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Background: Venous thromboembolism is the second leading cause of death in cancer patients and its incidence seems underestimated. In addition, cancer patients have an increased risk of developing atrial fibrillation, which may be the first presentation of cancer itself. The primary aim of this study was to define the incidence of venous thromboembolism (VTE) and atrial fibrillation in a real-word series of advanced cancer patients., Methods: We performed a retrospective single-institution study on patients diagnosed with stage IV solid neoplasia at the outpatient clinic of the Medical Oncology Unit (Spedali Civili Brescia, Italy), from January to December 2018., Results: A total of 403 patients were enrolled, with a mean age at presentation of 63 years (range 18-85 years). A VTE was observed in 24% of cases, half of which occurred after diagnosis of metastatic neoplasia, with a median time of onset of 5.5 months (range 0-84). About 3% of patients developed atrial fibrillation after cancer diagnosis. In this patient series, no statistically significant differences were found when comparing Khorana and PROTECHT thromboembolic risk scores, both before and after the start of chemotherapy. Overall, about 25% of the patients received anticoagulant therapy; in most cases, the drug of choice was low-molecular-weight heparin (LMWH)., Conclusion: This study showed for cancer patients a considerably higher incidence of VTE and a comparable incidence of atrial fibrillation than reported in literature. Validated thromboembolic risk scores appear to be poorly predictive, and LMWH remains the most widely used anticoagulant drug., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

To study the capability of the CYP17A1 inhibitor abiraterone acetate (AER) to antagonize the androgen receptor (AR) activation in human prostate cancer (PCa) cell lines. T877A-AR-LNCaP, WT-AR-VCaP, AR-negative DU145, and PC3 PCa cell lines were used by MTT and cell count to study the ability of AER and enzalutamide (ENZ) to modify cell viability. The role of ARs in LNCaP was demonstrated through a gene-silencing experiment. The mechanism of AER cytotoxicity in LNCaP cells was studied, as well as the ability of AER to modulate AR gene expression. The in silico docking approach was applied to study the interaction of AER and ENZ with T877A-AR. Through high-performance liquid chromatography, the production of the AER main metabolite Δ4A was studied. AER bound AR in an almost identical manner to that of dihydrotestosterone (DHT). The higher binding energy for AER in T877A-AR could explain the major cytotoxic effect observed in LNCaP cells. The capability of LNCaP cells to synthesize Δ4A could mediate, at least in part, this effect. AER cytotoxicity in LNCaP cells was mainly due to the activation of apoptosis. Further, AER induced modification of AR target gene expression, suggesting a direct effect on AR activity. AER-induced cytotoxicity on PCa cell lines seemed to be mediated by binding with AR. The higher affinity of AER for T877A-AR may suggest a potential role of AER in the management of CRPC carrying this mutation; however, T877A-AR expressing CRPC patients developed AER resistance, probably due to the increase of progesterone.

