Outcome improvement with chemotherapy and radiotherapy in primary, localized, radiation-associated angiosarcoma of the breast region: a retrospective case series analysis.

BACKGROUND: We report on a series of consecutive patients with localized radiation-associated angiosarcoma (RAAS) of the breast region (BR) treated at two Italian sarcoma reference centers. MATERIALS AND METHODS: We retrospectively reviewed all cases of primary, localized, resectable RAAS of the BR, treated at one of the two participating institutions from 2000 to 2019. Relapse-free survival (RFS) and overall survival (OS) were calculated. The prognostic role of several variables was investigated. A propensity score matched (PSM) analysis was carried out. RESULTS: Eighty-four patients were retrospectively identified. Nineteen out of 84 patients (22.6%) were pretreated with an anthracycline-based regimen for previous cancer. All patients but one underwent surgery, with 37/84 (44.1%) receiving surgery alone and 46/84 (54.8%) a multimodal approach: 18/84 (21.4%) received radiation therapy (RT) and 46/84 (54.9%) received chemotherapy. An anthracycline-based regimen was used in 10/84 patients (11.9%), while a gemcitabine-based regimen was used in 33/84 (39.3%). With a median follow-up of 51 months (interquartile range: 30-126 months), 36/84 patients (42.9%) relapsed and 35/84 patients (41.7%) died (8/84, 9.5% in the lack of metastatic disease). Five-year OS and 5-year RFS were 57% [95% confidence interval (CI) 43% to 68%] and 52% (95% CI 39% to 63%), respectively. Both (neo)adjuvant RT and chemotherapy were associated with better RFS [hazard ratio (HR) 0.25, 95% CI 0.08-0.83; HR 0.45, 95% CI 0.23-0.89] with a trend towards a better OS (HR 0.51, 95% CI 0.18-1.46; HR 0.60, 95% CI 0.29-1.24). Gemcitabine-based regimens seemed to perform better (HR 4.28, 95% CI 1.29-14.14). PSM analysis retained the above results. CONCLUSIONS: This retrospective study supports the use of (neo)adjuvant RT and chemotherapy, in primary, localized resectable RAAS of the BR. An effort to prospectively validate the role of (neo)adjuvant RT and chemotherapy is warranted.

Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.

A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22. Using a positional-cloning strategy, we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP).

Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D.

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20-50%), and specific locus. Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers. In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well. Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options. Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options.

The influence of collection zone on glucosinolates, polyphenols and flavonoids contents and biological profiles of Capparis sicula ssp. sicula.

This study aimed to evaluate the influence of collection zone on total phenol, flavonoid and glucosinolate contents and antioxidant and anti-inflammatory activities of caper (Capparis sicula ssp. sicula). This species has been characterized through the detection, isolation and quantitative evaluation of chemical markers (polyphenols, flavonoids and glucosinolates). The chemical investigation showed a different composition between the two collection zones. While the total amounts of phenolics and flavonoids of the two samples were quite the same, their high-performance liquid chromatography profiles were very different. In both samples, the most abundant aglycone was quercetin which accounted for 60% of total flavonoids. Nuclear magnetic resonance data analysis allowed the identification of two compounds: 3,5-dicaffeoylquinic and 4,5-dicaffeoylquinic acids which represented 6.67% and 15.94%, respectively, of the total amount of flavonoids in sample 1. In sample 2, these two acids were still present, but their percentages were much less (2.20% and 1.71%, respectively). As far as we know, this is the first report about the presence of dicaffeoylquinic acids in Capparis. With regard to glucosinolate content, sample 1 showed a higher content of glucosinolates. In both samples, glucocapparin was the most abundant compound. Antioxidant activity of the methanolic C. sicula extracts using diphenyl picrylhydrazyl, ß-carotene bleaching test and oxygen radical absorbance capacity showed that the sample 2 was more active than 1. As regards the inhibition of NO production, the extracts from sample 2 were more active than those from sample 1.

Thymic carcinoma with Lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy.

