Purpose: Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. Clinical data, however, have been conflicting. We have conducted a metaanalysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 in metastatic breast cancer. Experimental Design: Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the MantelHaenszel method. Results: Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results. Conclusions: HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.

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We have evaluated the activity and safety of gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with docetaxel as first-line treatment of women with metastatic breast cancer (MBC). In total, 41 patients with MBC were enrolled in a first-line combination therapy study with oral gefitinib (250 mg day À1 ) and intravenous docetaxel (75 mg m À2, the first 14 patients; or 100 mg m À2 , the following 27 patients, on day 1 of a 3-week cycle). Out of 41 patients, 38 received at least one cycle of therapy. There were no differences in activity or tolerability between the two docetaxel doses. G3/4 toxicities were neutropenia (49%), diarrhoea (10%), acne-like rash (5%), and anaemia (2%). Complete plus partial responses (CR þ PR) were observed in 22 out of 41 patients with a 54% response rate (95% confidence interval (CI) 45 -75%). The 22 patients that achieved a response following six cycles of docetaxel plus gefitinib continued gefitinib monotherapy (median duration, 24 weeks; range, 2 -108 þ weeks). Two patients with PR following combination therapy achieved a CR during gefitinib monotherapy. Complete plus partial responses correlated with oestrogen receptor (ER) status, since they occurred in 19 out of 27 (70%) patients with ER-positive tumours as compared to three out of 14 (21%) patients with ER-negative tumours (P ¼ 0.01).

Background and aims: No consensus exists on how aggressively to treat relapsing–remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC). Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups. Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5–11.7) years. Mean annual delta-EDSS values were all significantly ( p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01–0.19, p = 0.03) at 1 year to 0.30 (0.07–0.53, p = 0.009) at 5 years and to 0.67 (0.31–1.03, p = 0.0003) at 10 years. Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.

Targeted therapies are causing a dramatic change in cancer drug development. Trastuzumab, a humanized recombinant monoclonal antibody that recognizes the extracellular domain of HER2 trans-membrane protein, is among the first target-specific drugs that have been licensed for clinical use and its development represents a model of integration of new agents with classical treatment strategies. In preclinical models, trastuzumab has demonstrated a marked antiproliferative effect and a synergistic action with several chemotherapeutic agents. Monotherapy trials indicate that trastuzumab is active as a single agent in HER2 positive patients, is well tolerated, and is associated with preservation of quality of life (QoL). Furthermore, as first line therapy for metastatic breast cancer overexpressing HER2 receptor, the addition of trastuzumab to taxane-based chemotherapy significantly increased rate of objective response, time to disease progression and survival when compared with chemotherapy alone. Trastuzumab has shown important activity when used with many chemotherapeutic agents such as platinum salts, gemcitabine, vinorelbine and capecitabine and liposomal anthracyclines. Various trials are now ongoing to optimize the use of trastuzumab and to investigate its role in the adjuvant and in the neo-adjuvant setting.

This study was designed to evaluate the influence of occupational and non-occupational factors on urinary arsenic excretion in workers exposed to iAs (inorganic arsenic) in the dismantlement of a factory which once produced fertilisers. We measured iAs and its methylated metabolites in 108 urinary samples of workers exposed to iAs in July 2006. A total of 13.9% of the samples showed levels higher than the Biological Exposure Index (BEI) of 35 microg/l (mean value 23.9 microg/l). After the improvement of working conditions, in August-October 2006 we collected urinary samples from each of the 108 workers enrolled. We also administrated a questionnaire, in order to investigate the influence of occupational and non-occupational factors on the urinary arsenic excretion. A significant difference was observed in relation with seafood consumption and age stratification. We have found a significant reduction of urinary arsenic excretion between the two phases of biological monitoring, probably due to appropriate hygiene work-related interventions.

BACKGROUND AND PURPOSEThe 5-HT3 receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT3 receptor. EXPERIMENTAL APPROACH5-HT3 receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT3A receptor and also the mouse native 5-HT3 receptor that increases neuronal contraction of bladder smooth muscle. KEY RESULTSCl-indole (1-100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT3A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT3 receptor. Radioligand-binding studies identified that Cl-indole induced a small (∼twofold) increase in the apparent affinity of 5-HT for the h5-HT3A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT3 receptors. In contrast to its effect on the 5-HT3 receptor, Cl-indole did not alter human nicotinic α7 receptor responses. CONCLUSIONS AND IMPLICATIONSThe present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor. LINKED ARTICLESRecent reviews on allosteric modulation can be found at:

Background and aims Interferon beta (IFNβ) is a well‐established first‐line therapy for relapsing–remitting multiple sclerosis (RRMS) patients and remains the most widely prescribed agent. Atypical hemolytic uremic syndrome (aHUS) represents a rare but severe adverse effect (AE) that could occur even after many years from the beginning of IFNβ therapy. Eculizumab is currently approved for treatment of aHUS and recently for neuromyelitis optica spectrum disorder (NMOSD) with aquaporin‐4 antibodies (AQP4‐IgG). In this article, we report the case of the latest onset of IFNβ‐related aHUS experienced by an MS patient and we briefly review the literature on this topic. Methods We performed a systematic review of the literature using PubMed, and we performed a retrospective analysis of RRMS patients that received IFNβ‐1a in our center and developed thrombotic microangiopathy (TMA). From this search, we identified only one patient. Results In the published literature, we identified 24 MS patients who received IFNβ as disease‐modifying treatment (DMT) and then developed thrombotic microangiopathy with kidney injury. The aHUS has been diagnosed in 6, all received IFNβ‐1a and the latest onset was after 15 years. We report a case of a 39‐year‐old man affected by RRMS who assumed IFNβ‐1a since 1999. In July 2018, he developed an IFNβ‐related aHUS. After the failure of plasma exchange, he underwent eculizumab, with an improvement of glomerular filtration rate and without new signs of MS activity. Conclusion To our knowledge, this case represents the latest onset of IFNβ‐related aHUS in MS patients. Up to now, there are not literary reports about the possibility to reintroduce a DMT as add‐on therapy to eculizumab.