Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition.

We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity. Representing a new scaffold that is not yet found in nature, the construction of pyrrolidine-fused cyclohepta-, azepino-, or oxepinoindoles could be found valuable in the synthesis of new pseudo-natural products.

High Incidence of Thyroid Cancer in Southern Tuscany (Grosseto Province, Italy): Potential Role of Environmental Heavy Metal Pollution.

The incidence of thyroid cancer (TC) in Italy is one of the highest in Europe, and the reason for this is unclear. The intra-country heterogeneity of TC incidence suggests the possibility of an overdiagnosis phenomenon, although environmental factors cannot be excluded. The aim of our study is to evaluate the TC incidence trend in southern Tuscany, Italy, an area with particular geological characteristics, where the pollution and subsequent deterioration of various environmental matrices with potentially toxic elements (heavy metals) introduced from either geological or anthropogenic (human activities) sources are documented. The Tuscany cancer registry (ISPRO) provided us with the number of cases and EU standardized incidence rates (IR) of TC patients for all three provinces of southeast Tuscany (Siena, Grosseto, Arezzo) during the period of 2013-2016. In addition, we examined the histological records of 226 TC patients. We observed that the TC incidence rates for both sexes observed in Grosseto Province were significantly higher than those observed in the other two provinces. The increase was mostly due to the papillary (PTC) histotype (92% of cases), which presented aggressive variants in 37% of PTCs and tumor diameters more than 1 cm in 71.3% of cases. We demonstrated a high incidence of TC in Grosseto province, especially among male patients, that could be influenced by the presence of environmental heavy metal pollution.

Pd-Catalyzed Ring-Opening/Arylation/Cyclization of 2-Aminothiazole Derivatives Provides Modular Access to Isocytosine Analogues.

We report a Pd-catalyzed ring-opening/arylation/cyclization reaction sequence between 2-aminothiazoles and aryl (pseudo)halides that provides modular access to isocytosine analogues. The scope of the reaction is broad with respect to both coupling partners and a robustness test demonstrated the functional group tolerance of the methodology. Visual kinetic analysis revealed that the product may inhibit catalyst turnover for some substrates.

Dearomative Ring Expansion of Polycyclic Arenes.

Benzocycloheptenes constitute a common structural motif embedded in many natural products and biologically active compounds. Herein, we report their concise preparation from non-activated polycyclic arenes using a two-step sequence involving dearomative [4+2]-cycloaddition with arenophile in combination with palladium-catalyzed cyclopropanation, followed by cycloreversion-initiated ring expansion. The described strategy provides a working alternative to the Buchner reaction, which is limited to monocyclic arenes. Overall, this methylene-insertion molecular editing approach enables rapid and direct conversion of simple (hetero)arenes into a range of substituted (aza)benzocycloheptatrienes, which can undergo a myriad of downstream functionalizations.

Psychological impact of Covid-19 pandemic on oncological patients: A survey in Northern Italy.

The psychological impact of the Covid 19 pandemic on cancer patients, a population at higher risk of fatal consequences if infected, has been only rarely evaluated. This study was conducted at the Departments of Oncology of four hospitals located in the Verona area in Italy to investigate the psychological consequences of the pandemic on cancer patients under active anticancer treatments. A 13-item ad hoc questionnaire to evaluate the psychological status of patients before and during the pandemic was administered to 474 consecutive subjects in the time frame between April 27th and June 7th 2020. Among the 13 questions, 7 were considered appropriate to elaborate an Emotional Vulnerability Index (EVI) that allows to separate the population in two groups (low versus high emotional vulnerability) according to observed median values. During the emergency period, the feeling of high vulnerability was found in 246 patients (53%) and was significantly associated with the following clinical variables: female gender, being under chemotherapy treatment, age ≤ 65 years. Compared to the pre-pandemic phase, the feeling of vulnerability was increased in 41 patients (9%), remained stably high in 196 (42%) and, surprisingly, was reduced in 10 patients (2%). Overall, in a population characterized by an high level of emotional vulnerability the pandemic had a marginal impact and only a small proportion of patients reported an increase of their emotional vulnerability.

Management of advanced pancreatic cancer in daily clinical practice.

