Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study.

Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.

A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification.

BACKGROUND: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. PATIENTS AND METHODS: Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. RESULTS: Of 71 patients randomized (AZD4547 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P = 0.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. CONCLUSIONS: AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.

Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab.

BACKGROUND: Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS: An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS: A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS: Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial.

BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken. RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS. CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. CLINICALTRIALSGOV IDENTIFIER: NCT01246960.

Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines.

BACKGROUND: Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine). PATIENTS AND METHODS: Pharmacy records were used to identify patients receiving raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing raltitrexed. RESULTS: Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil ± leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity. CONCLUSION: Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.

A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer.

BACKGROUND: Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine-cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m(2), days 1/8) and cisplatin (75 mg/m(2), day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature. RESULTS: One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%-42.1%] with GC versus 20.0% (95% CI 11.9%-30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8-5.6) months with GC and 5.7 (95% CI 4.6-6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56-1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9-17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48-1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3-4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each). CONCLUSIONS: Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS. TRIAL REGISTRATION: ClinicalTrial.gov Identifier NCT01086254.

Assessing health-state utility values in patients with metastatic colorectal cancer: a utility study in the United Kingdom and the Netherlands.

PURPOSE: This study aimed to elicit EuroQol Quality of Life 5-Dimensions (EQ-5D) utility values from patients with second-line metastatic colorectal cancer (mCRC) pre- and post-progression. METHODS: A cross-sectional study was conducted in five hospitals in the Netherlands and the UK. Patients with mCRC were eligible if prescribed a second or subsequent line of therapy or best supportive care (BSC), received prior oxaliplatin in first-line therapy, and had Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-2 at second-line initiation. Patients completed the EuroQol Quality of Life 5-Dimensions 3-levels (EQ-5D-3L) questionnaire and were categorized as pre- or post-progression. Chart data including patient demographics, clinical history, prior/current treatments and serious adverse events (SAEs) were collected. Mean utilities were estimated; uni- and multivariate analyses were conducted. RESULTS: Seventy-five patients were enrolled; 42 were pre-progression defined as second line or third line following an AE on second line and 33 were post-progression defined as third or subsequent therapy lines or BSC. Patient/disease characteristics and number of SAEs were similar between cohorts. Mean utility scores were 0.741 (SD = 0.230) and 0.731 (SD = 0.292) for pre- and post-progression cohorts, respectively. Compared to pre-progression, more patients reported increased anxiety/depression (36 vs. 12 %) and fewer problems with daily activities (64 vs. 38 %) post-progression. More patients pre-progression were on active treatment at enrolment (83 vs. 42 %) compared to post-progression. CONCLUSIONS: This is the first real-world study to collect utilities for patients with second-line mCRC pre- and post-disease progression. Utility values were similar pre- and post-progression. To further explore the effect of radiological progression on utilities, longitudinal research is required that includes patients in palliative care centres.

Fast energy relaxation of hot carriers near the Dirac point of graphene.

We investigate energy relaxation of hot carriers in monolayer and bilayer graphene devices, demonstrating that the relaxation rate increases significantly as the Dirac point is approached from either the conduction or valence band. This counterintuitive behavior appears consistent with ideas of charge puddling under disorder, suggesting that it becomes very difficult to excite carriers out of these localized regions. These results therefore demonstrate how the peculiar properties of graphene extend also to the behavior of its nonequilibrium carriers.

Risk factors of early mortality in COVID-19 patients in Indonesia: A retrospective cohort study in a provincial referral hospital of Aceh.

Some of coronavirus disease 2019 (COVID-19) patients died after being hospitalized and early mortality is a matter of concern during the pandemic; therefore, it is critical to determine which patients are the most vulnerable of having early mortality. The aim of this study was to determine the risk factors for early mortality among hospitalized COVID-19 patients in Indonesia. A retrospective cohort study was conducted on hospitalized COVID-19 patients from July 2020 to September 2021 at Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia. Demographic data, clinical characteristics, laboratory findings, and mortality were collected. Early mortality was defined as a death before seven days of the hospitalization. Multivariate regression analysis was employed to determine the risk factors associated with early mortality. We included the data of 624 COVID-19 patients who died during the study period. More than half of the patients were male and aged over 50 years old. The average hospitalization period was 10 days and most patients had more than two comorbidities. Chronic lung disease was the most common comorbidity (46.0%) followed by respiratory disease (26.8%) and heart disease (14.3%). Multiple comorbidities and elevated D-dimers exceeding 3376.92 ng/mL were associated with early mortality with OR: 7.029; 95%CI: 2.02-24.43 and OR: 1.000085, 95%CI: 1.000028-1.000142, respectively. In conclusion, early mortality in COVID-19 patients was associated with having multiple comorbidities and elevated D-dimer level. Therefore, it is crucial to assess the presence of comorbidities and routine laboratory test while managing COVID-19 patients in order to prevent the early mortality.

