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The synthesis of Co-based two-dimensional (2D) metal azolate framework nanosheets (MAF-5-CoII NS) is described using a simple hydrothermal method. The product was isostructural to MAF-5 (Zn). The as-prepared MAF-5-CoII NS exhibited high surface area (1155 m2/g), purity, and crystallinity. The MAF-5-CoII NS–modified screen-printed electrode (MAF-5-CoII NS/SPE) was used for nonenzymatic detection of glucose in diluted human blood plasma (BP) samples with phosphate buffer saline (PBS, pH 7.4) and NaOH (0.1 M, pH 13.0) solutions. The MAF-5-CoII NS nanozyme displayed good redox activity in both neutral and alkaline media with the formation of CoII/CoIII redox pair, which induced the catalytic oxidation of glucose. Under the optimized detection potential, the sensor presented a chronoamperometric current response for the oxidation of glucose with two wide concentration ranges in PBS-diluted (62.80 to 180 μM and 305 to 8055 μM) and NaOH-diluted (58.90 to 117.6 μM and 180 to 10,055 μM) BP samples, which were within the limit of blood glucose levels of diabetic patients before (4.4–7.2 mM) and after (10 mM) meals (recommended by the American Diabetes Association). The sensor has a limit of detection of ca. 0.25 and 0.05 μM, respectively, and maximum sensitivity of ca. 36.55 and 1361.65 mA/cm2/mM, respectively, in PBS- and NaOH-diluted BP samples. The sensor also displayed excellent stability in the neutral and alkaline media due to the existence of hydrophobic linkers (2-ethyl imidazole) in the MAF-5-CoII NS, good repeatability and reproducibility, and interference-free signals. Thus, MAF-5-CoII NS is a promising nanozyme for the development of the disposable type of sensor for glucose detection in human body fluids. [ABSTRACT FROM AUTHOR]

After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c-Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed. [ABSTRACT FROM AUTHOR]

Ovarian cancers encompass a group of neoplasms originating from germinal tissues and exhibiting distinct clinical, pathological, and molecular features. Among these, epithelial ovarian cancers (EOCs) are the most prevalent, comprising five distinct tumor histotypes. Notably, high-grade serous ovarian cancers (HGSOCs) represent the majority, accounting for over 70% of EOC cases. Due to their silent and asymptomatic behavior, HGSOCs are generally diagnosed in advanced stages with an evolved and complex genomic state, characterized by high intratumor heterogeneity (ITH) due to chromosomal instability that distinguishes HGSOCs. Histologically, these cancers exhibit significant morphological diversity both within and between tumors. The histologic patterns associated with solid, endometrioid, and transitional (SET) and classic subtypes of HGSOCs offer prognostic insights and may indicate specific molecular profiles. The evolution of HGSOC from primary to metastasis is typically characterized by clonal ITH, involving shared or divergent mutations in neoplastic sub-clones within primary and metastatic sites. Disease progression and therapy resistance are also influenced by non-clonal ITH, related to interactions with the tumor microenvironment and further genomic changes. Notably, significant alterations occur in nonmalignant cells, including cancer-associated fibroblast and immune cells, during tumor progression. This review provides an overview of the complex nature of HGSOC, encompassing its various aspects of intratumor heterogeneity, histological patterns, and its dynamic evolution during progression and therapy resistance. [ABSTRACT FROM AUTHOR]

Objective: To screen and characterize germline variants for E-cadherin (CDH1) in non-hereditary gastric cancer (GC) patients and in subjects at risk of GC. Methods: 59 GCs, 59 first degree relatives (FDRs) of GC, 20 autoimmune metaplastic atrophic gastritis (AMAGs) and 52 blood donors (BDs) were analyzed for CDH1 by direct sequencing, structural modelling and bioinformatics. Functional impact on splicing was assessed for intronic mutations. E-cadherin/β-catenin immunohistochemical staining and E-cadherin mRNA quantification using RT-PCR were performed. Results: In GCs, 4 missense variants (p.G274S; p.A298T; p.T470I; p.A592T), 1 mutation in the 5′UTR (−71C>G) and 1 mutation in the intronic IVS12 (c.1937-13T>C) region were found. First pathogenic effect of p.A298T mutation was predicted by protein 3D modelling. The novel p.G274S mutation showed a no clear functional significance. Moreover, first, intronic IVS12 (c.1937-13T>C) mutation was demonstrated to lead to an aberrant CDH1 transcript with exon 11 deletion. This mutation was found in 2 GCs and in 1 BD. In FDRs, we identified 4 variants: the polymorphic (p.A592T) and 3 mutations in untranslated regions with unidentified functional role except for the 5′UTR (−54G>C) that had been found to decrease CDH1 transcription. In AMAGs, we detected 2 alterations: 1 missense (p.A592T) and 1 novel variant (IVS1 (c.48+7C>T)) without effect on CDH1 splicing. Several silent and polymorphic substitutions were found in all the groups studied. Conclusions: Overall our study improves upon the current characterization of CDH1 mutations and their functional role in GC and in individuals at risk of GC. Mutations found in untranslated regions and data on splicing effects deserve a particular attention like associated with a reduced E-cadherin amount. The utility of CDH1 screening, in addition to the identification of other risk factors, could be useful for the early detection of GC in subjects at risk (i.e. FDRs and AMAGs), and warrants further study. [ABSTRACT FROM AUTHOR]

Diagnostic and prognostic implications of endocrine differentiation were evaluated in 103 common gastric adenocarcinomas and undifferentiated carcinomas. Maturely differentiated exocrine and endocrine phenotypes were evaluated by using gastric exocrine and endocrine markers along with intestinal exocrine and endocrine markers. Immunohistochemical analysis revealed that 66 tumors (64%) were positive for generic endocrine markers such as chromogranin A and/or synaptophysin. The 14 patients with more than 20% tumor cells positive for at least 1 endocrine marker experienced a poorer prognosis than patients with no (n = 37) or 1% to 20% (n = 52) positivity. The 16 carcinomas expressing the maturely differentiated exocrine gastric phenotype significantly correlated with poorer outcome compared with carcinomas with mature exocrine intestinal (n = 22) or mixed/gastrointestinal (n = 64) phenotypes. Among tumors expressing chromogranin A and/or synaptophysin, the maturely differentiated endocrine gastric phenotype (n = 26) was a negative prognostic factor compared with mature endocrine intestinal (n = 21) and mixed/gastrointestinal (n = 5) phenotypes. Endocrine differentiation and maturely exocrine/ endocrine gastric phenotypes are associated with an unfavorable prognosis and may identify subsets of patients for tailored therapy. [ABSTRACT FROM AUTHOR]

