting accessibility to digitised pathology images for research purposes. Considering the increasing interest in deep learning applications of digital pathology, SlideTiler has a positive impact on this field. Moreover, SlideTiler has been conceived as a dynamic tool in constant evolution, and more updated and efficient versions will be released in the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The following are the supplementary data related to this article. Supplementary video 1Supplementary video 1 Supplementary data to this article can be found online at https://doi.org/10.1016/j.jpi.2023.100356., (© 2023 The Authors.)

Background: Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8 + T cells seem to be related to a better prognosis, but the mechanisms affecting the immune landscape in HCC are still mostly unknown. Necroptosis is a programmed, caspase-independent cell death that, unlike apoptosis, evokes immune response by releasing damage-associated molecular factors. However, in HCC, the relationship between the necroptotic machinery and the tumor-infiltrating lymphocytes has not been fully investigated so far., Methods: We investigated the association between the main necroptosis-related genes, that is, RIPK1 , RIPK3, MLKL-p , and CD3 + /CD8 + tumor-infiltrating T cell by RNA-seq data analysis in 371 patients with primary HCC from The Cancer Genome Atlas and then by immunohistochemistry in two independent cohorts of HCC patients from Italy (82) and Japan (86)., Results: Our findings highlighted the immunogenetic role of necroptosis and its potential prognostic role in HCC: RIPK1, RIPK3 and MLKL-p were found significantly associated with intratumoral CD3 + and CD8 + T cells. In addition, multivariate survival analysis showed that the expression of RIPK1, RIPK3 and MLKL-p was associated with better overall survival in the two independent cohorts., Conclusions: Our results confirmed the immunogenetic properties of necroptosis (NCP) in human HCC, showing that tumor-infiltrating lymphocytes (TILs) and, specifically, CD8+ T cells accumulate in tumors with higher expression of the necroptosis-related genes. These results suggest the importance of further studies to better assess the specific composition, as well as the functional features of the immune environment associated with a necroptotic signature in order to explore new possible diagnostic and immunotherapeutic scenarios., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Metabolomic profiling of human malignant effusion remain a field poorly investigated. Proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy is a rapid relatively low cost technique, and effusion is an optimal biospecimen suitable for metabonomic investigations. With this study we addressed metabolomic profiling of malignant ascitic effusion (mAE) from patients with high grade serous ovarian carcinoma (HGSOC), Hepatocellular carcinoma (HCC), and benign AEs (bAEs) from patients with reactive peritonitis., Methods: Metabolic profiling with 1 H-NMR was performed on 72 AEs (31 HGSOC, 16 HCC and 25 bAE) prospectively collected in our cytology service. Histological confirmation was requested for all malignant case. Multivariate analysis comprising PCA and PLS-DA was applied to discover metabolites suitable to differentiate effusions among the investigated groups., Results: 1 H-NMR metabonomic analysis showed clearly different spectra for malignant and benign AEs, as well as for HGSOC vs. HCC effusion. When compared with HCC effusions, the HGSOC effusion were enriched, among all, in alanine, lipids, N-acetyl groups and phenylalanine and depleted in glutamine., Conclusions: Subject to validation in further larger studies, 1 H-NMR metabonomics could be an effective and reliable ancillary tool for AE investigations and diagnosis particularly in acellular effusions., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2020 Zennaro et al., published by De Gruyter.)

Purpose: The term aspirin-exacerbated respiratory disease (AERD) refers to a combination of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and acute respiratory tract reactions to nonsteroidal anti-inflammatory drugs. AERD has now been included among the CRSwNP endotypes, and is considered one of the most aggressive in terms of disease recurrence. Cortactin is a multi-domain protein with a part in several cellular mechanisms involving actin assembly and cytoskeleton arrangement. Cortactin seems to have a role in inflammatory responses and to be implicated in human airway secretion and contraction mechanisms. The novel aim of the present study was to examine cortactin expression in nasal polyps of a consecutive cohort of AERD patients and in nasal mucosa of a control group of patients., Materials and Methods: Cortactin expression was assessed immunohistochemically in nasal polyps from 18 consecutive AERD patients who underwent endoscopic sinus surgery and in nasal mucosa of 19 patients without chronic rhinosinusitis., Results: Concomitant allergy was found in 11 AERD patients, most of them male (8 cases; p = 0.02). Cortactin expression in nasal polyps was definitely high (+3) in 17 out of 18 cases, in both epithelial cells (cytoplasmic and membranous immunoreactivity) and activated fibroblasts. A higher cortactin expression was seen in female than in male AERD patients (p = 0.05)., Conclusions: Given this preliminary evidence of cortactin upregulation in the polyps of AERD patients, prospective studies could further investigate the role of cortactin in the biology of AERD, and the potential role of cortactin-targeted approaches in integrated AERD treatments., (Copyright © 2017. Published by Elsevier Inc.)

Background: Differential diagnosis between malignant pleural mesothelioma (MPM) and benign mesothelial conditions is still challenging and there is a lack of useful markers. Programmed cell death 4 (PDCD4) is a well-known tumor suppressor gene in several cancers, its post-transcriptional activity is directly controlled by miR-21, whose over-expression has been recently reported in MPM compared to normal mesothelium. Aim of this study was to test this suppressor gene as a possible new marker of malignant transformation in mesothelial cells, as well as a new prognostic marker., Methods: PDCD4 nuclear expression was assessed by immunohistochemistry (IHC) in 40 non-neoplastic pleural (NNP) and 40 MPM formalin-fixed and paraffin-embedded specimens. PDCD4 and miR-21 expressions were analyzed by qRT-PCR in all cases. In situ hybridization (ISH) of miR-21 was performed in 5 representative cases of both groups. The prognostic relevance of PDCD4 was assessed in a public available gene expression dataset., Results: IHC showed that PDCD4 nuclear expression was significantly lower in MPM than in NNP. PDCD4 was down-regulated, whereas miR-21 was over-expressed in MPM cases compared to NNP ones. ISH detected miR-21 only in MPM specimens. Down-expression of PDCD4 was found significantly associated with short overall survival in publicly available data., Conclusions: These findings highlighted a switch between PDCD4 and miR-21 expression in MPM. Further studies should assess the diagnostic reliability of these two markers for MPM in biopsy and effusion specimens., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.