Correlation between high sensitivity C reactive protein (Hs-CRP) and neutrophil-to- lymphocyte ratio (NLR) with functional capacity in post COVID-19 syndrome patients.

Post coronavirus disease 2019 (COVID-19) syndrome is one of the causes of reduced functional capacity and work productivity, in particular for healthcare workers. The pathophysiology of the post COVID-19 syndrome is related to complex and multisystem inflammatory mechanisms, and cardiopulmonary exercise rehabilitation program is one of the efforts to improve the recovery process for patients with post COVID-19 syndrome. The aim of this study was to determine the correlation between the level of high sensitivity C-reactive protein (Hs-CRP) and neutrophil-to-lymphocyte ratio (NLR) with functional capacity (VO2max) in individuals with post-COVID-19 syndrome who received moderate- and high-intensity supervised cardiopulmonary exercise. A prospective cohort study was conducted at the Integrated Cardiac Rehabilitation Center of Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia. The supervised cardiopulmonary exercise was conducted for six weeks according to the participant's baseline VO2max. Spearman's and Pearson's correlation tests were used to assess the correlations. A total of 30 individuals (19 and 11 had moderate and high intensity exercise, respectively) were involved in this study. At moderate intensity exercise, the average Hs-CRP and NLR were 3.3 mg/L and 1.99, respectively; while at high intensity, the values were 3.8 mg/L and 1.79, respectively. No significant correlation between Hs-CRP level and functional capacity in both moderate-intensity and high intensity groups. In contrast, NLR was negatively correlated with functional capacity (r=-0.545, p=0.016) in moderate intensity exercise group. In conclusion, NLR value was negatively correlated with functional capacity in individuals with post-COVID-19 syndrome after receiving moderate intensity supervised cardiopulmonary exercise program. Therefore, moderate intensity of cardiopulmonary exercise maybe be used as a program to accelerate the recovery for those with post COVID-19 syndrome.

Direct imaging of electron states in open quantum dots.

We use scanning gate microscopy to probe the ballistic motion of electrons within an open GaAs/AlGaAs quantum dot. Conductance maps are recorded by scanning a biased tip over the open quantum dot while a magnetic field is applied. We show that, for specific magnetic fields, the measured conductance images resemble the classical transmitted and backscattered trajectories and their quantum mechanical analogue. In addition, we prove experimentally, with this direct measurement technique, the existence of pointer states. The demonstrated direct imaging technique is essential for the fundamental understanding of wave function scarring and quantum decoherence theory.

KI and TEDA influences towards the retention of radiotoxic CH3I by activated carbons.

Activated carbons (AC) are widely used within the ventilation networks of nuclear facilities to trap volatile iodine species. In this paper, the performances of various commercial activated carbons towards the trapping of γ-labelled methyl iodide were evaluated in semi-pilot scale under different R.H. according to normalized procedures. A combination between the retention performances and the physico-chemical properties as deduced from several techniques was performed to gain insights about the AC influencing parameters on γ-CH3I capture. Different trends were obtained depending on the impregnant nature and the studied conditions. A high sensitivity of KI/AC towards water vapor was outlined. At R.H. = 40%. The enhancement of water uptake by KI/AC as deduced from water adsorption experiments, leads to decrease the available microporosity for CH3I physisorption, inducing therefore the reduction of performances as a function of KI content at these conditions. At R.H. = 90%, the adsorption mechanism was found to be governed by isotopic exchange reaction since 90% of the microporosity was occupied by water molecules. Therefore, a slight increase of DF was obtained in these conditions. This sensitivity was found to be of a lesser extent for TEDA/AC displaying the highest retention performances whatever the studied condition.

Jet exhaust particles alter human dendritic cell maturation.

OBJECTIVE AND DESIGN: Among combustion-derived air pollutants, little is known about jet kerosene characteristics and effects. MATERIALS AND METHODS: Particles yielded by experimental kerosene combustion in a jet engine were characterized with electron microscopy and X-ray energy dispersive spectroscopy. Immature human monocyte-derived dendritic cells were exposed for 18 h to 10, 25 or 100 µg/mL jet exhaust particles and/or Escherichia coli-derived endotoxin. Antigen-presenting and costimulation molecules (HLA DR, CD40, CD80, CD86, CD11c), tumor necrosis factor-α and interleukin-10 production were measured. RESULTS: The primary particles of jet exhaust are spherical (9.9 nm), carbonaceous and exert an adjuvant effect on human monocyte-derived dendritic cell maturation in vitro. Concomitant particle and endotoxin stimulation induced a high cytokine production with low antigen-presenting molecules; particle contact prior to endotoxin contact led to an opposite phenotype. Finally, low cytokine production and high costimulation molecules were present when particle adjunction followed endotoxin contact. CONCLUSIONS: Jet exhaust particles act as adjuvants to endotoxin-induced dendritic cell maturation, suggesting possible implications for human health and a role for the time pattern of infectious and pollutant interplay.