Head-Neck Squamous Cell Carcinoma (HN-SCC) is a clinically challenging disease associated with a high mortality rate. The chemo-radiotherapy treatments that aim to preserve the organ represent the current gold standard therapy for advanced laryngeal disease, reserving surgery only for non-responsive or relapsed cases. Despite these aggressive approaches, local persistent or recurrent disease remains the primary cause of treatment failure but we still do not have known factors and/or markers able to predict the outcome of the disease and in particular the risk of local relapse. Here we address this point on a series of 54 cases of HN-SCC for whom the presence of local relapse was known. Using immunohistochemistry (IHC) analysis to evaluate protein expression and localization in the recurrence free and recurrence positive samples, we studied the expression of key cell cycle regulators including p53, p16, p27, pRB, Cyclin D1, Cyclin D3, and Stathmin. Overall by analyzing seven different cell cycle regulators we can hypothesize that the alteration of G1/S regulation represents a fundamental event in the onset/progression of HN-SCC cancers and that the associate use of Cyclin D1/p16 expression should be considered as a possible biomarker toward the identification of those patients that will probably develop a recurrent disease and thus should benefit of a more aggressive treatment. J. Cell. Physiol. 227: 233-238, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Describes a medical case of a patient with primary Hodgkin's disease (PHD) of the vagina presenting with stage IEB. Medical history; Clinicopathological and phenotypic features of PHD; Administration of chemotherapy followed by radiation therapy.

Background: The contribution of the tumor microenvironment and extracellular matrix to the aggressive biology of Gastric Cancer (GC) has been recently characterized; however, the role of EMILIN-1 in this context is unknown. EMILIN-1 is an essential structural element for the maintenance of lymphatic vessel (LV) integrity and displays anti-proliferative properties as demonstrated in skin and colon cancer. Given the key role of LVs in GC progression, the aim of this study was to investigate the role of EMILIN-1 in GC mouse models. Methods: We used the syngeneic YTN16 cells which were injected subcutaneously and intraperitoneally in genetically modified EMILIN-1 mice. In alternative, carcinogenesis was induced using N-Methyl-N-nitrosourea (MNU). Mouse-derived samples and human biopsies were analyzed by IHC and IF to the possible correlation between EMILIN-1 expression and LV pattern. Results: Transgenic mice developed tumors earlier compared to WT animals. 20 days post-injection tumors developed in EMILIN-1 mutant mice were larger and displayed a significant increase of lymphangiogenesis. Treatment of transgenic mice with MNU associated with an increased number of tumors, exacerbated aggressive lesions and higher levels of LV abnormalities. A significant correlation between the levels of EMILIN-1 and podoplanin was detected also in human samples, confirming the results obtained with the pre-clinical models. Conclusions: This study demonstrates for the first time that loss of EMILIN-1 in GC leads to lymphatic dysfunction and proliferative advantages that sustain tumorigenesis, and assess the use of our animal model as a valuable tool to verify the fate of GC upon loss of EMILIN-1. [ABSTRACT FROM AUTHOR]

A case of single breast metastasis from colon adenocarcinoma, with omolateral axillary micrometastasis, is reported with a brief review of the pertinent literature. The originality of the oncological concept of metastasis from metastasis, through lymphatics penetration, is discussed in the setting of a rare condition of breast metastasis from a colorectal carcinoma. The demonstration of axillary lymph node micrometastasis has been possible because fine needle aspiration cytology of the breast nodule was suspicious, but not conclusive for metastasis from colon cancer, so lumpectomy with sentinel node biopsy was planned. Although no disseminated nodal metastases were evident on computerized tomography scan and ultrasonography before breast surgery, the patient developed brain metastases and deteriorated rapidly; she died 16 months after presenting with the breast mass. In conclusion, solid cancers are able to further metastasize, via well-known pathways also recognized in primary cancers such as neoplastic cell invasion of peritumoral lymphatics. [ABSTRACT FROM AUTHOR]

In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)–aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA–complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity. [ABSTRACT FROM AUTHOR]

Schematic representation of multiple ROS-generation-based tumor-therapy approach of AgNP. [Display omitted] • A simple mixing procedure has been utilized to synthesize bimetallic silver nitroprusside (AgNP) as CDT agent together with peroxynitrite generator. • AgNP decomposes more endogenous H 2 O 2 to produce highly toxic radicals. • AgNP are involved in the inhibition of AKT pathway, which is involved in cell survival, angiogenesis, proliferation, and apoptosis. • AgNP showed biocompatible nature towards normal mouse liver and ovarian organoids while are toxic on PDTO through altering the redox homeostasis. Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H 2 O 2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome. To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli. A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism. AgNP have an effective ability to decompose endogenous H 2 O 2 in cells. The decomposed endogenous H 2 O 2 generates several different types of reactive species (•OH, O 2 •−) including peroxynitrite (ONOO−) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO). This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis. [ABSTRACT FROM AUTHOR]

Simple Summary: This clinical investigation reports the results of a prospective, multicenter phase II trial designed to evaluate the activity and safety of combining non-pegylated liposomal doxorubicin (NPLD) with ifosfamide as a first-line treatment for advanced/metastatic STS. The study results demonstrate a remarkable overall response rate (ORR) alongside a satisfactory disease control rate (DCR) while maintaining acceptable levels of toxicity. The addition of NPLD to ifosfamide, showing high activity and a low toxicity profile, makes this drug combination a useful option for patients with advanced/metastatic STS. These findings provide a promising basis for further comprehensive research into the clinical application of this drug combination in this disease setting. Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand–foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m2) on day 1 along with ifosfamide (3000 mg/m2 on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29–0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73—0.90), while only 16% (95% CI: 0.08–0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity. [ABSTRACT FROM AUTHOR]

Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs “E-cadherin” to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment. [ABSTRACT FROM AUTHOR]

