A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer.

INTRODUCTION: MEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690). METHODS: A standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype. RESULTS: Thirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months-NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1-mutated patients, the ORR was 42.8%. CONCLUSION: The addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.

Vascular endothelial growth factor activity after switching of bisphosphonate treatment for metastatic breast cancer.

BACKGROUND: Recent data have shown a fall in vascular endothelial growth factor (VEGF) concentrations after bisphosphonate (BP) treatment in BP-naïve patients. It has therefore been proposed that BPs may have in vivo anti-VEGF effects. AIMS: To explore whether VEGF concentrations change after administration of a more potent BP in patients receiving long-term BP treatment. METHODS: 31 patients with breast cancer who had progressive metastatic bone disease despite treatment with early-generation BPs were switched to zoledronic acid. Serum VEGF concentrations were measured at baseline, and weeks 1, 2, 3, 4, 8 and 12. RESULTS: VEGF concentration per platelet count did not change significantly at any time during the 12 weeks after treatment with zoledronic acid. CONCLUSIONS: Switching to zoledronic acid did not suppress circulating serum VEGF concentrations in BP-pretreated patients. Novel approaches to assess the effect of BPs on the bone milieu may provide further insight into the possible antiangiogenic properties of BPs.

Predictors of mortality in patients undergoing autologous hematopoietic cell transplantation admitted to the intensive care unit.

Between January 2001 and July 2006, 1013 patients received autologous hematopoietic cell transplants (AHCT) at Canada's largest transplant center. In this retrospective cohort study of AHCT patients admitted to the intensive care unit (ICU), we describe the outcomes following ICU admission and the variables measured in the first 24 h of ICU admission associated with overall ICU mortality. Results indicate a 3.3% ICU admission rate (n=34) with 13 deaths (1% overall mortality rate, 38% in ICU mortality rate). The worst outcome was in AL amyloid patients of whom 28% were admitted to the ICU, with an ICU mortality rate of 55%. The Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score in the first 24 h were statistically associated with mortality by univariate analysis. Other variables measured at 24 h and associated with ICU mortality included multiorgan failure, mechanical ventilation, inotropic support >4 h and Gram-negative sepsis. Our data indicate that ICU admission in the autotransplant population is rare and that it is influenced by underlying diagnosis, with AL amyloid patients having the highest risk. Our observations may assist clinical decision-making regarding the continuation of intensive care delivered 24 h after ICU admission.

Drug-induced immune thrombocytopenic purpura secondary to sunitinib.

SUNITINIB (SUTENT: Pfizer, New York, NY, U.S.A.) is an oral multi-targeted tyrosine kinase inhibitor approved for use in various solid tumour malignancies. Many side effects secondary to sunitinib have been documented. In particular, sunitinib administration is known to result in thrombocytopenia, with the cause being attributed to myelosuppression. Here, we present the first case report to demonstrate immune-mediated thrombocytopenia secondary to sunitinib administration.

A primer of bone metastases management in breast cancer patients.

Bone is the most common site for distant spread of breast cancer. Following a diagnosis of metastatic bone disease, patients can suffer from significant morbidity because of pain and skeletal related events (SRES). Bisphosphonates are potent inhibitors of osteoclastic function and the mainstay of bone-directed therapy for bone metastases. The aims of bisphosphonates are to prevent and delay SRES, to reduce bone pain, and to improve quality of life. Bisphosphonate therapy appears to have revolutionized treatment of bone metastases, but bisphosphonate use has several limitations. Those limitations include the high cost of the agents and the need for return trips to the clinic for intravenous treatment. Moreover, many uncertainties surround bisphosphonate use-for example, the timing of bisphosphonate initiation, the choice of bisphosphonate to use, the optimal duration of treatment, and the appropriate means to identify patients who will and will not benefit. In addition, potentially serious adverse effects have been associated with bisphosphonate use-for example, renal toxicity, gastrointestinal side effects, and osteonecrosis of the jaw. The present review is intended as a primer for oncology specialists who treat patients with bone metastases secondary to breast cancer. It focuses on bisphosphonate treatment guidelines, the evidence for those guidelines, and a discussion of new therapeutic agents. It also discusses the use of biochemical markers of bone metabolism, which show promise for predicting the risk of a patient's developing a SRE and of benefiting from bisphosphonate treatment.

Cathepsins B and L and their inhibitors stefin B and cystatin C as markers for malignant progression of benign meningiomas.

