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ObjectiveCurrently, there is no clear guidance defining the ideal candidate for minimally invasive interval debulking surgery. This study aimed to identify predictive factors for a minimally invasive approach in patients with advanced ovarian cancer who are candidates for interval debulking surgery after neoadjuvant chemotherapy.MethodsThis was a single institution retrospective study conducted between January 2014 and June 2020 Perioperative variables were used to predict the likelihood of minimally invasive interval debulking surgery using multivariable models. A nomogram was developed, and internal validation was performed using the bootstrapping correction technique. This nomogram was built to visualize the effect of perioperative variables on the estimated probability of minimally invasive interval debulking surgery in patients with a clinical response after neoadjuvant chemotherapy. We used the four significant perioperative variables according to logistic regression.ResultsA total of 108 (28.4%) and 272 (71.6%) patients underwent interval debulking surgery by a minimally invasive or open approach, respectively. Absence of omental cake (odds ratio (OR) 9.15, 95% confidence interval (CI) 4.26 to 19.64, pConclusionsOur nomogram may serve as a useful tool to choose the surgical approach in patients with advanced ovarian cancer undergoing interval debulking surgery.

Galectin-3 binding protein (Gal-3BP) is a multifunctional glycoprotein involved in cell–cell and cell–matrix interactions known to be upregulated in cancer and various viral infections, including HIV-1, HCV, and SARS-CoV-2, with a key role in regulating the antiviral immune response. Studies have identified a direct correlation between circulating levels of Gal-3BP and the severity of disease and/or disease progression for some viral infections, including SARS-CoV-2, suggesting a role of Gal-3BP in these processes. Due to Gal-3BP’s complex biology, the molecular mechanisms underlying its role in viral diseases have been only partially clarified. Gal-3BP induces the expression of interferons (IFNs) and proinflammatory cytokines, including interleukin-6 (IL-6), mainly interacting with galectin-3, targeting the TNF receptor-associated factors (TRAF-6 and TRAF-3) complex, thus having a putative role in the modulation of TGF-β signaling. In addition, an antiviral activity of Gal-3BP has been ascribed to a direct interaction of the protein with virus components. In this review, we explored the role of Gal-3BP in viral infections and the relationship between Gal-3BP upregulation and disease severity and progression, mainly focusing on SARS-CoV-2. Augmented knowledge of Gal-3BP’s role in virus infections can be useful to evaluate its possible use as a prognostic biomarker and as a putative target to block or attenuate severe disease.

Simple Summary PD-1/PD-L1 axis blockade immunotherapy leverages on assessment of tumour PD-L1 status by immunohistochemistry for identifying cancer patients’ who would benefit most from this therapy. Because some PD-L1 negative cancer patients also benefit from the treatment, it has been postulated that spatial heterogeneity of PD-L1 expression in tumour tissue may reduce the predictive value of the test. Here we demonstrate for the first time the presence of PD-L1+ circulating tumor–derived microvesicles in the blood stream of high grade serous ovarian cancer patients and propose the assessment of tumor-derived circulating PD-L1+ microvesicles to be inserted in predictive algorithms for complementing tumour PD-L1 status. Abstract Background: Ovarian cancer (OC) has recently attracted attention for the use of PD-1/PD-L1 axis blocking agents, with durable activity reported only in a subset of patients. The most used biomarker for sensitivity to the PD-1/PD-L1 axis blockade is tumour PD-L1 status by immunohistochemistry. However, patient stratification using this method suffers from intrinsic heterogeneity of OC, likely contributing to the unsatisfactory results obtained so far. Cells communicate with each other by releasing microvesicles (MVs) that carry parental cell surface features. Thus, we hypothesised that PD-L1+ tumour cells (TC) and infiltrating PD-L1+ leukocytes should shed MVs carrying surface PD-L1 that may serve as a proxy for the whole tumour PD-L1 status. Results: We showed for the first time the presence of measurable amounts of TC- and leukocyte-derived PD-L1+ MVs (range: 1.4–178.8 MVs/μL and 6.2–504.8 MVs/μL, respectively) in the plasma of high-grade serous OC (HGSOC) patients (n = 63), using a sensitive flow cytometry platform. The concentration of PD-L1+ MVs of either origin did not associate with the PD-L1 status of TCs and leukocytes in the tumour biopsies, suggesting that the circulating PD-L1+ MVs also included ones from locations not selected for immunohistochemistry analysis and represented the PD-L1 status of the whole tumour mass. In this study, we also describe the serendipitous discovery of circulating PD-L1+ MVs of platelet origin (10.3–2409.6 MVs/μL). Conclusions: The enumeration of circulating PD-L1+ MVs in HGSOC patients may provide a novel direction for assessing the tumour PD-L1 status and contribute to HGSOC patient stratification for immunotherapy interventions. The presence of circulating PD-L1+ MVs of platelet origin, a finding not yet reported in HGSOC patients, warrants further studies.