Linitis plastica (LP) is a very aggressive and rare carcinoma with a scirrhous stroma that affects the submucosal and muscular layers of the stomach even without mucosal alterations. Lack of timely diagnosis is a crucial problem related to its prognosis and treatment. In this study, we investigated the LP-associated vascular pattern as a possible means to improve the diagnosis of these patients. During standard endoscopy, mucosal architecture, tortuosity and enlargement of vessels, as well as the presence of vascular leakage and efficiency of the blood flow were assessed in six LP patients using probe-based Confocal Laser Endomicroscopy (pCLE). In all LP patients, we detected abnormal changes in vasculature. The aberrant features of the vascular network were common to all LP patients examined and consisted of vessel enlargement, tortuosity, and leakage associated with the affected submucosal layer. This is the first study to highlight the presence of marked vascularization associated with LP, characterized by the presence of abnormal and non-functional vessels, similar to what is observed in neoplastic tissues. Therefore, the analysis of LP by pCLE may provide a new endoscopic approach and strategy to better define these patients. [ABSTRACT FROM AUTHOR]

In this study, we aimed to assess the accuracy of the proposed novel, noninvasive serum DSC test in predicting the risk of gastric cancer before the use of upper endoscopy. To validate the DSC test, we enrolled two series of individuals living in Veneto and Friuli-Venezia Giulia, Italy (n = 53 and n = 113, respectively), who were referred for an endoscopy. The classification used for the DSC test to predict gastric cancer risk combines the coefficient of the patient's age and sex and serum pepsinogen I and II, gastrin 17, and anti-Helicobacter pylori immunoglobulin G concentrations in two equations: Y1 and Y2. The coefficient of variables and the Y1 and Y2 cutoff points (>0.385 and >0.294, respectively) were extrapolated using regression analysis and an ROC curve analysis of two retrospective datasets (300 cases for the Y1 equation and 200 cases for the Y2 equation). The first dataset included individuals with autoimmune atrophic gastritis and first-degree relatives with gastric cancer; the second dataset included blood donors. Demographic data were collected; serum pepsinogen, gastrin G17, and anti-Helicobacter pylori IgG concentrations were assayed using an automatic Maglumi system. Gastroscopies were performed by gastroenterologists using an Olympus video endoscope with detailed photographic documentation during examinations. Biopsies were taken at five standardized mucosa sites and were assessed by a pathologist for diagnosis. The accuracy of the DSC test in predicting neoplastic gastric lesions was estimated to be 74.657% (65%CI; 67.333% to 81.079%). The DSC test was found to be a useful, noninvasive, and simple approach to predicting gastric cancer risk in a population with a medium risk of developing gastric cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Extramammary Paget's disease of the vulva (EMPDV) is a rare disease. However, an association between EMPDV and other premalignant/malignant vulvar lesions is not uncommon. Due to its potential clinical implication, such an association should be carefully evaluated in all women diagnosed with and treated for EMPDV. The aim of the present study was to evaluate the incidence of concomitant vulvar cancers or premalignant lesions in women surgically treated for extramammary Paget's disease of the vulva (EMPDV) through a multicenter case series. The medical records of all women diagnosed with and treated for EMPDV from January 2010 to December 2020 were retrospectively analyzed. Women with EMPDV and synchronous vulvar cancer, vulvar intraepithelial neoplasia (VIN) and/or lichen sclerosus (LS) at the histology report were included in the study. A total of 69 women eligible for the present study were considered. Concomitant vulvar lesions occurred in 22 cases (31.9%). A total of 11 cases of synchronous VIN (50%) and 14 cases (63.6%) of concomitant LS were observed. One patient (4.5%) had synchronous vulvar SCC (FIGO stage 1B). Women with EMPDV and concomitant premalignant/malignant vulvar lesions had a significantly higher rate of invasive EMPDV and wider lesions with an extravulvar involvement. The specific meaning of the association between EMPDV, VIN, SCC and LS remains unclear. The potential overlapping features between different vulvar lesions highlight the importance of dedicated gynecologists and pathologists in referral centers. [ABSTRACT FROM AUTHOR]

PIN1 is considered as a therapeutic target for a wide variety of tumours. However, most of known inhibitors are devoid of cellular activity despite their good enzyme inhibitory profile. Hence, the lack of effective compounds for the clinic makes the identification of novel PIN1 inhibitors a hot topic in the medicinal chemistry field. In this work, we reported a virtual screening study for the identification of new promising PIN1 inhibitors. A receptor-based procedure was applied to screen different chemical databases of commercial compounds. Based on the whole workflow, two compounds were selected and biologically evaluated. Both ligands, compounds VS1 and VS2, showed a good enzyme inhibitory activity and VS2 also demonstrated a promising antitumoral activity in ovarian cancer cells. These results confirmed the reliability of our in silico protocol and provided a structurally novel ligand as a valuable starting point for the development of new PIN1 inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] Monoacylglycerol lipase (MAGL) is a promising target for cancer therapy due to its involvement in lipid metabolism and its impact on cancer hallmarks like cell proliferation, migration, and tumor progression. A potent reversible MAGL inhibitor, MAGL23, has been recently developed by our group, demonstrating promising anticancer activities. To enhance its pharmacological properties, a nanoformulation using nanocrystals coated with albumin was prepared (MAGL23AF). In a previous work, the formulated inhibitor showed potency in ovarian and colon cancer cell lines in terms of IC 50 , and was tested on mice in order to assess its biocompatibility, organs biodistribution and toxicity. In the present work, we expanded the investigation to assess the potential in vivo application of MAGL23AF. Stability assays in serum and in human derived microsomes showed a good structural stability in physiological conditions of MAGL23AF. The antitumor efficacy tested on mice bearing ovarian cancer tumor xenografts demonstrated that MAGL23AF is more potent than the non-formulated drug, leading to necrosis-driven cancer cell death. In vivo studies revealed that albumin-complexed nanocrystals improved the therapeutic window of MAGL23, exhibiting a favorable biodistribution with slightly increased accumulation in the tumor. In conclusion, the MAGL23AF showed increased in vitro stability in conditions mirroring the bloodstream environment and hepatic metabolism coupled with an optimal antitumor efficacy in vivo. These results not only validates the efficacy of our formulation but also positions it as a promising strategy for addressing challenges related to the solubility of drugs in body fluids. [ABSTRACT FROM AUTHOR]

