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ABSTRACTIntroductionDespite recent advances in the molecular characterization of triple-negative breast cancer (TNBC), the standard treatment for early-stage TNBC is represented by the historically used anthracycline and taxane-based chemotherapy. In this modern era of precision medicine, several new therapeutic strategies and novel agents have been investigated in the neoadjuvant setting of TNBC, in order to individualize treatment.Areas coveredThis review provides a comprehensive overview of the currently available evidence regarding the activity and efficacy of platinum agents, PARP- and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, highlighting the available data on potential predictive biomarkers of response or resistance to such treatments.Expert opinionThe genomic and immune landscape of TNBC has encouraged the exploration of drugs that interfere with the DNA repair mechanism and that modulate immune response. Overall, these drugs seem to improve the pCR rate in TNBC, despite preliminary and heterogeneous results. Taking into account the economic issues and the side effects of these drugs, it is crucial to further explore the potential predictive role of BRCA mutational status and homologous recombination deficiency score, for platinum agents and PARP-inhibitors, and tumor infiltrating lymphocytes and other immune biomarkers for checkpoint inhibitors, respectively.

ABSTRACTIntroduction:The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3rdgeneration ALK-inhibitors Lorlatinib (PF-06463922), Entrectinib (RxDx-101) and Ensartinib (X-398) provided promising advantages in terms of both clinical activity and safety.Areas covered:In this review, the efficacy and tolerability of Crizotinib for 1stand 2nd-line treatment, and the clinical and preclinical data that led to the development of innovative second and third generation ALK-inhibitors are described.Expert opinion:The better characterization of the mechanisms of resistance to Crizotinib led to the development of newest drugs, which are active both after Crizotinib failure and in patients naïve from ALK-inhibitors. Tumor characterization at disease progression will allow to further personalize the treatment by establishing optimal sequences, which represent tough challenges for the future research in this field of cancer treatment.

ABSTRACTIntroduction: Although the advent of target therapy for lung cancer has brought about outstanding results, this benefit is confined to a subgroup of molecularly selected patients, whereas for most non-small cell lung cancer (NSCLC) patients, chemotherapy still represents the milestone of treatment. Since their introduction into clinics, microtubule targeting agents (MTA), including vinca alkaloids and taxanes, have been extensively used for NSCLC in different settings and combinations.Areas Covered: In this review, MTA are classified according to their mechanism of action, with a focus on the most common mechanisms of resistance. Moreover, an overview of the most remarkable clinical data regarding MTA in adjuvant, neoadjuvant and advanced setting is provided. Finally, the novel mitotic kinases inhibitors are described according to their different mechanism of action and clinical activity compared to MTA.Expert Opinion: Unfortunately, the awaited benefit deriving from the actually available chemotherapeutic regimens for advanced NSCLC has reached a plateau. In this scenario, the identification of reliable predictive biomarkers represents a major challenge. Moreover, different schedules for MTA administration are currently under investigation, such as the combination of MTA with other drugs able to bypass the resistance derived from the ‘mitotic slippage’and the use of metronomic administration of spindle poisons with anti-angiogenic or immunomodulatory agents.

Introduction:In the recent years, the growing attention to the molecular background of non-small-cell lung cancer (NSCLC) led to the identification of different molecular subtypes according to genetic abnormalities driving the disease development and progression. Whereas the addicted pathways were successfully inhibited (such as the mutant epidermal growth factor receptor), clinicians have witnessed a dramatic survival improvement. In this regard, the molecular portrait of adenocarcinoma was recently enriched by the identification of a specific patients' subgroup characterized by abnormalities in the anaplastic lymphoma kinase (ALK), with unclear prognostic features but impressive response to specific inhibitors.Areas covered:In this article, updated data derived from the development and the use of crizotinib (the most advanced in development among tyrosine kinase ALK inhibitors) in comparison with standard second-line chemotherapy for patients affected by ALK-altered NSCLC are reviewed.Expert opinion:Taking into account the available data, pretreated NSCLC patients carrying the ALK-translocation require a selected targeted therapy which significantly improves activity, efficacy and symptoms control versus chemotherapy. In this context, the identification of this disease entity and the availability of such impressive therapeutic targeting represent a further step toward the understanding of the molecular complexity behind the adenocarcinoma of the lung.