Neutron diffraction study of water freezing on aircraft engine combustor soot.

The study of the formation of condensation trails and cirrus clouds on aircraft emitted soot particles is important because of its possible effects on climate. In the present work we studied the freezing of water on aircraft engine combustor (AEC) soot particles under conditions of pressure and temperature similar to the upper troposphere. The microstructure of the AEC soot was found to be heterogeneous containing both primary particles of soot and metallic impurities (Fe, Cu, and Al). We also observed various surface functional groups such as oxygen-containing groups, including sulfate ions, that can act as active sites for water adsorption. Here we studied the formation of ice on the AEC soot particles by using neutron diffraction. We found that for low amount of adsorbed water, cooling even up to 215 K did not lead to the formation of hexagonal ice. Whereas, larger amount of adsorbed water led to the coexistence of liquid water (or amorphous ice) and hexagonal ice (I(h)); 60% of the adsorbed water was in the form of ice I(h) at 255 K. Annealing of the system led to the improvement of the crystal quality of hexagonal ice crystals as demonstrated from neutron diffraction.

Effect of top dielectric medium on gate capacitance of graphene field effect transistors: implications in mobility measurements and sensor applications.

We have carried out Hall measurement on back-gated graphene field effect transistors (FET) with and without a top dielectric medium. The gate efficiency increases by up to 2 orders of magnitude in the presence of a high κ top dielectric medium, but the mobility does not change significantly. Our measurement further shows that the back-gate capacitance is enhanced dramatically by the top dielectric medium, and the enhancement increases with the size of the top dielectric medium. Our work strongly suggests that the previously reported top dielectric medium-induced charge transport properties of graphene FETs are possibly due to the increase of gate capacitance, rather than enhancement of carrier mobility.

Periodic scarred States in open quantum dots as evidence of quantum Darwinism.

Scanning gate microscopy (SGM) is used to image scar structures in an open quantum dot, which is created in an InAs quantum well by electron-beam lithography and wet etching. The scanned images demonstrate periodicities in magnetic field that correlate to those found in the conductance fluctuations. Simulations have shown that these magnetic transform images bear a strong resemblance to actual scars found in the dot that replicate through the modes in direct agreement with quantum Darwinism.

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer.

BACKGROUND: The combination of cisplatin and etoposide (PE) has been a standard treatment for patients with poor-prognosis small cell lung cancer (SCLC). This non-inferiority design trial aimed to determine whether the combination of gemcitabine and carboplatin (GC) results in similar survival but is less toxic with better quality of life. METHODS: Previously untreated patients with SCLC with extensive disease or limited stage with poor prognostic factors were randomly assigned to six 3-weekly cycles of GC or PE. RESULTS: 241 patients (121 GC, 120 PE) were recruited, of which 216 (90%) had died. There was no difference in overall survival (HR 1.01, 95% CI 0.77 to 1.32). Median survival with GC and PE was 8.0 and 8.1 months, respectively. Median progression-free survival was 5.9 months with GC and 6.3 months with PE. Grade 3 or 4 myelosuppressions were more frequent with GC (anaemia: 14% GC vs 2% PE; leucopenia: 32% GC vs 13% PE; thrombocytopenia: 22% GC vs 4% PE), but these were not associated with increased hospital admissions, infections or fatalities. Grade 2-3 alopecia (68% PE vs 17% GC) and nausea (43% PE vs 26% GC) were more frequent with PE. Patients given GC received more chemotherapy as outpatients (89% GC vs 66% PE of treatment cycles). In QoL questionnaires, more patients receiving PE reported being upset by hair loss (p = 0.004) and impaired cognitive functioning (p = 0.04). CONCLUSIONS: GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients. TRIAL REGISTRATION NUMBER: ISRCTN 39679215.

Regulation of HMG-CoA reductase degradation requires the P-type ATPase Cod1p/Spf1p.

The integral ER membrane protein HMG-CoA reductase (HMGR) is a key enzyme of the mevalonate pathway from which sterols and other essential molecules are produced. HMGR degradation occurs in the ER and is regulated by mevalonate-derived signals. Little is known about the mechanisms responsible for regulating HMGR degradation. The yeast Hmg2p isozyme of HMGR undergoes regulated degradation in a manner very similar to mammalian HMGR, allowing us to isolate mutants deficient in regulating Hmg2p stability. We call these mutants cod mutants for the control of HMG-CoA reductase degradation. With this screen, we have identified the first gene of this class, COD1, which encodes a P-type ATPase and is identical to SPF1. Our data suggested that Cod1p is a calcium transporter required for regulating Hmg2p degradation. This role for Cod1p is distinctly different from that of the well-characterized Ca(2+) P-type ATPase Pmr1p which is neither required for Hmg2p degradation nor its control. The identification of Cod1p is especially intriguing in light of the role Ca(2+) plays in the regulated degradation of mammalian HMGR.