Background: Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published.Methods: A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®).Results: A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4-53.1) and OS was 105.4 months (95% CI: 82.7-not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found.Conclusions: MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor's characteristics.Clinical Trial Registration: This study is registered under NCT02408536 on ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

To find prognostic factors for advanced ovarian cancer patients undergoing first-line therapy with carboplatin, paclitaxel and bevacizumab, we investigated the expression of a disintegrin and metalloprotease 17 (ADAM17) in cancer tissues. ADAM17 has been involved in ovarian cancer development, progression and cell resistance to cisplatin. Tissue microarrays from 309 ovarian cancer patients enrolled in the MITO16A/MANGO-OV2 clinical trial were analyzed by immunohistochemistry for ADAM17 protein expression. Intensity and extent of staining were combined into a semi-quantitative visual grading system (H score) which was related to clinicopathological characteristics of cases and the clinical outcome of patients by univariate and multivariate Cox regression models. ADAM17 immunostaining was detected in most samples, mainly localized in the tumor cells, with variable intensity across the cohort. Kaplan–Meier survival curves, generated according to the best cut-off value for the ADAM17 H score, showed that high ADAM17 expression was associated with worse prognosis for PFS and OS. However, after the application of a shrinkage procedure to adjust for overfitting hazard ratio estimates, the ADAM17 value as prognostic factor was lost. As subgroup analysis suggested that ADAM17 expression could be prognostically relevant in cases with no residual disease at baseline, further studies in this patient category may be worth planning. [ABSTRACT FROM AUTHOR]

Vulvar lymphedema is an uncommon and disabling side-effect of pelvic lymphadenectomy and pelvic radiotherapeutic treatment for invasive genital cancer. Lymphorrhea, a complication of lymphedema, may be extremely distressing for patients due to the requirement to wear sanitary towels and as the pain and loss of elasticity of the vulvar skin and mucosa can cause discomfort during coitus. Surgical treatments of lymphorrhea and vulvar lymphedema secondary to gynecological cancer treatments remain controversial and are not currently considered to be the standard therapy. The present study reports two cases of vulvar lymphedema complicated by vulvar lymphorrhea in females who had undergone treatment for cervical and endometrial cancer, respectively; a review of the literature is also included. In the two present cases, vulvar lymphedemas were refractory to standard treatments, including decongestive therapy, manual lymph drainage, elastic bandaging, low-stretch bandaging, exercises and skin care. Laser CO2 excision and vaporization of the whole skin and mucosal tissue of the vulva was successfully performed to treat the lymphorrhea and improve quality of life. Thus, the present two cases indicated that laser CO2 surgery may present an additional therapy for the treatment of genital lymphedema that is refractory to other treatments. [ABSTRACT FROM AUTHOR]

Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency. [ABSTRACT FROM AUTHOR]

The mechanochemical syntheses of allyl and indenyl palladate complexes are reported. All compounds were obtained in quantitative yields and microanalytically pure without the need of any workup. These complexes are stable in chlorinated and polar (DMSO or DMSO/H2O solutions) solvents. In chlorinated solvents, they appear as ionic pairs of which crystals suitable for single X‐ray diffraction studies have been obtained. Bonding and solvation properties are rationalized through scalar relativistic DFT calculations. Moreover, most complexes showed excellent cytotoxicity towards ovarian cancer cell lines, with IC50 values comparable or lower than cisplatin. The potent anticancer activity of two IPrCl and IPr*‐based palladate complexes was examined in a high‐grade serous ovarian cancer (HGSOC) patient‐derived tumoroid. Moreover, the inhibition of the antioxidant enzyme thioredoxin reductase (TrxR) was noticed, and structure‐activity relationships could be derived, suggesting the ROS detoxifying system is involved in the mode of action. [ABSTRACT FROM AUTHOR]

This paper reports on an ultrasensitive and label-free electrochemical immunosensor for monitoring the SARS-CoV-2 spike protein (SARS-CoV-2 SP). A self-supported electrode, which can simultaneously serve as an antibody immobilization matrix and electron transport channel, was initially fabricated by a controlled partial exfoliation of a flexible graphitic carbon foil (GCF). Mild acidic treatment enabled the partial oxidation and exfoliation (down to a few layers) of the flexible GCF; this also provided a high percentage of oxygen functionality and an enhanced surface roughness. The substrate electrode was further functionalized with ethylenediamine (EDA) to provide a suitable platform with even a higher surface roughness, for the covalent immobilization of an anti-SARS-CoV-2 antibody. The change in the current response for the [Fe(CN) 6 ]3−/4− redox couple, induced by the binding of SARS-CoV-2 SP to the antibody immobilized on the electrode surface, was used to determine the SARS-CoV-2 SP concentration. The immunosensor thus prepared could detect SARS-CoV-2 SP within 30 min with high reproducibility and specificity over a wide concentration range (0.2–100 ng/mL). Detection limits of 25 pg/mL and 27 pg/mL were found in a phosphate buffer solution (pH 7.4), and diluted blood plasma, respectively. The immunosensor was also employed to detect SARS-CoV-2 SP in artificial human saliva. A self-supported ethylene diamine (EDA) functionalized flexible graphitic carbon foil (GCF) is prepared by controlled and mild acidic oxidation and exfoliation of GCE surface of few layers with the subsequent EDA functionalization. The prepared self-supported EDA-GCF electrode provides an ultrasensitive immunoassay platform for label-free detection of SARS-CoV-2 spike protein at pg/mL levels within 30 min [Display omitted] • Flexible carbon-foils are functionalized to obtain electrochemical immunosensors. • The sensors are characterized by spectroscopic and electrochemical techniques. • An antibody-based electrochemical sensor is used for detecting COVID-19. • The immunosensor allows achieving a very low detection limit. [ABSTRACT FROM AUTHOR]

A straightforward synthetic route to a selection of new ferrocenyl complexes bearing different organopalladium fragments is reported. The target complexes were fully characterized by Nuclear Magnetic Resonance, High Resolution Mass Spectrometry, Infrared Spectroscopy, X‐ray Diffraction, and electrochemical techniques. All compounds, with the exception of Pd(0)‐olefin derivatives, showed excellent antitumor activity on ovarian cancer cells and, in the case of Pd (II)‐allyl and Pd (II)‐butadienyl complexes, a lower cytotoxicity towards normal cells. [ABSTRACT FROM AUTHOR]

