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Background: Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients., Methods: A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male)., Results: Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01)., Conclusions: Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Competing interests: None.

After neoadjuvant chemoradiotherapy for esophageal adenocarcinoma, up to 29% of patients have a pathological complete response (pCR). What to do afterward is still under debate. The aim of this prospective study was to define which local markers of immune response might act as predictors of pCR and of recurrence after pCR. The peritumoral healthy mucosa of the surgical specimen was sampled at esophagectomy and analyzed by immunohistochemistry, flow cytometry and Real-Time PCR. One hundred and twenty-three patients received neoadjuvant therapy for esophageal adenocarcinoma and were included in the study. Significantly higher rate of natural killer (NK) cells (CD57+), intraepithelial CD8 + T lymphocytes and degranulating T- and NK-cells (CD107+) were observed in the healthy mucosa of patients with pCR. Moreover, pCR was characterized by a lower immune-check points gene expression level. T-cell activation markers mRNA levels were significantly lower in patients with pCR and recurrent disease, showing an excellent accuracy in the prediction of the postoperative recurrence. Costimulatory molecules mRNA relative levels tended to be lower in patients with pCR and recurrent disease, showing a good accuracy in the prediction of postoperative recurrence in patients with pCR. The immune profile identified in this study might further be tested in large prospective trials as marker of pCR after neoadjuvant therapy and as predictor of recurrence after pCR., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking., Patients and Methods: Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of "super" responders and "clearly" refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS)., Results: In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463)., Conclusion: A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy., Implications for Practice: Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability-high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer., (© AlphaMed Press 2020.)

Huriez syndrome is a rare cancer-prone genodermatosis confined to the hands and feet connects with an increase in squamous cell carcinoma on affected skin. Its diagnosis is complex due to not well defined symptoms and since only few cases are described in literature. The differential diagnoses are many and the treatment is focused only on symptoms control and tumours eradication. Our case report is highly interesting because add new knowledge about this disease describing a new important feature of the syndrome. For the first time in literature we describe the arising of basal cell carcinoma from affected skin. KEY WORDS: H, Basal cell carcinoma, Huriez syndrome, Palmoplantar keratoderma.

Background: V600E BRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600E BRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes., Methods: Data and tissue specimens from 155 V600E BRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS)., Results: CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS., Conclusion: The present study provides new evidence on how several well-established biomarkers perform in a homogenous V600E BRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients' stratification in clinical trials and in routine clinical practice to better estimate patients' prognosis.

Background: No data is available on the molecular background of the extra-nodal extension (ENE) of lymph node metastasis (LN) in colorectal cancer (CRC)., Methods: A series of 22 ENE-positive CRCs was considered and three samples per case were selected (the primary CRC, an ENE-negative and an ENE-positive metastatic LN). Samples (n = 66) were analysed by immunohistochemistry for PD-L1, CD4, CD8, CD68 and CD80. Fifteen out of twenty-two cases were further profiled through a hotspot multigene mutational custom panel, including 164 hotspot regions of AKT1 , APC , BRAF , CTNNB1 , KIT , KRAS , NRAS , PDGFRA , PIK3CA , PTEN and TP53 genes., Results: A significantly higher percentage of CD4-, CD8- and CD68-positive cells was observed at the invasive front of both CRCs and in ENE in contrast with what observed at the core of both CRCs and their matched nodal metastases. ENE was also characterized by a significantly higher number of CD80-positive cells. No significant difference was observed in PD-L1 distribution among the different specimens. Fourteen out of 15 CRCs (93%) showed at least a driver mutation. The most frequently mutated gene was TP53 (n = 8 tumors), followed by APC (n = 6), BRAF (n = 4), KRAS , NRAS and PIK3CA (n = 2). In 11 out of 15 CRCs (73%) the mutational profiling of the primary tumor was consistent with what obtained from the two matched LNs., Conclusions: A heterogeneous intratumor immune-microenvironment has been observed in ENE-positive CRCs, which are characterized by an increased leukocytic infiltration at the ENE invasive front.

Here, we report a case of a 38-year-old woman with a history of systemic sarcoidosis who developed cutaneous verrucous sarcoidosis simulating a squamous cell carcinoma. This modality of presentation is unusual in both caucasic patients and in woman and may represent a diagnostic challenge for dermatologists.

We investigated by immunocytochemistry (ICC) the distribution in the rat heart of adrenomedullin (AM), a potent and long-lasting hypotensive peptide which is expressed in the cardiovascular system, where it is known to play a major regulatory role. Hearts were collected from adult male Sprague-Dawley rats, and were perfused for 20 min, according to the Langendorff technique, with endothelin-1 (ET-1) or the mast cell-degranulator compound 48/80. Hearts were frozen, and ICC was performed using standard techniques and a specific anti-rat AM1-50 antibody. We confirmed the presence of a low AM-immunoreactivity in cardiomyocytes and cardiac fibroblasts, as well as in endothelial and smooth muscle cells of coronary vessels. Moreover, we provided evidence of the presence in both atria and ventricles of sparse voluminous AM-positive cells, mainly located near coronary vessels. These cells had the same juxtavascular location of toluidine blue-positive mast cells and their number decreased upon acute exposure to the 48/80 compound. However, ICC showed that in these cells AM was always colocalized with atrial and brain natriuretic peptides. Moreover, AM-storing cells were also positive to MyHC-Apla2, indicating that they share some phenotypic features with immature smooth muscle cells. The number of AM-storing cells underwent a dramatic decrease in response to the potent vasoconstrictor ET-1, suggesting an acute release of stored vasodilatory AM aimed at counteracting coronary constriction. Taken together, our present findings support the hypothesis that these cells may represent a novel subset of endocrine cells, strategically located near blood vessels in the mammalian heart, where they can release vasoactive peptides.