In this article we will reflect on the possible implications that the pandemic and lockdown has brought upon adoptive families. Some adoptive parents have taken this time as an opportunity to meet and strengthen their bond with their children, others have perceived it as a learning experience. However, for many it has meant an increase of stress that interferes with their parental role. We reflect on the aspects that enhance a secure and protective bond in adoptive families, in which parents welcome their children and their emotions. Adoptive parents who are open to reflect on their own histories and their children’s, are emotionally more available to face the difficulties that life during the pandemic brings.

HER-3 is becoming an attractive target for antibody–drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic cleavable linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.

Ovarian cancer (OC) remains a fatal malignancy because most patients experience recurrent disease, which is resistant to chemotherapy. The outcomes for patients with platinum-resistant OC are poor, response rates to further chemotherapy are low and median survival is lower than 12 months. The complexity of platinum-resistant OC, which comprises a heterogeneous spectrum of diseases, is indeed far from being completely understood. Therefore, comprehending tumors' biological behaviour to identify reliable biomarkers, which may predict responses to therapies, is a demanding challenge to improve OC management. In the age of precision medicine, efforts to overcome platinum resistance in OC represent a dynamic and vast field in which innovative drugs and clinical trials rapidly develop. This review will present the exceptional biochemical environment implicated in OC and highlights mechanisms of chemoresistance. Furthermore, innovative molecules and new therapeutic opportunities are presented, along with currently available therapies and ongoing clinical trials.

A 42-year-old woman with abnormal vaginal bleeding was referred to the Department of Obstetrics and Gynecology of the Fondazione Policlinico Universitario A. Gemelli, IRCCS in Rome, in June 2019, with a diagnosis of complex hyperplasia with atypia versus well-differentiated endometrioid

ObjectivesThe aim of this study was to evaluate the immunohistochemical (IHC) expression of Ki-67, estrogen receptors α (ERsα), and progesterone receptors (PRs) in high-risk endometrial cancer patients and to assess their prognostic impact.Methods/MaterialsImmunohistochemical expression of Ki-67, ERsα, and PRs was evaluated in primary untreated endometrial cancer. The correlation among IHC staining and risk factors of recurrence such as age, Federation International of Gynecology and Obstetrics stage, grading, depth of invasion, and metastatic spread was assessed.ResultsEighty-two patients were available for the analysis. Mean ± SD age was 65.05 ± 10.48 years. The IHC assessment revealed a lack of ERα in 46.3% and of PR in 48.7% as well as a high Ki-67 in 31.7%. Loss of ERα and PR was associated with a significant higher rate of advanced stage of disease, a higher frequency of G3 tumors, and a myometrial invasion greater than 50%. A strong Ki-67 expression correlated with a deeper myometrial invasion. Analysis of the interrelationship between receptor immunonegativity revealed a relevant association of ERα immunolocalization with PR and with a high Ki-67 expression. The present study also showed that loss of ERα (P = 0.003), advanced Federation International of Gynecology and Obstetrics stage (P < 0.001), and high Ki-67 (P = 0.004) were independent prognostic factors of a shorter disease-free survival. Importantly, loss of ERα, loss of PR, and a high Ki-67 were correlated with a higher incidence of distant recurrence.ConclusionsA systematic immunohistochemistry should be a key step in the therapeutic algorithm and could contribute to the identification of high-risk tumors.

Simple Summary Antibody Drug Conjugates are an emerging class of biopharmaceuticals that have seen an impressive increase of attention in the field of cancer therapy. Here, we describe the therapeutic activity of 1959-sss/DM3, a non-internalizing ADC targeting LGALS3BP, a secreted, extracellular vesicles-associated protein expressed by the majority of human cancers, including neuroblastoma. We show that 1959-sss/DM3 treatment can cure mice with established neuroblastoma tumours in pseudometastatic, orthotopic and Patient Derived Xenograft models. Abstract Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas.