In situ follicular lymphoma (FL) is usually an incidental finding in otherwise reactive lymph node. This report describes two cases of lymph nodal in situ FL complicated by the association with nonlymphoid neoplasms. In case 1, in situ FL was discovered incidentally on a biopsy performed for an unexplained cervical lymphadenopathy 6 months after the resection of a carotid body paraganglioma. In case 2, in situ FL was detected incidentally during surgery for radical resection of prostatic carcinoma. In the lymph nodes, the in situ FL foci were characterized immunohistologically by strong coexpression of BCL2 and CD10 in the involved GCs. FISH study demonstrated BCL2 rearrangement in one of the two tested cases. These data extend the spectrum of the clinical situations that may be associated with in situ FL, but the biological and clinical significance of the association of in situ FL with nonlymphoid neoplasms deserves further investigation. Important fields of investigation should include: (1) how to approach these patients who have a risk of progression to overt lymphoma; (2) is the association of in situ FL with concurrent nonlymphoid neoplasia incidental, related to immunosuppression or to previous treatment? [ABSTRACT FROM AUTHOR]

Probe-based Confocal Laser Endomicroscopy (pCLE) is a novel imaging technique for gastrointestinal endoscopy providing in vivo microscopy at subcellular resolution. It offers the possibility to analyze neoangiogenesis and vessel density in vivo. Angiogenetic switch is essential in cancer progression. Aim of the paper was to review the use of this imaging tool to analyze colorectal and gastric cancers vascularization in vivo. The aim is to provide the possibility of combining diagnostic evidences with vascularization and molecular profile to evaluate the efficacy of an antiangiogenic treatment in association with conventional therapy. pCLE can be considered a revolutionary method for real-time assessment of changes in vascularization pattern in this tumors and it may open the possibility to address the use of anti-angiogenic therapy in order to improve the outcome of the treatment. [ABSTRACT FROM AUTHOR]

Proteomic technologies are being used with increasing frequency in the scientific community. In this review, we have highlighted their use in celiac disease (CD). The available techniques, which include two-dimensional (2D) gel electrophoresis, mass spectrometry, and antibody and tissue arrays, have been used to identify proteins or changes in protein expression specific to gut tissue from patients with CD. A number of studies have employed proteomic methodologies to determine the diagnostic biomarkers in body fluids or to examine changes in protein expression and posttranslational modifications during signaling. A fast technological development of these methods, along with the combination of classic techniques with proteomics, will lead to new discoveries, which will consent a better understanding of the pathogenesis of CD. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of wheat gliadin and related proteins in genetically predisposed individuals. To find a proteomic CD diagnostic signature and to gain a better understanding of pathogenetic mechanisms associated with CD, we analyzed the intestinal mucosa proteome alterations using two dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF ms) of CD patients with varying degrees of histological abnormalities defined by Marsh criteria and controls. Our results clearly evidenced the presence of two groups of patients: Group A, including controls and Marsh 0-I CD patients; and Group B, consisting of CD subjects with grade II-III Oberhuber-Marsh classification. Differentially expressed proteins were involved mainly in lipid, protein and sugar metabolism. Interestingly, in Group B, several downregulated proteins (FABP1, FABP2, APOC3, HMGCS2, ACADM and PEPCK) were implicated directly in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Moreover, Group B patients presented a deregulation of some proteins involved in apoptosis/survival pathways: phosphatidylethanolamine-binding protein 1 (PEBP1), Ras-related nuclear protein (Ran) and peroxiredoxin 4 (PRDX4). PEBP1 downregulation and RAN and PRDX4 upregulation were associated with more severe tissue damage. Likewise, IgMs were found strongly upregulated in Group B. In conclusion, our results indicate that a downregulation of proteins involved in PPAR signaling and the modulation of several cancer-related proteins are associated with the highest CD histological score according to Oberhuber-Marsh classification. [ABSTRACT FROM AUTHOR]

The diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid cancer. The classical chemotherapy regimen given to these patients was the CHOP (Cyclophosphamide, Hydroxydaunorubicin or Adriamycin, Oncovin or Vincristine, Prednisone or Prednisolone), but recently rituximab with CHOP (R-CHOP) increased the number of cases responding to first line therapy. DLBCL classification identified three principle subgroups. The first one, named germinal centre B cell-like (GCB), responds to both CHOP and R-CHOP treatment and it is mainly characterised by the expression of markers like Bcl-6 and CD10. The second, the activated B-cell like (ABC), has a worse prognosis in comparison with GCB, and is mainly characterised by the expression of IRF-4, PRDM1 and NF-κB. It is interesting to notice that IRF-4 and PRDM1 are under the transcriptional control of NF-κB, whose high activation level is associated with a worse prognosis. The third one, mediastinal large B-cell lymphoma (PMBCL) is an uncommon subtype characteristically found in young females. Gene expression profiling suggests that this disease resembles Hodgkin lymphoma more than other types of DLBCL. The impact of rituximab on the outcome of patients with PMBCL has still not been fully assessed. It was seen that rituximab inhibits NF-κB pathway in vitro. However, the clinical significance of this finding is still unknown, because both ABC and GCB DLBCL show a significant improvement of overall survival after R-CHOP treatment. In this review, the NF-κB pathway is suggested as a target for new chemotherapy strategies based on the association of CHOP with molecules more effective than rituximab in this pathway inhibition. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is one of the most frequent and deadly tumors. Among the key regulators of CRC growth and progression, the microenvironment has emerged as a crucial player and as a possible route for the development of new therapeutic opportunities. More specifically, the extracellular matrix acts directly on cancer cells and indirectly affecting the behavior of stromal and inflammatory cells, as well as the bioavailability of growth factors. Among the ECM molecules, EMILIN-2 is frequently down-regulated by methylation in CRC and the purpose of this study was to verify the impact of EMILIN-2 loss in CRC development and its possible value as a prognostic biomarker. Methods: The AOM/DSS CRC protocol was applied to Emilin-2 null and wild type mice. Tumor development was monitored by endoscopy, the molecular analyses performed by IHC, IF and WB and the immune subpopulations characterized by flow cytometry. Ex vivo cultures of monocyte/macrophages from the murine models were used to verify the molecular pathways. Publicly available datasets were exploited to determine the CRC patients' expression profile; Spearman's correlation analyses and Cox regression were applied to evaluate the association with the inflammatory response; the clinical outcome was predicted by Kaplan-Meier survival curves. Pearson correlation analyses were also applied to a cohort of patients enrolled in our Institute. Results: In preclinical settings, loss of EMILIN-2 associated with an increased number of tumor lesions upon AOM/DSS treatment. In addition, in the early stages of the disease, the Emilin-2 knockout mice displayed a myeloid-derived suppressor cells-rich infiltrate. Instead, in the late stages, lack of EMILIN-2 associated with a decreased number of M1 macrophages, resulting in a higher percentage of the tumor-promoting M2 macrophages. Mechanistically, EMILIN-2 triggered the activation of the Toll-like Receptor 4/MyD88/NF-κB pathway, instrumental for the polarization of macrophages towards the M1 phenotype. Accordingly, dataset and immunofluorescence analyses indicated that low EMILIN-2 expression levels correlated with an increased M2/M1 ratio and with poor CRC patients' prognosis. Conclusions: These novel results indicate that EMILIN-2 is a key regulator of the tumor-associated inflammatory environment and may represent a promising prognostic biomarker for CRC patients. [ABSTRACT FROM AUTHOR]