PURPOSE: The aim of this outcome study was to evaluate the management of advanced pancreatic cancer in a real-world clinical practice; few such experiences have been reported in the literature. METHODS: A retrospective analysis was performed of all consecutive patients with advanced pancreatic ductal adenocarcinoma followed at our medical oncology unit between January 2003 and December 2013. RESULTS: We evaluated 78 patients, mostly with metastatic disease (64.1%). Median follow-up was 10.77 months, by which time 74 patients (94.9%) had died. Median overall survival was 8.29 months. Median age was 67 years. In univariate analysis, pain at onset (p = 0.020), ECOG performance status (p<0.001), stage (p = 0.047), first-line chemotherapy (p<0.001), second-line chemotherapy (p<0.001) and weight loss at diagnosis (p = 0.029) were factors that had an impact on overall survival. In multivariate analysis, the presence of pain at onset (p = 0.043), stage (p = 0.003) and second-line chemotherapy (p = 0.004) were confirmed as independent prognostic factors. CONCLUSIONS: Our data, derived from daily clinical practice, confirmed advanced pancreatic cancer as an aggressive malignant disease with a very short expected survival. Second-line treatment seems to provide an advantage in terms of overall survival in patients who showed a partial response as their best response to first-line treatment.

Ampulla of Vater carcinoma in real-world clinical practice: a case series.

AIMS AND BACKGROUND: The aim of this report was to describe the way in which a rare and niche disease like ampulla of Vater carcinoma (AVC) was treated in real-world clinical practice. METHODS AND STUDY DESIGN: A retrospective analysis of consecutive patients with a diagnosis of AVC treated at our medical oncology unit between August 2004 and August 2013 was performed. RESULTS: We evaluated 8 consecutive patients with a median age of 60 years (range 56-84). At the last follow-up, 4 patients were alive without evidence of disease and 4 patients had died. The median follow-up time was 21.51 months (range 1-100.43), the median overall survival 23.19 months (range 7.07-102.2), and the median disease-free survival 18.26 months (range 0-102.2). Six patients underwent surgery, which consisted of pylorus-preserving pancreaticoduodenectomy, R0 in all cases. Tumor histology was adenocarcinoma in all patients. Two patients presented with locally advanced disease. Only 1 patient presented with metastases while 3 patients subsequently developed metastases. Two patients received chemotherapy for metastatic disease; in both cases disease progression was observed at the first disease evaluation. CONCLUSIONS: We can consider AVC as a pathology niche and pancreaticoduodenectomy as the effective treatment for these patients.

The pharmacological costs of complete liver resections in unselected advanced colorectal cancer patients: a review of published Phase II and III trials.

The pharmacological costs of regimens used as front-line therapy in advanced colorectal cancer patients and their impact on the liver resection rates have not been considered. In this paper, we made a review of published randomized Phase II and III trials that reported the liver resection rates following upfront chemotherapy and linked this outcome to the pharmacological costs of drugs used. The costs are calculated based on the price at Pharmacy of our Hospital in Legnago (Italy), and as a measure of activity, we used the number of patients needed to treat to get one complete liver resection. Number needed to treat is highly variable among the different trials according to patient's characteristics, tumor biology and the efficacy of chemotherapy administered. The range of activity is greatly amplified when the costs are compared.

Carboplatin-containing regimens as front-line treatment for advanced non-small-cell lung cancer in two groups of elderly.

OBJECTIVES: We evaluated the impact of a carboplatin-based doublet in two groups of elderly patients with advanced non-small cell lung cancers (NSCLC). MATERIALS AND METHODS: A retrospective analysis of all consecutive elderly patients (≧70 year old) with advanced NSCLC who received a carboplatin-based doublet as front-line therapy at our medical oncology unit was performed. RESULTS: In the study, 57 consecutive elderly patients with advanced NSCLC were included. Carboplatin was combined with vinorelbine in 41 patients (71·9%) and with gemcitabine in 16 patients (28·1%). Overall, a total of 227 cycles were administered to 57 patients - 142 cycles were administered to patients in group 1 and 85 cycles were given to patients in group 2 - median number of administered cycles per patient was 4 (range 1-6). Of the patients, 35 (62%, group 1) were 'young-old' (70-74-year old) and 20 (38%, group 2) were 'old-old' (75-82-year old). Toxicity was mild in both subgroups (grade 3-4 neutropenia in 17·1% of group 1 and in 9·1% of group 2). At the univariate analysis, the median overall survival (OS) was 10·07 months (P = 0·789, 95% CI: 8·49-11·64), 10·1 months in group 1 and 9·8 months in group 2. CONCLUSIONS: This evaluation shows the safety and efficacy of a carboplatin-based doublet given as first-line chemotherapy in elderly advanced NSCLC patients. The combination with vinorelbine or gemcitabine is associated with a very good toxicity profile that does not seem to have a detrimental effect on efficacy.