OBJECTIVE: To evaluate the efficacy of ospemifene in treating dyspareunia associated with postmenopausal vulvo-vaginal atrophy (VVA).METHODS: A structured search was carried out in PubMed-Medlin, Embase, Cochrane Controlled Trials Register databases through to 31 July 2018. The search included the following terms: "Ospemifene", "vulvovaginal atrophy", "dyspareunia", "SERM" and "randomized controlled trial" (RCTs). Four outcomes were selected: vaginal pH; proportions of parabasal and superficial vaginal cells; and perception of the most bothersome symptom (vaginal dryness or dyspareunia). A random-effects model was used in the meta-analysis. Study quality and bias risk were assessed with the Cochrane tool.RESULTS: Six RCTs comparing the efficacy of ospemifene against placebo after 12 and 52 weeks of treatment were included in the meta-analysis. At 12 weeks, changes in vaginal Ph (SMD: -0.96, 95% CI:-1.12 to -0.81; p CONCLUSION: The present meta-analysis suggests that ospemifene 60 mg is associated with significant improvement in the morphological and physiological features of the vaginal mucosa that correlate with the symptoms associated with postmenopausal VVA.

Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues.

This extensive review summarizes clinical evidence on immunotherapy and targeted therapy currently available for endometrial cancer (EC) and reports the results of the clinical trials and ongoing studies. The research was carried out collecting preclinical and clinical findings using keywords such as immune environment, tumor infiltrating lymphocytes, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, immune checkpoint inhibitors, anti-PD-1/PD-L1 antibodies and others' on PubMed. Finally, we looked for the ongoing immunotherapy trials on ClinicalTrials.gov. EC is the fourth most common malignancy in women in developed countries. Despite medical and surgical treatments, survival has not improved in the last decade and death rates have increased for uterine cancer in women. Therefore, identification of clinically significant prognostic risk factors and formulation of new rational therapeutic regimens have great significance for enhancing the survival rate and improving the outcome in patients with advanced or metastatic disease. The identification of genetic alterations, including somatic mutations and microsatellite instability, and the definition of intracellular signaling pathways alterations that have a major role in in tumorigenesis is leading to the development of new therapeutic options for immunotherapy and targeted therapy.

OBJECTIVE: To evaluate the tolerability and safety of ospemifene in treating dyspareunia associated with postmenopausal vulvo- vaginal atrophy (VVA).METHODS: The literature was searched through to 31 July 2018 to identify randomized controlled trials comparing ospemifene 60 mg against placebo for the treatment of VVA. Two groups of outcomes were selected: 1) side-effects, including hot flushes, urinary tract infection (UTI), headache, deep venous thrombosis (DVT), coronary heart disease (CHD), cardiovascular event (CVE), discontinuation due to side-effects, serious adverse event (SAE); 2) Safety, in relation to endometrial thickness, vaginal bleeding, breast tenderness, breast and endometrial cancer. A random-effects model was used in the meta-analysis. Study quality and bias risk were assessed with the Cochrane tool.RESULTS: In the group of patients treated with ospemifene, there was a slightly higher rate of hot flushes (OR:2.36, 95% CI 1.26-4.42; p = 0.007) and UTI (OR:1.97, 95% CI 1.23-3.14, p = 0.005) at 12 weeks of treatment, but no differences were noted after 52 weeks. The incidence of headaches, DVT, CHD, CVE, discontinuation of treatment, and SAEs was not significantly different between groups. Ospemifene treatment was statistically associated with a greater endometrial thickness in women with an intact uterus both at 12 weeks (SMD: 0.40, (95% CI 0.17 to 0.63, p CONCLUSIONS: This meta-analysis suggests that ospemifene treatment is well tolerated and presents a good safety profile. Long-term safety studies with larger samples, which include patients at high risk, are warranted.