IMPORTANCE: Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. OBJECTIVE: Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. DESIGN: We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. RESULTS: Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. CONCLUSIONS AND RELEVANCE: This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: In our previous works, we demonstrated that patients' sex affects the efficacy of immune checkpoint inhibitors (ICIs) in patients with several advanced solid tumors. Here, we assessed the sex-based heterogeneity of efficacy of anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) given as monotherapy, for advanced non-small-cell lung cancer (NSCLC) expressing high PD-L1 levels, to evaluate if available evidence supports this therapeutic option for both women and men. METHODS: We carried out a systematic review and meta-analysis including all randomized, controlled trials testing anti-PD-1/anti-PD-L1 drugs in monotherapy, as first-line treatment of advanced NSCLC expressing high PD-L1 levels. The primary endpoint was the difference in efficacy of anti-PD-1/anti-PD-L1 drugs versus chemotherapy, between men and women, measured in terms of the difference in overall survival (OS) log [hazard ratio (HR)] reported in male and female study participants. RESULTS: We analyzed four randomized, controlled trials, including 1672 patients, of whom 1224 (73.2%) were men and 448 (26.8%) were women. The pooled OS-HR comparing anti-PD-1/anti-PD-L1 versus chemotherapy was 0.59 [95% confidence interval (CI), 0.50-0.69] for men and only 0.84 (95% CI, 0.64-1.10) for women. The pooled ratio of the OS-HRs reported in men versus women was 0.71 (95% CI, 0.52-0.98; P-heterogeneity: 0.04), indicating a significantly greater effect for men. No heterogeneity among single-study estimates was observed in either male patients (Q = 2.39, P = 0.50, I2 = 0%) or in female patients (Q = 1.13, P = 0.50, I2 = 0%). CONCLUSION: Evidence available indicates anti-PD-1/anti-PD-L1 monotherapy as highly effective in men but not in women, even in NSCLCs expressing high PD-L1 levels. Prospective trials testing sex-based tailored immunotherapy strategies are needed.

Clinical management of patients with thymic epithelial tumors: the recommendations endorsed by the Italian Association of Medical Oncology (AIOM).

The Italian Association of Medical Oncology recommendations on thymic epithelial tumors, which have been drawn up for the first time in 2020 through an evidence-based approach, report indications on all the main aspects of clinical management of this group of rare diseases, from diagnosis and staging, to new available systemic treatments, such as targeted therapies and immunotherapies. A summary of key recommendations is presented here and complete recommendations are reported as Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100188.

Jaw osteonecrosis in patients treated with bisphosphonates: an ultrastructural study.

Osteonecrosis of the jaw is a severe bone disorder traditionally associated with periodontal disease, local malignancy, chemotherapy, glucocorticoid therapy, or trauma. Recently a growing number of publications reported the occurrence of osteonecrosis of the jaw in patients undergoing treatment with bisphosphonates. The mechanism by which bisphosphonates might contribute to the development of osteonecrosis of the jaw is far from being fully elucidated. Suppression of bone turnover, infection, tissue hypoxia and cellular toxicity were proposed as possible mechanisms by which bisphosphonates may exert adverse effects on bone metabolism. Here, we studied 25 consecutive patients treated with bisphosphonates for osteoporosis or tumoral pathologies. We provide good evidence of hyperactive osteoclastic bone resorption and suggest a direct cytotoxic effect of bisphosphonates on bone tissue through induction of osteocyte cell death. We also demonstrate that bisphosphonates only have limited adverse effects on bone vascular network.

Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors.

PURPOSE: The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS). METHODS: We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites. RESULTS: The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28-0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23-0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13-0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10-0.55; p = 0.001). CONCLUSIONS: These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.

CADASIL: extended polymorphisms and mutational analysis of the NOTCH3 gene.

CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene. Most mutations result in a gain or loss of cysteine residue in one of the 34 epidermal growth factor-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. To date, more than 130 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Many polymorphisms have also been identified in the NOTCH3 coding sequence, some of them leading to amino acid substitutions. The aim of the present study was to analyze the NOTCH3 gene in a large group of patients affected by leukoencephalopathy and to investigate the presence of genetic variants. The molecular analysis revealed several nucleotide alterations. In particular, we identified 20 different mutations, 22 polymorphisms, and 8 genetic variants of unknown pathological significance never reported previously. We hope that this NOTCH3 gene mutational analysis, performed in such a significant number of unrelated and related patients affected by leukoencephalopathy, will help in molecular screening for the NOTCH3 gene, thus contributing to enlargement of the NOTCH3 gene variation database.

A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.

Influence of obstetric complication severity on brain morphology in schizophrenia: an MR study.