Meningiomas are, in general, slowly growing benign tumors attached to the dura mater and composed of neoplastic meningothelial (arachnoidal) cells. They have a wide range of histopathological appearances and are classified, according to the aggressiveness of their growth and the risk of recurrence, as WHO grade I (benign) meningiomas, WHO grade II (atypical) meningiomas and WHO grade III anaplastic (malignant) meningiomas. As invasion of normal tissue may occur in all grades, independent biological markers are needed to identify the more aggressive and recurrent meningiomas. The lysosomal cysteine proteinases, cathepsins B and L, have been associated with tumor invasiveness and the aim of this study was therefore to evaluate them, together with their endogenous inhibitors stefin B and cystatin C, as potential markers for the aggressiveness of meningiomas. The expression of cathepsins B and L and their inhibitors stefin B and cystatin C in 21 benign (grade I) and 9 atypical (grade II) meningiomas has been compared by immunohistochemical staining, QRT-PCR and Northern blot analysis. The protein levels of cathepsins B (p=0.050) and L (p=0.019) were found to be significantly higher in atypical than in benign meningiomas. In contrast, their mRNA levels did not differ, indicating that the synthesis of cathepsins was accelerated at the translational level. Protein and mRNA levels of stefin B (p= 0.007), but not cystatin C, were significantly lower in atypical compared with benign meningiomas. The expression of cathepsins and inhibitors was not different between central and peripheral meningioma tissue or between histological subtypes of meningiomas, with the exception of cathepsin L, the level of which was significantly lower in transitional meningiomas. We conclude that higher protein levels of cathepsins B and L and lower mRNA levels of stefin B are potential diagnostic markers for invasive and aggressive behavior of meningiomas. The diagnostic and prognostic value for relapse of meningioma needs to be confirmed in a larger population of patients.

Evaluation of the needs of spouses of female carriers of mutations in BRCA1 and BRCA2.

The process of genetic testing involves the entire family, including spouses. The objective of this study was to measure the specific needs and to describe the experiences of spouses of women who received genetic counseling for a positive BRCA1/2 result. We surveyed 59 spouses of female mutation carriers. The mean length of relationships was 26 years (range: 2.5-50 years). All were supportive of their spouses' decision to undergo genetic testing and counselling. Four respondents stated that they wished that they had received additional support at the time of test disclosure and 20% felt that their wives had received inadequate support. One-quarter of the spouses believed that their relationship had changed because of genetic testing; most felt that they had become closer to their wives. Husbands were most concerned about the risk of their wife dying of cancer (43%), followed by the risk of their spouse developing cancer (19%) and the risk that their children would test positive for the BRCA mutation (14%). Distress levels, measured by the Impact of Event scale, suggest that few spouses were experiencing clinical levels of distress.

A Novel Coordination Mode of 7-Methyl-7-sila-nido-undecaborate(1-).

B-N-M bridges, resulting from the activation of two B,H units, are present in the anion [Nb(MeSiB(10)H(8))(µ-NMe(2))(2)Br(3)](-) (see structure depicted). Thus, this is an example for a hitherto unknown coordination mode in the chemistry of heteroborane clusters.

On the convergent cell movements of gastrulation in Fundulus.

Mainly because of its transparency, the Fundulus gastrula constitutes ideal material for direct study of morphogenetic cell movements in vivo. Marking studies show that deep cells of the germ ring converge toward and enter the embryonic shield, where they undergo extension. Those close to the shield move faster. Analysis of videotapes reveals that all deep cells of the dorsal germ ring move toward the shield. But none moves in a direct line. All meander considerably. Germ ring cells nearer the shield move toward it at a higher net rate than those farther away because they meander less. This suggests that exogenous factors promote their directionality. Cells in the prospective yolk sac adjacent to the germ ring also show net convergence, but they meander more. Directional forces are apparently stronger in the germ ring. Converging deep cells move both by filolamellipodia and, less frequently, by blebs. However, there is very little individual cell movement; all cells are almost always in adhesive contact with other cells in moving cell clusters. Clusters vary constantly in size, continually aggregating with other cells and other clusters and splitting. Filolamellipodial cells show contact inhibition of cell movement. Nevertheless, they move and do so directionally, presumably in part because, as members of cell clusters, much of their movement is passive. They also show intercalation or invasive activity, but, consistent with their contact-inhibiting properties, only when neighboring cells separate and provide free space. Cells moving by blebbing locomotion are non-contact inhibiting and intercalate readily. Cell division continues during convergence. Although this temporarily arrests their movement, the daughter cells soon join in the mass convergent movement.