CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

Fluorometric sensing of hydroxylamine in an aqueous medium utilizing a diphenyl imidazole-based probe.

The detection of hydroxylamine in an aqueous medium is challenging due to its very similar chemical reactivity to its nearest competitors such as hydrazine hydrate and primary amines. Moreover, the detection of hydroxylamine at neutral pH adds further complexity to the sensing phenomenon due to its poor reactivity in a neutral aqueous medium. In this work, we have presented a diphenyl imidazole benzaldehyde (DIB) probe which demonstrates the detection of hydroxylamine (HA) in micromolar concentrations with high selectivity in 5% DMSO phosphate buffer solution at pH 7.4 via a fluorescence "turn-on" signal. The interaction of hydroxylamine with the probe has been comprehensively studied by using fluorescence spectroscopy, proton NMR, FTIR, ESI-mass spectrometry and DLS measurements. The experimental results were further corroborated with the DFT studies. These results could pave the way toward the development of molecular indicators for hydroxylamine in chemical and biological platforms.

Butterfly pea (Clitoria ternatea) extract as a green analytical tool for selective colorimetric detection of bisulphate (HSO4-) ion in aqueous medium.

The blue color of butterfly pea (Clitoria ternatea) was extracted by Milli-Q water and evaluated for selective detection of bisulphate (HSO4-) ions. The stability of the Clitoria ternatea extract was established by UV-visible and fluorescence techniques. The blue water extract from Clitoria ternatea selectively recognizes HSO4- ions over various anions via a distinct visual color change from blue to purple with a significant hypsochromic shift of 68 nm in the UV-visible absorption spectra. Thus Clitoria ternatea extract provides a selective real time colorimetric monitoring of HSO4- ions which would pave the way for the development of low cost green analytical tool. This type of detection technique enhances the environmental and economic benefits and can emerge as an alternative form of synthetic chelating sensors.

Sequential displacement strategy for selective and highly sensitive detection of Zn2+, Hg2+ and S2- ions: An approach toward a molecular keypad lock.

A thiocarbonohydrazone locked salicylidene based macrocycle ligand L has been synthesized and its ion sensing properties were examined by UV-visible and fluorescence spectroscopy. The macrocycle serves as a highly selective colorimetric sensor for Hg2+ ions while it acts as an excellent fluorescent sensor for Zn2+ ions by exhibiting a green fluorescence at 498 nm even in the presence of interfering ions. A detailed analysis of binding characteristics such as complex stoichiometry, association constant and detection limits of L toward Hg2+ and Zn2+ ions were evaluated by UV-visible and fluorescence experiments which revealed a stronger binding affinity and higher detection limit of L toward the mercury ions. Further, the sequential displacement strategy for the chromofluorogenic detection of Zn2+, Hg2+ and S2- ions by ligand L, has been studied comprehensively. Finally, the ion-responsive fluorescence output signal of L were employed to design a molecular keypad lock which could be accessible by two users having two different set of chemical passwords (inputs) through distinguishable optical trajectories.

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study.

BACKGROUND: Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents. METHODS: We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35-70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11,963). FINDINGS: We included 114,970 adults, of whom 12,904 (11%) were from high-income countries (HICs), 24,408 (21%) were from upper-middle-income countries (UMICs), 48,845 (43%) were from lower-middle-income countries (LMICs), and 28,813 (25%) were from low-income countries (LICs). Median follow-up was 4.3 years (IQR 3.0-6.0). Current drinking was reported by 36,030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0.76 [95% CI 0.63-0.93]), but increased alcohol-related cancers (HR 1.51 [1.22-1.89]) and injury (HR 1.29 [1.04-1.61]). High intake was associated with increased mortality (HR 1.31 [1.04-1.66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0.84 [0.77-0.92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1.07 [0.95-1.21]; pinteraction<0.0001). INTERPRETATION: Current alcohol consumption had differing associations by clinical outcome, and differing associations by income region. However, we identified sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

Metformin: On Ongoing Journey across Diabetes, Cancer Therapy and Prevention.

Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide.

Efficacy and tolerability of lapatinib in the management of breast cancer.

Approximately 20%-25% of all breast cancers over express a key cell surface growth factor receptor known as HER2. HER2 plays a key role in cell growth and proliferation and is linked to worse clinical outcomes, making it a logical therapeutic target. The first HER2 targeted drug to be approved by the FDA, was the humanized monoclonal antibody trastuzumab, after it showed improvements in survival in the adjuvant setting, and delayed time to progression in the metastatic setting. Although highly effective, for reasons that are not clear, some patients display resistance to trastuzumab. Lapatinib is an oral, small molecule tyrosine kinase inhibitor, that inhibits both the HER1 ahd HER2 receptors and may be able to overcome trastuzumab resistance. Lapatinib is approved in the second line setting for use in combination with capecitabine or with letrozole. In this review, we will discuss the indications, concerns or any issues with regards to the drug.

Prevention of thrombosis in ambulatory patients with cancer.

Cancer patients with solid tumors or hematologic malignancies receive most of their cancer treatment as outpatients. Thromboembolism, when it occurs, complicates the clinical care of these patients because of the associated morbidity and the need for anticoagulant treatment. It would seem that prevention of venous thromboembolism in these patients would be worthwhile. However, to date there are relatively few trials of anticoagulant prophylaxis in ambulatory patients with cancer and it is not possible to recommend prophylaxis for most patients. Research is needed to better define a population at high enough risk to warrant pharmacologic prophylaxis and to develop new antithrombotic agents for this indication.