The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression. Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects depending on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression, by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role, representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages, and thus inhibit its progression. Lastly, we discuss innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis, from basic cancer research to clinical practice, as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain, as well as test drug toxicity and drive personalized and precision medicine in brain cancer. [Display omitted] • Low dose polyphenols are chemoprotective through the activation of Nrf2 pathway and vitagenes according to the hormesis concept. • Constitutive upregulation of Nrf2, as the "dark side" , leads to brain cancer growth and chemoresistance to therapy. • Combined nano-polyphenols and chemotherapeutics are cytotoxic to cancer cells inhibiting tumor proliferation. • Mini-brain cancer organoids are an innovative tool to develop precision medicine in clinical management of brain cancer. [ABSTRACT FROM AUTHOR]

Assessment of glucose concentration is important in the diagnosis and treatment of diabetes. Since the introduction of enzymatic glucose biosensors, scientific and technological advances in nanomaterials have led to the development of new generations of glucose sensors. This field has witnessed major developments over the last decade, as the novel nanomaterials are capable of efficiently catalyzing glucose directly (i.e., act as artificial enzymes, therefore defined nanozymes) or to entrap enzymes that are able to oxidize glucose. Among other nanomaterials, metal–organic frameworks (MOFs) have recently provided a tremendous basis to construct glucose sensing devices. MOFs are large porous crystalline compounds with versatile structural and tuneable chemical properties. In addition, they possess catalytic, peroxidase‐like, and electrochemical redox activity. This review comprehensively summarizes the general characteristics of MOFs, their subtypes, and MOF composites, as well as MOF‐derived materials employed to construct electrochemical, optical, transistor, and microfluidic devices for the detection of glucose. They include enzymatic, nonenzymatic, wearable, and flexible sensing devices and methods. The review also outlines the design and synthesis of MOFs and the working principles of the different transduction‐based glucose sensors and highlights the current challenges and future perspectives. [ABSTRACT FROM AUTHOR]

High grade serous ovarian carcinoma (HGSOC) is the most common type of malignant ovarian neoplasm and the main cause of ovarian cancer related deaths worldwide. Although novel biomarkers such as homologous recombination deficiency testing have been implemented into the clinical decision-making algorithm since diagnosis, morphological classification and immunohistochemistry analysis are essential for diagnostic purpose. This study aims at identifying histologic and clinical features that can be predictive of patients' prognosis. Morphological and architectural characterization including SET (Solid-Endometroid-Transitional)/Classic features was carried out in a cohort of 234 patients analyzing 695 slides. From each slide tumor infiltrating lymphocyte (TILs), the presence of necrosis, the number of mitoses, the presence of psammoma bodies, giant cells and atypical mitoses were recorded. Morphological heterogeneity was quantified by the Shannon's diversity index (SDI) considering the percentage of each architectural pattern per patient's slide. The frequency of architectural patterns and morphological variables varied with respect of the surgical strategy (primary debulking surgery vs interval surgery after neoadjuvant chemotherapy). HGSOCs exhibiting SET features had a longer overall as well as progression free survival. Among SET features, pseudo-endometrioid and transitional like patterns had the best outcome, while it was heterogenous for solid pattern, that had better outcome for BRCA 1 negative and less heterogeneous tumors. In patients submitted to neoadjuvant chemotherapy a higher intratumor heterogeneity as defined by SDI was a negative independent prognostic factor. A comprehensive histological examination considering architectural patterns and their heterogeneity can help in prognostication of HGSOCs. • In HGSOCs the definition of morphological architectural patterns and intratumor heterogeneity are useful in prognosis. • HGSOCs with SET features had longer overall and progression free survival • The Shannon diversity index (SDI) is a proposed method to measure intratumor heterogeneity. • In HGSOCs higher intratumor heterogeneity by SDI was a negative independent prognostic factor in patients treated with NACT. [ABSTRACT FROM AUTHOR]

Endoscopy is widely used to detect and diagnose precancerous lesions and gastric cancer (GC). The probe-based Confocal Laser Endomicroscopy (pCLE) is an endoscopic technique suitable for subcellular resolution and for microvasculature analyses. The aim of this study was to use pCLE to identify specific vascular patterns in high-risk and early stage GC. Mucosal architecture, vessel tortuosity, enlargements and leakage were assessed in patients with autoimmune gastritis and early gastric cancer (EGC). We were able to stratify gastritis patients by identifying distinct vascular profiles: gastritis was usually associated with increased vascularization characterized by a high number of tortuous vessels, which were also found in atrophic autoimmune disease. Leaky and tortuous vessels, distributed in a spatially irregular network, characterized the atrophic metaplastic mucosa. The mucosal vasculature of EGC patients displayed tortuous vessels, but unlike what detected in atrophic gastritis, they appeared patchy, as is in neoplastic gastric tissue. Very importantly, we detected vascular changes even in areas without lesions, supporting the contention that vascular alterations may provide a favorable microenvironment for carcinogenesis. This report confirms that pCLE is a valid endoscopic approach to improve the definition of patients with malignant lesions or at increased risk for GC by assessing vascular changes. [ABSTRACT FROM AUTHOR]

