Positive Airway Pressure Treatment of Obstructive Sleep Apnea-Hypopnea in Hypertensive Disorders of Pregnancy: A Pilot Randomized Proof-of-Concept Clinical Trial.

Rationale: Maternal obstructive sleep apnea-hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). OSAH treatment with positive airway pressure (PAP) in the general population lowers blood pressure (BP). However, there are limited data on the effects of PAP therapy in maternal OSAH. Objectives: Our primary objective was to assess the feasibility of recruitment to a pilot randomized trial and adherence to PAP therapy for OSAH in women with HDP. Secondary objectives included assessment of PAP effects on 24-h BP, arterial stiffness, and maternal and fetal outcomes. Methods: Women with singleton pregnancies at ⩾12 weeks' gestation and hypertension underwent home level 2 polysomnography; those with mild to moderate OSAH (apnea-hypopnea index ⩾ 5 events/h; women with severe OSAH with apnea-hypopnea index > 30 events/h and oxygen desaturation index > 30 were excluded) were randomized to either PAP or nasal dilator strip (NDS; control) therapy. After PAP education, adherence was monitored online with episodic phone or in-person support by research personnel. Twenty-four-hour BP and arterial stiffness were assessed at baseline and before delivery. Maternal and fetal outcomes were also recorded. Results: Of 105 potentially eligible participants, 67 agreed to undergo screening for OSAH over 38 months; 48 women meeting OSAH inclusion criteria were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 14 PAP (52%) and 13 NDS (62%) participants completed all predelivery measurements, with lack of completion due to urgent delivery (19% in the PAP group, 14% in the NDS group), PAP intolerance at initiation (19%), or other factors. Mean PAP use was 3.1 ± 2.5 h/night, with use ⩾4 h/night on 38.4 ± 33.7% of nights during 9.6 ± 4.0 weeks of treatment. BP was controlled within the target range in most participants. There were no differences in mean change in 24-hour BP or arterial stiffness measurements or in adverse maternal and fetal outcomes between the PAP and NDS groups in either intention-to-treat or per-protocol analyses. Conclusions: PAP adherence was suboptimal in this HDP cohort despite education and troubleshooting. Further work is required to identify optimal OSAH treatment strategies during pregnancy. Clinical trial registered with www.clinicaltrials.gov (NCT03309826).

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. Significance: Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

Correction: Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Correction: Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.

BACKGROUND: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. PATIENTS AND METHODS: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. RESULTS: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). CONCLUSION: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. IMPLICATIONS FOR PRACTICE: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.

Guideline No. 393-Diabetes in Pregnancy.

OBJECTIVES: This guideline reviews the evidence relating to the diagnosis and obstetrical management of diabetes in pregnancy. OUTCOMES: The outcomes evaluated were short and long-term maternal outcomes including pre-eclampsia, Caesarean section, future diabetes and other cardiovascular complications; and fetal outcomes including congenital anomalies, stillbirth, macrosomia, birth trauma, hypoglycemia and long-term effects. EVIDENCE: Published literature was retrieved through searches of PubMed and The Cochrane Library using appropriate controlled vocabulary (MeSH terms "diabetes" and "pregnancy"). Where appropriate, results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits but results were limited to English or French language materials. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. SUMMARY STATEMENTS: RECOMMENDATIONS.

Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA1) pathway is implicated in IPF etiology. Safety and efficacy of BMS-986020, a high-affinity LPA1 antagonist, was assessed vs placebo in a phase 2 study in patients with IPF. METHODS: IM136003 was a phase 2, parallel-arm, multicenter, randomized, double-blind, placebo-controlled trial. Adults with IPF (FVC, 45%-90%; diffusing capacity for carbon monoxide, 30%-80%) were randomized to receive placebo or 600 mg BMS-986020 (once daily [qd] or bid) for 26 weeks. The primary end point was rate of change in FVC from baseline to week 26. RESULTS: Of 143 randomized patients, 108 completed the 26-week dosing phase. Thirty-five patients discontinued prematurely. Patient baseline characteristics were similar between treatment groups (placebo: n = 47; 600 mg qd: n = 48; 600 mg bid: n = 48). Patients treated with BMS-986020 bid experienced a significantly slower rate of decline in FVC vs placebo (-0.042 L; 95% CI, -0.106 to -0.022 vs -0.134 L; 95% CI, -0.201 to -0.068, respectively; P = .049). Dose-related elevations in hepatic enzymes were observed in both BMS-986020 treatment groups. The study was terminated early because of three cases of cholecystitis that were determined to be related to BMS-986020 after unblinding. CONCLUSIONS: BMS-986020 600 mg bid treatment for 26 weeks vs placebo significantly slowed the rate of FVC decline. Both regimens of BMS-986020 were associated with elevations in hepatic enzymes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01766817; URL: www.clinicaltrials.gov.

An Evaluation of the Collagen Fragments Related to Fibrogenesis and Fibrolysis in Nonalcoholic Steatohepatitis.

