Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.     

Theory of mind,mental state talk and social relationships in aging: The case of friendship

Objectives: Previous research has shown a decline in Theory of mind (ToM) associated with normal aging. However, very few studies have investigated older people’s ToM using an ecological approach. The present study was designed to fill this gap and examine older people’s frequency of mental state talk (MST) in describing their best friend, together with their performance on a traditional ToM task. In addition, the study examined the association between these two ToM indices and relationships with friends and family members.

Method: Seventy-two healthy older adults (age range 60–79) participated in the study. We measured ToM ability with a classic measure, the Faux Pas task, and selected the Describe-a-friend task to measure MST frequency; social relationships were investigated with the Lubben Social Network Scale. Correlation and regression analyses were performed.

Results: No significant association between MST and scores on the Faux Pas task emerged. In addition, MST (but not Faux Pas scores) significantly predicted friendships (but not family relationships) over and above general cognitive functioning.

Conclusion: These findings show the crucial distinction between possessing an ability and using it in daily life and suggest the need to move toward more ecological measures of older adults’ abilities. In addition, the present results indicate that the spontaneous use of ToM ability, not the ability per se, impacts on older adults’ social relationships.     

Measuring female intrasexual competition by the scale for intrasexual competition: a validation of the German version

Competitive behaviour amongst members of the same sex is termed intrasexual competition. The tendency to engage in such competition appears to be strongly related to stable individual characteristics such as personality traits. Additionally, recent studies have revealed transient fluctuations in competitiveness according to the female menstrual cycle. To date, no German questionnaire exists to measure intrasexual competition. Our first study aimed to translate and validate the Intrasexual Competition Scale (ICS) by Buunk and Fisher (J Evol Psychol 7:37–48, 2009) in a population of healthy Swiss females (n = 241). Our second study applied the validated German ICS in a group of healthy, regularly cycling females (n = 49) in order to examine possible associations between the menstrual cycle phase and ICS scores. The psychometric properties suggest that the German ICS is a reliable and valid tool to assess individual differences in female intrasexual competition. Furthermore, our second study demonstrated that on average, women showed higher intrasexual competition scores when tested in the late follicular phase (M = 35.77 ± SD = 12.03) compared to the mid-luteal phase (M = 30.93 ± SD = 10.20). Our studies support previous findings of an association between ICS scores and relatively stable individual characteristics such as personality traits. Furthermore, our research endorses the assumption of cycle-dependent fluctuations in intrasexual competition. Future research should clarify the precise mechanisms underlying these findings and include biomarkers such as oestrogen and testosterone.

     

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.     

Current pharmacological treatment of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies are uncommon and heterogeneous disorders. Their classification is based on distinct clinicopathologic features. Although idiopathic inflammatory myopathies share some similarities, different subtypes may have variable responses to therapy, so it is very important to distinguish the correct subtype.

There are few randomised, double blind placebo controlled studies to support the current treatment. High dose corticosteroids continue to be the first-line therapy and other immunosupressive drugs are used in refractory cases, as well as steroid-sparing agents.

Some novel therapeutic approaches have emerged as potential treatment including tacrolimus, intravenous immunoglobulin and rituximab, following good outcomes reported in case studies. However, more randomised controlled trials are needed.

This review considers the current and the potential future therapies for inflammatory myopathies.     

Notch signaling deregulation in multiple myeloma: A rational molecular target

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.