Simple Summary: Environmental factors such as UVR exposure and altitude of residence can contribute to the development of cutaneous melanoma. We hereby report that altitude of residence significantly associates with the molecular profiling of CM and melanoma specific survival. The fact that different miRNAs and transcriptomic profile vary with different geographical areas and residences altitude could support for possible regulatory mechanisms induced by environmental conditions, such as hypoxic environment and/or higher UVR exposure. Cutaneous melanoma (CM) incidence is rising worldwide and is the primary cause of death from skin disease in the Western world. Personal risk factors linked to environmental ultraviolet radiation (UVR) are well-known etiological factors contributing to its development. Nevertheless, UVR can contribute to the development of CM in different patterns and to varying degrees. The present study aimed at investigating whether altitude of residence can contribute to the development of specific types of CM and/or influence its progression. To this aim, 306 formalin-fixed and paraffin-embedded (FFPE) tissues from primary CM diagnosed in different geographical areas were submitted to B-RAF proto-oncogene serine/threonine kinase (BRAF) and N-RAS proto-oncogene GTPase (NRAS) mutational status detection and mRNA and miRNA profiling by qPCR. Genes were chosen for their functions in specific processes, such as immune response (CD2, PDL1, or CD274) and pigmentation (MITF, TYRP1, and TRPM1). Furthermore, four microRNAs, namely miR-150-5p, miR-155-5p, miR-204-5p, and miR-211-5p, were included in the profiling. Our results highlight differences in the gene expression profile of primary CM with respect to the geographical area and the altitude of residence. Melanoma-specific survival was influenced by the gene expression of mRNA and miRNAs and varied with the altitude of patients' residence. In detail, TYRP1 and miR-204-5p were highly expressed in patients living at higher altitudes, unlike miR-150-5p, miR-155-5p, and miR-211-5p. Since miRNAs are highly regulated by reactive oxygen species, it is possible that different regulatory mechanisms characterize CMs at different altitudes due to the different environment and UVR intensity. [ABSTRACT FROM AUTHOR]

A new dinuclear Pd(I) complex coordinating two bis(NHC) ligands revealed an unsuspected stability despite the unsaturation of the two metal centres. Even more surprisingly, the compound showed high and selective antiproliferative activity against different cancer cell lines and ovarian cancer tumoroids, and the mechanism of action was different from that of cisplatin. [ABSTRACT FROM AUTHOR]

The first palladium organometallic compounds bearing N‐trifluoromethyl N‐heterocyclic carbenes have been synthesized. These η3‐allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02–0.5 μm). By choosing 1,3,5‐triaza‐7‐phosphaadamantane (PTA) as co‐ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2‐methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3‐allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids. [ABSTRACT FROM AUTHOR]

• Patients immunogenetics can impact tumor response to radiotherapy. • Unmet need of prognostic markers in locally advanced rectal cancer. • Two immunogenetic prognostic markers in IL17F were identified. • Tumor Regression Grade prognostic value is integrated by IL17F -rs641701 and IL17F- rs9463772. • Additional stratification criteria for the selection of an organ sparing strategy. The role of the immune system in tumor response to chemo-radiotherapy (CRT) is an emerging issue. This work aimed at identifying predictive and prognostic immunogenetic variants in LARC patients after preoperative (po)-CRT and surgery. A set of 192 polymorphisms in 34 candidate genes involved in the regulation of the immune response signalling network, was selected and analyzed in 370 LARC patients treated with po-CRT and surgery, split into a Test Set (n = 233) and a Validation Set (n = 137). Immunogenetic markers were selected based on a concordant significant effect on 2-year relapse-free survival (2-yrRFS) (bootstrapped P < 0.05) in both patients Sets. The effect of the selected immunogenetic variants on 5-year metastases-free (5yrMFS), 5-year disease-free (5yrDFS), and 10-year overall (10yrOS) survival was tested in the entire Set of 370 patients. Two immunogenetic IL17F (IL17F -rs641701 and IL17F -rs9463772) markers predictive of 2yrRFS, 5yrDFS, 5yrMFS, and 10yrOS were identified. The combination of tumor regression grade (TRG) and patients genotype for IL17F -rs641701 and IL17F -rs9463772 allowed the identification of subgroups of patients with differential prognosis in term of both 5yrDFS (HR 11.29, P -value <0.001, and HR 5.86, P-value = 0.001, respectively) and 10yrOS (HR 7.07, P -value = 0.005, and HR 6.05, P -value = 0.002, respectively). IL17F -rs641701 and IL17F -rs9463772 were highlighted as promising immunogenetic markers significantly associated with the prognosis of LARC patients. After a prospective validation of the herein reported findings, the combination of TRG and patients genotype should be considered to provide additional stratification criteria for the selection of a personalized multimodality treatment. [ABSTRACT FROM AUTHOR]

Background: EBV produces miRNAs with important functions in cancer growth, tumor invasion and host immune surveillance. The discovery of EBV miR-BARTs is recent, and most of their functions are still unknown. Nonetheless, some new studies underline their key roles in EBV-associated malignancies. Main body: In EBV-associated tumors, the expression profile of miR-BARTs varies according to the cell type, autophagic process and signals received from the tumor microenvironment. By the same way of interest is the interaction between tumor cells and the tumor environment by the release of selected EBV miR-BARTs in addition to the tumor proteins trough tumor exosomes. Conclusion: In this review, we discuss new findings regarding EBV miR-BARTs in Hodgkin lymphoma and gastric cancer. The recent discovery that miRNAs are released by exosomes, including miR-BARTs, highlights the importance of tumor and microenvironment interplay with more specific effects on the host immune response. [ABSTRACT FROM AUTHOR]