The onset of a new histology is a resistant mechanism to tyrosine kinase inhibitors (TKI) in lung adenocarcinoma (ADK), but this phenomenon has not yet been fully clarified. We present a pooled analysis of the outcomes of EGFR-mutated ADK patients with changed phenotype to squamous cell carcinoma (SqCC) following TKI, along with the description of an additional case. A 67-year-old woman with EGFR-mutated NSCLC received gefitinib and subsequently osimertinib, due to the presence of T790 M at progression. The re-biopsy after third-generation TKI revealed SqCC histology along with the basal EGFR mutation, while T790 M disappeared. The patient rapidly progressed and died despite two chemotherapy cycles. Since this first description of SqCC transformation appearing after treatment with the third-generation TKI osimertinib, other 16 patients, with EGFR-mutated ADK developing a transformation to SqCC histology after treatment with TKIs, were up to now published. From our pooled analysis emerged that most patients were female (82%), 41% were former smokers and no current smokers were identified. Median time to SqCC onset was 11.5 months. In all cases, basal EGFR mutation was maintained, and 11 patients (65%) developed an acquired mutation on exon 20. Interestingly also 790 M mutation appeared in 8 patients (47%). The median survival after SqCC diagnosis was 3.5 months regardless the treatments received. Therefore, EGFR-mutated lung ADK destined to develop a squamous phenotype were often smokers and maintained the baseline genomic alterations. The prognosis after SqCC diagnosis was extremely poor and current treatments largely inefficacious., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To assess the predictive and prognostic value of pre-treatment CT texture features in lung adenocarcinoma treated with tyrosine kinase inhibitors (TKI)., Materials and Methods: Texture analysis was performed using commercially available software (TexRAD Ltd, Cambridge, UK) on pre-treatment contrast-enhanced CT studies from 50 patients with metastatic lung adenocarcinoma treated by TKI. Texture features were quantified on a 5-mm-thick central slice of the primary tumor and were correlated with progression-free and overall survival (PFS and OS) using an internally cross-validated machine learning approach then validated on a bootstrapped sample., Results: Median PFS and OS were 10.5 and 20.7 months, respectively. A noninvasive signature based on five texture parameters predicted 6-month progression with Area Under the Curve (AUC) of 0.8 (95% CI) and 1-year progression with AUC of 0.76. A high-risk group had hazard ratios for progression of 4.63 and 5.78 when divided by median and best cut-off points, respectively. Texture signature did not correlate with OS. Available clinical variables did not correlate with PFS or with OS., Conclusion: Texture features seem to be associated with PFS in lung adenocarcinoma treated with TKI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to investigate efficacy and safety of eribulin in heavily pretreated patients with advanced breast cancer (BC) in a real-life setting., Methods: This retrospective monocentric study included patients with HER-2-negative metastatic BC, pretreated with anthracyclines and taxanes, who were referred to the Oncology Department of Spedali Civili of Brescia from May 2012 to April 2017. Patients received the same dose of eribulin as that used in the EMBRACE trial: 1.4 mg/m2 on days 1 and 8 every 21 days., Results: In a total of 53 patients, 32% obtained a partial response, 11% a stable disease, and 43% a clinical benefit (CB). After a median follow-up of 36 months, median progression-free survival (PFS) was 4.7 months and median overall survival (OS) 13.53 months. Median PFS was significantly longer in patients who reported a CB compared to those with no CB, while survival outcomes (PFS and OS) were better in patients who received > 6 cycles of eribulin. Eribulin showed a good tolerability profile with acceptable toxicities, similar to those reported in EMBRACE., Conclusions: Our experience in a real-world setting confirms the activity, efficacy, and good tolerability profile of eribulin in heavily pretreated BC patients., (© 2018 S. Karger AG, Basel.)

Background: The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES)., Methods: The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated., Results: Amiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability., Conclusions: The combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro., (© 2017 S. Karger AG, Basel.)

Introduction: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. (18)F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients., Patients & Methods: After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS)., Results: EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05)., Conclusion: The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival.

Tallimustine is a novel benzoyl mustard derivative from distamycin A with a unique mode of action. It is a DNA minor groove binder and produces highly sequence-specific alkylations. Previous studies have shown significant anti-tumour effects in animal models. We performed a phase II study in previously untreated patients with advanced colorectal cancer, using a schedule of i.v. bolus infusions of 900 microgram m-2 once every 4 weeks. Seventeen patients were enrolled, and no responses were documented in 14 evaluable patients. Toxicity mainly consisted a highly selective neutropenia, which warrants further investigation of this agent in combination with myeloid growth factors.

One hundred and two patients with advanced solid tumors receiving chemotherapy were treated with metoclopramide (MCP; 100 mg) to prevent emesis. Twenty-six of 102 patients who had more than five episodes of vomiting were considered MCP-resistant and were randomized to receive MCP (100 mg) plus placebo versus MCP plus dexamethasone (DM; 48 mg) iv in a double-blind, crossover trial. The median number of vomiting episodes was 18 after MCP plus placebo and five after MCP plus DM (P less than 0.001). The median duration of vomiting episodes was 40 hours after MCP plus placebo and 10 hours after MCP plus DM. Immediate toxicity of the antiemetics was not enhanced by the addition of DM to MCP.