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BACKGROUND:There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. METHODS:Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. RESULTS:At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p

The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients.Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted.Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p

BackgroundTamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between alpha6beta4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance.Methods and findingsUsing human breast cancer cell lines displaying different levels of alpha6beta4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the alpha6beta4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival.ConclusionsWe provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERbeta1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen.

Background Patients with sepsis and immobility in the intensive care unit are associated with muscle weakness, and early mobilisation can counteract it. However, during septic shock, mobilisation is often delayed due to the severity of the illness. Neuromuscular electrical stimulation (NMES) may be an alternative to mobilise these patients early. This study aims to identify whether NMES performed within the first 72 hours of septic shock diagnosis or later is safe from a metabolic perspective. Methods This is the analysis of two randomised controlled crossover studies. Patients with acute septic shock (within the first 72 hours of diagnosis) and sepsis and septic shock in the late phase (after 72 hours of diagnosis) were eligible. Patients were submitted in a random order to the intervention protocol (dorsal decubitus position with the lower limbs raised and NMES) and control (dorsal decubitus position with the lower limbs raised without NMES). The patients were allocated in group 1 (intervention and control) or group 2 (control and intervention) with a wash-out period of 4 to 6 hours. Metabolic variables were evaluated by indirect calorimetry. Results Sixteen patients were analysed in the acute septic shock study and 21 in the late sepsis/septic shock study. There were no significant differences between Oxygen Consumption (VO2) values in the acute phase of septic shock when the baseline period, intervention, and control protocols were compared (186.59 ± 46.10; 183.64 ± 41.39; 188.97 ± 44.88, p>0.05- expressed in mL/Kg/min). The same was observed when the VO2 values in the late phase were compared (224.22 ± 53.09; 226.20 ± 49.64; 226.79 ± 58.25, p>0.05). The other metabolic variables followed the same pattern, with no significant differences between the protocols. When metabolic variables were compared between acute to late phase, significant differences were observed (pConclusions As metabolic rates in septic shock patients had no increase during NMES, either in the first 72 hours of diagnosis or later, NMES can be considered safe from a metabolic viewpoint, even despite the higher metabolic demand in the acute phase of shock. Trial registration NCT03193164; NCT03815994. Registered on June 5, 2017; November 13, 2018 (clinicaltrials.gov/).