The clinical application of nanomaterials for chemodynamic therapy (CDT), which generate multiple reactive oxygen species (ROS), presents significant challenges. These challenges arise due to insufficient levels of endogenous hydrogen peroxide and catalytic ions necessary to initiate Fenton reactions. As a result, sophisticated additional delivery systems are required. In this study, a novel bimetallic copper (II) pentacyanonitrosylferrate (Cu(II)NP, Cu[Fe(CN) 5 NO]) material was developed to address these limitations. This material functions as a multiple ROS generator at tumoral sites by self-inducing hydrogen peroxide and producing peroxynitrite (ONOO-) species. The research findings demonstrate that this material exhibits low toxicity towards normal liver organoids, yet shows potent antitumoral effects on High Grade Serous Ovarian Cancer (HGSOC) organoid patients, regardless of platinum resistance. Significantly, this research introduces a promising therapeutic opportunity by proposing a single system capable of replacing the need for H 2 O 2 , additional catalysts, and NO-based delivery systems. This innovative system exhibits remarkable multiple therapeutic mechanisms, paving the way for potential advancements in clinical treatments. [Display omitted] • CuNP overcome the low endogenous H 2 O 2 level issue, due to which CDT is severely restricted by increasing the H 2 O 2 level. • CuNP provides (Fe+2, Cu+2) dual metal cations in a single system to improve the catalytic activity of Fenton reaction. • CuNP also produced ONOO− as apoptosis inducer specifically at tumoral sites. • This single system also inhibits the expression of multiple cancerous genes e.g., CuNP inhibits (SOD1, c-myc, NF-κB). [ABSTRACT FROM AUTHOR]

Background: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%–3% of the LS patients and represents a classical secondary, constitutional and tissue‐specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu‐mediated recombination. Methods: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation‐dependent probe amplification (MLPA) and then defined by Long‐Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS). Results: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556‐490_*8438del and c.858+1193_*5826del are novel; c.859‐1430_*2033del and c.859‐670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in‐frame or out‐of‐frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae. Conclusion: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients. [ABSTRACT FROM AUTHOR]

Peptidyl‐prolyl cis–trans isomerase, NIMA‐interacting 1 (PIN1) is a peptidyl‐prolyl isomerase that binds phospho‐Ser/Thr‐Pro motifs in proteins and catalyzes the cis–trans isomerization of proline peptide bonds. PIN1 is overexpressed in several cancers including high‐grade serous ovarian cancer. Since few therapies are effective against this cancer, PIN1 could be a therapeutic target but effective PIN1 inhibitors are lacking. To identify molecules with in vivo inhibitory effects on PIN1, we used consensus docking to model existing PIN1‐ligand X‐ray structures and to screen a chemical database for candidate inhibitors. Ten molecules were selected and tested in cellular assays, leading to the identification of VS10 that bound and inhibited PIN1. VS10 treatment reduced the viability of ovarian cancer cell lines by inducing proteasomal PIN1 degradation, without effects on PIN1 transcription, and also reduced the levels of downstream targets β‐catenin, cyclin D1, and pSer473‐Akt. VS10 is a selective PIN1 inhibitor that may offer new opportunities for treating PIN1‐overexpressing tumors. [ABSTRACT FROM AUTHOR]

The potential role of the probe-based confocal laser endomicroscopy (pCLE) has been analyzed in different pathologic conditions of the gastrointestinal tract. Here, we analyzed a case of extrapulmonary high grade neuroendocrine rectal carcinoma (HGNEC) using, for the first time, the pCLE system. A 72-year old man was diagnosed with an 8 cm diameter rectal HGNEC by standard colonoscopy integrated with the pCLE system. The diagnosis of neuroendocrine carcinoma was confirmed by immunohistochemical analyses. By using the pCLE system, we well defined and resolved vascular structures and mucosal architecture. An altered mucosal pattern and vascular defects, peculiar for HGNEC, were observed at high magnification, allowing the identification of a pattern which was quite different from that observed in poorly differentiated adenocarcinomas (PDA) where tissues appear darker, very irregular, even if glandular structures can still be recognized. This underlines the usefulness of pCLE in discriminating HGNECs from PDAs. In conclusion, pCLE could represent a valid and helpful method for in vivo HGNEC diagnosis, allowing prompt and careful management of the patient. [ABSTRACT FROM AUTHOR]

Over the last decade, our understanding of the mechanisms underlying immune modulation has greatly improved, allowing for the development of multiple therapeutic approaches that are revolutionizing the treatment of cancer. Immunotherapy for gastric cancer (GC) is still in the early phases but is rapidly evolving. Recently, multi-platform molecular analyses of GC have proposed a new classification of this heterogeneous group of tumors, highlighting subset-specific features that may more reliably inform therapeutic choices, including the use of new immunotherapeutic drugs. The clinical benefit and improved survival observed in GC patients treated with immunotherapeutic strategies and their combination with conventional therapies highlighted the importance of the immune environment surrounding the tumor. A thorough investigation of the tumor microenvironment and the complex and dynamic interaction between immune cells and tumor cells is a fundamental requirement for the rational design of novel and more effective immunotherapeutic approaches. This review summarizes the pre-clinical and clinical results obtained so far with immunomodulatory and immunotherapeutic treatments for GC and discusses the novel combination strategies that are being investigated to improve the personalization and efficacy of GC immunotherapy. [ABSTRACT FROM AUTHOR]

The biobanks, providers of biospecimens, and the scientists, users of biological material, are both strategic actors in translational medicine but the communication about those two subjects seems to be delicate. Recently, biobank managers from US and Europe stressed the danger of underuse of biospecimens stored in their biobanks thus stimulating the debate about innovative ways to collect samples and to communicate their availability. We hypothesize that the already stored collections meet the interest of present scientists only in specific situations. Serial biospecimens from patients with large associated clinical data concerning voluptuary habits, environmental exposure, anthropomorphic information are needed to meet the even more specific projects the scientists are planning. The hypothesis of activation of specific sections in ranked journals aimed to facilitate the communication between partners interested in finding/collecting ad hoc biospecimens is discussed. [ABSTRACT FROM AUTHOR]

Somatic mutations in TP53 are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including TP53, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel TP53 somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: TP53 c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); TP53 c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); TP53 c.826_827GC>AT (p.Ala276Ile, missense); TP53 c.1022insT (p.Arg342Profs*5, frameshift INDEL); TP53 c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and TP53 c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel TP53 variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported TP53 somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications. [ABSTRACT FROM AUTHOR]