INTRODUCTION: The purpose of this study was to determine if a causal relationship exists between obstetric complications (OCs) severity and linear magnetic resonance (MR) measurements of brain atrophy in patients with schizophrenia. MATERIALS AND METHODS: Linear measurements of ventricular enlargement (bifrontal span, Evans ratio, and bicaudate ratio) and hippocampal atrophy (interuncal distance) were completed on MR images obtained in 47 patients with schizophrenia. Regression analysis was used to look at association with OCs severity, assessed by the "Midwife protocol" of Parnas and colleagues. The relationship between MR measurements and phenomenologic variables such as age at onset, illness duration, and exposure to antipsychotic medications was explored. The relationship between MR measurements, OCs severity, and symptom presentation was also investigated. RESULTS: OCs severity was significantly associated with MR measurements of ventricular enlargement (bifrontal span, Evans ratio). As the severity of OCs increased, bifrontal span and Evans ratio increased. This effect was independent of age at onset, illness duration, or even antipsychotic treatment. Interestingly, bifrontal span, Evans ratio, and OCs severity score all showed a significant positive correlation with hallucinatory symptomatology. CONCLUSION: Although confirmatory studies are needed, our findings would support the idea that environmental factors, in this case severe OCs, might partly contribute to ventricular abnormalities in schizophrenia.

Pathological findings in subsynovial connective tissue in idiopathic carpal tunnel syndrome.

Recent studies suggest that in patients with carpal tunnel syndrome, pathological changes occur in the subsynovial connective tissue. Such changes are non-inflammatory synovial fibrosis and vascular proliferation. Thickening of the tendon sheet may cause an increase of canal pressure and damages to the median nerve in the wrist; however, the causes of such events still remain to be clarified. We examined synovial specimens from 26 patients operated on for idiopathic carpal tunnel syndrome. Analysis included histological, ultrastructural and immunohistochemical examination in order to establish a pathological underlying pattern. An explanation for the pathogenesis of the found changes suggested. Our data confirm the presence of a non-inflammatory fibrosis with irregular bundles of collagen. De novo blood vessel formation was also noted. Interestingly the neo-angiogenesis consists of anomalous vessels and may be triggered from various cell types secreting vascular endothelial growth factor (VEGF), including macrophage-like elements similar to endothelial progenitor cells. Therefore, we believe that in the future a non-surgical management of carpal tunnel syndrome might be conjecturable via anti-VEGF drugs.

A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy.

Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.

A novel locus for dHMN with pyramidal features maps to chromosome 4q34.3-q35.2.

The distal hereditary motor neuropathy (dHMN) is a rare genetically and clinically heterogeneous disorder characterized by weakness and wasting of distal limb muscles in absence of overt sensory abnormalities. Recently, pyramidal signs have been also described in some patients with dominant or recessive dHMN, and two different loci have been identified in families affected by dHMN complicated with pyramidal dysfunction. We investigated an Italian family affected by an autosomal dominant dHMN complicated by pyramidal signs in order to map a new gene locus. The disease maps to a novel locus in a 26-cM region flanked by D4S1552 and D4S2930 on chromosome 4q34.3-35.2. Three candidate genes (SNX25, CASP3 and TUBB4Q) located in the critical region were screened for the presence of mutations by heteroduplex analysis. No mutations have been detected in the analyzed genes. In conclusion, the new private genetic locus we reported further confirms the wide heterogeneity of dHMN.

Antiproliferative activity against human tumor cell lines and toxicity test on Mediterranean dietary plants.

Sixteen edible plants from Southern Italy were evaluated for their in vitro antiproliferative properties, using the sulforodamine B (SRB) assay, on four human cancer cell lines: breast cancer MCF-7, prostate cancer LNCaP, amelanotic melanoma C32 and renal adenocarcinoma ACHN. After 48 h of incubation the most antiproliferative plant extract was Cynara cardunculus ssp. cardunculus on C32 and ACHN cell lines with IC(50) of 21 and 18 microg/ml, respectively. Mentha aquatica showed a selective antiproliferative activity on breast cancer while significant activity was exerted by Cichorium intybus on melanoma. These species contained the highest amount of phenolics. The acute toxicity of the hydroalcohol extracts from all the plants were evaluated by using the Microtox acute toxicity test. This bacterial test measures the decrease in light emission from the marine luminescent Vibrio fischeri bacteria when exposed to organic extracts. This inhibition test was revealed to be highly sensitive, cost effective and easy to operate, requiring just 15 min to predict the sample toxicity. All the extracts analyzed resulted to give values very less than a limit of 20% value, demonstrating so an irrelevant toxicity for the human health. In contrast, Echium vulgare and Malva sylvestris showed bioluminescence inhibition values of 19.42% and 17.32%, respectively, just under the established limit.