// Emily Capone 1, 2 , Enza Piccolo 1 , Imma Fichera 1, 6 , Paolo Ciufici 3 , Daniela Barcaroli 3 , Arturo Sala 3, 4 , Vincenzo De Laurenzi 2 , Valentina Iacobelli 1, 5 , Stefano Iacobelli 1, 2, * and Gianluca Sala 1, 2, * 1 MediaPharma s.r.l., 66100, Chieti, Italy 2 Dipartimento di Scienze Mediche, Orali e Biotecnologiche; University “G. d’Annunzio” Chieti-Pescara, Centro Studi sull’Invecchiamento, CESI-MeT, 66100 - Chieti, Italy 3 Dipartimento di Scienze Psicologiche, della Salute e del Territorio, University “G. d’Annunzio” Chieti-Pescara, Centro Studi sull’Invecchiamento, CESI-MeT, 66100 - Chieti, Italy 4 College of Health and Life Sciences, Brunel University London, UK 5 Department of Gynecology and Obstetrics, University of Rome “La Sapienza”, 00100 - Rome, Italy 6 Current address: Nouscom SRL 100 I-00128 Rome, Italy * These authors share senior authorship Correspondence to: Stefano Iacobelli, email: s.iacobelli@mediapharma.it Keywords: endosialin, ADC, sarcoma, duocarmycin, target therapy Received: May 11, 2017 Accepted: June 19, 2017 Published: July 22, 2017 ABSTRACT The endosialin/CD248/TEM1 receptor is expressed on the cell surface of tumor-associated stroma cells as well as in sarcoma and neuroblastoma cells. This receptor is emerging as an attractive molecule in diagnostics and therapeutics because of its expression across the stroma of many human tumors, the low to absent expression in normal tissues and accessibility from the vascular circulation. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ENDOS/ADC). It consists of a humanized endosialin monoclonal antibody, named hMP-E-8.3, conjugated to a potent duocarmycin derivative. In endosialin expressing cancer cell lines, this ENDOS/ADC showed a powerful, specific and target-dependent killing activity. High expression levels of endosialin in cells correlated with efficient internalization and cytotoxic effects in vitro . Efficacy studies demonstrated that ENDOS/ADC treatment led to a long-lasting tumor growth inhibition of a cell line-based model of human osteosarcoma. Taken together, our results demonstrate that endosialin is an attractive target in sarcoma and suggest that ENDOS/ADC has the potential to be developed into a bio-therapeutic agent for these malignancies.

Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome. Vice versa, targeted inhibition of BRAF-V600E with the selective inhibitor PLX 4032 (Vemurafenib) is severely limited due to feedback re-activation of EGFR in these tumors. Mounting evidence indicates that upregulation of the ErbB-3 signaling axis may occur in response to several targeted therapeutics, including Vemurafenib, and NRG-1β-dependent re-activation of the PI3K/AKT survival pathway has been associated with therapy resistance. Here we show that colon CSCs express, next to EGFR and ErbB-2, also significant amounts of ErbB-3 on their membrane. This expression is functional as NRG-1β strongly induces AKT/PKB and ERK phosphorylation, cell proliferation, clonogenic growth and promotes resistance to Vemurafenib in BRAF-V600E mutant colon CSCs. This resistance was completely dependent on ErbB-3 expression, as evidenced by knockdown of ErbB-3. More importantly, resistance could be alleviated with therapeutic antibody blocking ErbB-3 activation, which impaired NRG-1β-driven AKT/PKB and ERK activation, clonogenic growth in vitro and tumor growth in xenograft models. In conclusion, our findings suggest that targeting ErbB-3 receptors could represent an effective therapeutic approach in BRAF-V600E mutant colon cancer.

Background A previous report has shown that LGALS3BP (also known as 90K or Mac-2 BP) has antitumor activity in colorectal cancer (CRC) via suppression of Wnt signalling with a novel mechanism of ISGylation-dependent ubiquitination of β-catenin. The role of LGALS3BP in CRC prognosis was investigated. Methods The role of LGALS3BP on CRC progression and clinical prognosis was analyzed by combining cell cultures, in vitro assays, and immunohistochemistry. Results Silencing of LGALS3BP in HCT-116 human colon cancer cells resulted in enhanced β-catenin expression that was reversed by addition of human recombinant LGALS3BP. Moreover, intra-tumor delivery of LGALS3BP reduced tumor growth of xenografts originating from LGALS3BP-silenced HCT-116 cells. Finally, in a series of 196 CRC patients, LGALS3BP expression in tumor tissue associated with clinical outcome. Patients with high LGALS3BP expression had lower risk of relapse and a longer overall survival time than those with low LGALS3BP expression. Multivariate analyses confirmed LGALS3BP expression status as the only independent prognostic factor of survival. Conclusions These results provide evidence that low expression of LGALS3BP participates in malignant progression of CRC and implicates poor prognosis, highlighting its augmentation as a potential therapeutic approach.