Objective: Several lines of research suggested that aripiprazole might be a useful treatment for acute bipolar depression. The aim of this open-label trial is to give more evidence of the clinical effectiveness and tolerability of aripiprazole in acute bipolar depression. Research design and methods: Aripiprazole response was prospectively assessed for 16 weeks using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Severity Scale (CGI-S), and the Young Mania Rating Scale in 85 bipolar patients with acute depression inadequately responsive to one mood stabilizer. Main outcome measures: Aripiprazole was well tolerated. Only three (3.5%) patients discontinued the study for side effects. The most common side effect was akathisia, occurring in 17/80 (21.2%) patients. Patients showed statistically insignificant weight gain (0.9 ± 2.64 kg) over the 16-week trial. Results: Patients showed a significant decrease in mean MADRS and CGI-S, and 80 (94.1%) patients completed the 16-week trial. Thirty-nine (45.8%) patients received aripiprazole as monotherapy and 46 received the drug adjunctively (54.1%). Fifty-two (65%) patients met criteria for response (≥ 50% reduction in MADRS total score), 30 (37.5%) patients met criteria for remission (final MADRS total score ≤ 12). Conclusions: Aripiprazole was associated with beneficial effects on mood in patients with bipolar depression, and appears well tolerated with very small changes in mean body weight. These results highlight the potential benefits of aripiprazole for bipolar disorder patients. However, double-blind, placebo-controlled studies are necessary to confirm aripiprazole's efficacy, tolerability and safety in bipolar depression.

Objective: Premenstrual dysphoric disorder (PMDD) is a complex clinical syndrome that is notoriously difficult to treat. The purpose of the present study was to provide preliminary data on the effectiveness of duloxetine in PMDD. Research design and methods: Fifty-five women with PMDD were treated with a 60 mg/day dosage of duloxetine for two menstrual cycles. Responses were assessed at first and second treatment cycle. Main outcome measures: Outcome measures included a visual analogue scale, the Zung Self-rating Scale for Depression, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale and the Clinical Global Impressions Scale. Results: Fifty patients completed the trial. All had significant improvement of depression and anxiety and response, defined as a 50% decrease in daily symptom scores, occurred in 39 (78%) patients. The effects of active treatment were marked by the first active cycle of menstruation. Conclusions: Duloxetine 60 mg/day was effective in reducing PMDD symptoms and generally well tolerated. Limitations of the study were open-label design and lack of placebo control. However, the results appeared to be strong and consistent across measures. Adverse events (nausea, insomnia, poor appetite) were low. Further studies are needed to confirm these results.

Oxcarbazepine (OXC) is a keto-congener of carbamazepine, which has fewer side effects and drug interactions. However, the efficacy of OXC in treating bipolar disorder is not as well established as that of carbamazepine. This article is a systematic literature review of all studies regarding OXC and bipolar disorders, with particular attention to papers published in the last 6 years. Using the terms ‘oxcarbazepine and bipolar disorder, ‘oxcarbazepine and mania or ‘oxcarbazepine and bipolar depression, a computer-aided search of MEDLINE for the years 2000 – 2006 has been conducted. Since its introduction as an antiepileptic drug in early 2000, clinical research regarding the potential role of OXC in the treatment of bipolar disorder remains limited. There is a lack of double-blind, placebo-controlled studies. Studies recently published have small samples of patients, with insufficient follow-up periods and other methodological weaknesses. The efficacy of OXC in bipolar disorder has not been widely studied. Some authors recommend using OXC as monotherapy or as add-on therapy in refractory mania, although results are not conclusive. It is unknown whether OXC has efficacy in the maintenance treatment of bipolar disorder. OXC can be particularly useful as an add-on treatment in bipolar disorder patients for whom previous treatments have failed, or in patients who have difficulty tolerating adequate dosages of standard approved treatments.