The chromatin remodelling component SMARCB1/INI1 influences the metastatic behavior of colorectal cancer through a gene signature mapping to chromosome 22.

BACKGROUND: INI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known. METHODS: We examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines. RESULTS: Herein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients' survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1. CONCLUSION: Our findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.

Platinum doublets as first-line treatment for elderly patients with advanced non-small cell lung cancer.

AIMS AND BACKGROUND: More than 50% of patients with advanced non-small cell lung cancer are diagnosed in the elderly. Few prospective clinical data with cisplatin-based chemotherapy are available, and some authors have suggested that a non-platinum single agent should be the preferred form of cure in these patients. The aim of the study was to evaluate the efficacy and safety of first-line chemotherapy based on platinums (carboplatin or cisplatin) plus a third generation compound (vinorelbine or gemcitabine) in elderly patients with advanced non-small cell lung cancer in daily clinical practice. METHODS: A retrospective analysis of consecutive elderly (≥70 years of age) patients with advanced non-small cell lung cancer treated at our Medical Oncology Unit from February 2005 to September 2011 was performed. RESULTS: A total of 249 cycles of chemotherapy was administered to 62 patients (median age, 72 years; range, 70-81) presenting a median Charlson comorbidity index of 1 and a good ECOG PS (0-1, 52 patients; 2, 10 patients). The median number of cycles/patient was 4, and all 62 patients received a platinum-based doublet as first-line chemotherapy: 57 with carboplatin (92%) and 5 with cisplatin (8%). As best response to the treatment, 19 (31%) partial responses and 20 (32%) stable diseases were observed. Median overall survival was 9.8 months. Toxicity was mild; grade III-IV neutropenia was the most frequently observed side effect in 19 administered cycles (8%). CONCLUSIONS: Advanced non-small cell lung cancer in elderly patients can be safely treated with a platinum-based doublet. Observed toxicity is manageable, and overall survival is in keeping with data from the literature.

Weekly Taxotere and cisplatin with continuous-infusion 5-fluoruracil for the treatment of advanced gastric and esophageal cancer: a prospective, observational, single-institution experience.

The combination of Taxotere (docetaxel), cisplatin, and prolonged-infusion 5-fluorouracil (5-FU) has emerged as an active treatment for advanced gastric cancer. However, the regimen proposed by van Cutsem et al. (J Clin Oncol 24:4991-7, 2006) is associated with significant toxicity and therefore alternative schedules are needed. In the present study, patients with advanced gastric or esophageal cancer received Taxotere 35 mg/m(2) and cisplatin 25 mg/m(2) on day 1, followed by 5-FU 180 mg/m(2)/day as a 7-day prolonged infusion. Drugs were given weekly for 3 consecutive weeks followed by 1 week's rest. Cycles were repeated every 4 weeks. Overall, a total of 110 cycles were administered to 27 patients (median age 63 years, range 40-78 years). The median number of cycles per patient was 4 (range 2-6). Nine partial responses were obtained, resulting in an overall response rate of 33% [95% confidence interval (CI) 16-51], a median time to progression of 6.4 months (95% CI 5.4-7.4), and a median overall survival of 10.7 months (95% CI 6.6-14.8). Toxicity was mild; grade III-IV neutropenia was the most frequently observed side effect, in 9 administered cycles (8%); neutropenia was complicated by fever in 2 cycles. Other grade III-IV toxicities observed in >5% of patients were anemia and mucositis.

Rhabdoid carcinoma of the colon: a distinct entity with a very aggressive behavior: a case report associated with a polyposis coli and review of the literature.

Rhabdoid colon tumors (RCTs) are rare lesions whose existence as an independent distinct entity remains controversial. To date, 6 RCTs have been reported. This study reports a novel case associated with polyposis coli in a 73-year-old woman. Histologically, the neoplasia was heterogeneous consisting of an adenocarcinoma associated with rhabdoid features. In rhabdoid component, an intense expression of MSH2 was noted but MLH1 was negative. A BRAF V600E mutation and no KRAS mutations were identified. The promoter regions of subset of genes highly specific to characterize the CIMP status (NEUROG1, IGF2, RUNX3, SOCS1, including MLH1) were hypermethylated, suggesting the presence of CIMP+ and MSI high tumor. In conclusion, all RCTs have similar clinical features. The presence of polyposis and adenocarcinoma component as well as the expression of mesenchymal marker suggests a sarcomatous dedifferentiation. It is argued that RCT could be a very aggressive entity of colon, which could benefit from new biological colonic treatments.

Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin A and gemcitabine.

We investigated the ability of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to interact with gemcitabine (GEM) in inducing pancreatic cancer cell death. The combined treatment with TSA and GEM synergistically inhibited growth of four pancreatic adenocarcinoma cell lines and induced apoptosis. This effect was associated with the induction of reactive oxygen species (ROS) by GEM, increased expression of the pro-apoptotic BIM gene by both TSA and GEM and downregulation of the 5'-nucleotidase UMPH type II gene by TSA. The expression of other genes critical for GEM resistance (nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ribonucleotide reductase genes) was not affected by TSA. The functional role of ROS in cell growth inhibition by GEM was supported by (i) a significantly reduced GEM-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine, and (ii) a positive correlation between the basal level of ROS and sensitivity to GEM in 10 pancreatic cancer cell lines. The functional role of both Bim and 5'-nucleotidase UMPH type II in cell growth inhibition by TSA and GEM was assessed by RNA interference assays. In vivo studies on xenografts of pancreatic adenocarcinoma cells in nude mice showed that the association of TSA and GEM reduced to 50% the tumour mass and did not cause any apparent form of toxicity, while treatments with TSA or GEM alone were ineffective. In conclusion, the present study demonstrates a potent anti-tumour activity of TSA/GEM combination against pancreatic cancer cells in vitro and in vivo, strongly supporting the use of GEM in combination with an HDAC inhibitor for pancreatic cancer therapy.

Increased stability of P21(WAF1/CIP1) mRNA is required for ROS/ERK-dependent pancreatic adenocarcinoma cell growth inhibition by pyrrolidine dithiocarbamate.

We present evidence that pyrrolidine dithiocarbamate (PDTC) inhibits growth of p53-negative pancreatic adenocarcinoma cell lines via cell cycle arrest in the S-phase, while it has no effect on primary fibroblast proliferation. Growth inhibition of cancer cells is dependent on ROS and ERK1/2 induction as indicated by a significantly reduced PDTC-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine (NAC) or the MEK/ERK1/2 inhibitor (PD98059). Moreover, ERK1/2 induction is dependent on ROS production as demonstrated by a complete removal of PDTC-mediated ERK1/2 phosphorylation by NAC. p21(WAF1/CIP1) activation has a central role in growth inhibition by PDTC, as revealed by P21(WAF1/CIP1) silencing experiments with antisense oligonucleotide, and occurs via increased mRNA stability largely mediated by ROS/ERK induction. Conversely, PDTC does not affect P21(WAF1/CIP1) gene expression in primary fibroblasts, although it is able to activate p53 and the p53-regulated antioxidant SESN2. These results suggest that the resistance of fibroblasts to the cytotoxic action of PDTC may be related to the up-regulation of p53-dependent antioxidant genes. Finally, in vivo studies on PaCa44 cells subcutaneously xenografted in nude mice show that treatment with 100 or 200 mg/kg PDTC reduces of 30% or 60% the tumour volume, respectively, and does not cause any apparent form of toxicity.

Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation.

Pancreatic cancer is an aggressive neoplasia, and standard chemotherapies are by and large ineffective. The purpose of this work was to get a comprehensive preclinical study on the ability of anticancer drug combinations that best inhibit growth of pancreatic adenocarcinoma cells. We evaluated the in vitro growth inhibition of ten pancreatic cancer cell lines to gemcitabine and 5-fluorouracil, newer generation cytotoxic agents (oxaliplatin, irinotecan), targeted therapy (gefitinib) and a histone deacetylase (HDAC) inhibitor (trichostatin A). Cells were treated with the single drug alone and all pairwise drug association. Our results demonstrate that TSA can effectively increase the drug sensitivity of all the cell lines studied. The association of TSA and irinotecan determines an increase in growth inhibition on the highest percentage of cell lines (80%). Our findings may represent an experimental basis for potential clinical application of HDAC inhibitors, in particular in association with drugs used in cancer clinical treatment, supporting the idea that HDAC inhibitors could act as sensitizers for chemotherapy.