Fibrosis, resulted from the imbalance of fibrogenesis and fibrolysis, is a key readout of disease progression in nonalcoholic steatohepatitis (NASH) and reflects mortality risk. Non-invasive biomarkers capable of diagnosing fibrosis stages and monitoring fibrosis changes in NASH patients are urgently needed. This study is to evaluate collagen formation and degradation biomarkers, reflective of fibrogenesis or fibrolysis, in patients with biopsy proven NASH. Collagen formation biomarker PRO-C3 and PRO-C6 levels were significantly higher in patients with advanced fibrosis stage 3-4 than those with fibrosis stage 0-2. Elevated PRO-C3 levels were also associated with severe lobular inflammation and ballooning, but not with steatosis. Multivariate logistic regression analysis identified PRO-C3 and PRO-C6 to be independently related to fibrosis stage. PRO-C3 showed similar performance to identify patients with advanced fibrosis in discovery and validation cohorts. Furthermore, in a longitudinal study cohort with paired biopsies, mean PRO-C3 increased with worsening of fibrosis and decreased with fibrosis improvement. The results suggest that PRO-C3 may be a potentially useful biomarker in identifying patients with advanced fibrosis and active fibrogenesis, as well as in assessing changes in fibrosis over time. It is worthy of further evaluation to confirm its diagnostic value and clinical utility.

HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib.

HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx FISH and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4,674 patients in a central laboratory for eligibility (1,995 cases) and for confirmation of local HER2 results (333 cases). Of 1,995 adenocarcinomas screened centrally, 322 (16.1%) had HER2-amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%), 487 patients (89%) were centrally confirmed as having HER2-amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2 In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low. Mol Cancer Ther; 16(1); 228-38. ©2016 AACR.

A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma.

Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients.Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.

Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib.

IMPORTANCE: The value of the intrinsic subtypes of breast cancer (luminal A, luminal B, human epidermal growth factor receptor 2 [currently known as ERBB2, but referred to as HER2 in this study]-enriched, and basal-like) in the metastatic setting is currently unknown. OBJECTIVE: To evaluate the association of the intrinsic subtypes of breast cancer with outcome and/or benefit in hormone receptor (HR)-positive metastatic breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Unplanned retrospective analysis of 821 tumor samples (85.7% primary and 14.3% metastatic) from the EGF30008 phase 3 clinical trial (NCT00073528), in which postmenopausal women with HR-positive invasive breast cancer and no prior therapy for advanced or metastatic disease were randomized to letrozole with or without lapatinib, an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Tumor samples were classified into each subtype using the research-based PAM50 classifier. Prior neoadjuvant/adjuvant antiestrogen therapy was allowed. Patients with extensive symptomatic visceral disease were excluded. Treatment effects were evaluated using interaction tests. MAIN OUTCOMES AND MEASURES: Primary and secondary end points were progression-free survival and overall survival. RESULTS: The median (range) age was 62 (31-94) years. Intrinsic subtype was the strongest prognostic factor independently associated with progression-free survival and overall survival in all patients, and in patients with HER2-negative (n = 644) or HER2-positive (n = 157) diseases. Median progression-free survival differed across the intrinsic subtypes of clinically HER2-negative disease: luminal A (16.9 [95% CI, 14.1-19.9] months), luminal B (11.0 [95% CI, 9.6-13.6] months), HER2-enriched (4.7 [95% CI, 2.7-10.8] months), and basal-like (4.1 [95% CI, 2.5-13.8] months). Median OS also differed across the intrinsic subtypes: luminal A (45 [95% CI, 41-not applicable {NA}] months), luminal B (37 [95% CI, 31-42] months), HER2-enriched (16 [95% CI, 10-NA] months), and basal-like (23 [95% CI, 12-NA] months). Patients with HER2-negative/HER2-enriched disease benefited from lapatinib therapy (median PFS, 6.49 vs 2.60 months; progression-free survival hazard ratio, 0.238 [95% CI, 0.066-0.863]; interaction P = .02). CONCLUSIONS AND RELEVANCE: This is the first study to reveal an association between intrinsic subtype and outcome in first-line HR-positive metastatic breast cancer. Patients with HR-positive/HER2-negative disease with a HER2-enriched profile may benefit from lapatinib in combination with endocrine therapy. The clinical value of intrinsic subtyping in hormone receptor-positive metastatic breast cancer warrants further investigation, but patients with luminal A/HER2-negative metastatic breast cancer might be good candidates for letrozole monotherapy in the first-line setting regardless of visceral disease and number of metastases.

Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials.

PURPOSE: Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome. EXPERIMENTAL DESIGN: Patients with BRAF V600 mutation-positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined. RESULTS: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K-positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation-positive cfDNA in plasma had higher response rates to dabrafenib and trametinib. CONCLUSIONS: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation-positive tumors. The lack of circulating, BRAF mutation-positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome.

Low-technology assisted reproduction and the risk of preterm birth in a hospital-based cohort.

OBJECTIVE: To estimate the risk of preterm birth in singleton infants conceived through low-technology assisted reproduction (intrauterine insemination and/or ovulation induction/stimulation). DESIGN: Hospital-based cohort study. SETTING: University-affiliated hospital. PATIENT(S): Singleton babies born between 2001 and 2007 to 16,712 couples with no reported infertility (reference category), 378 babies conceived with low-technology treatment; 437 conceived with high-technology treatment; and 620 conceived naturally after a period of infertility. INTERVENTION(S): None. Treatment data were obtained from couples undergoing standard infertility investigation and care. MAIN OUTCOME MEASURE(S): Preterm birth, defined at three clinical endpoints: <37, <35, and <32 weeks of completed gestation. RESULT(S): After adjustment for age, parity, education, smoking, alcohol/drug use, and body mass index, the risk ratios and 95% confidence intervals (CI) of preterm birth for low technology were: 1.49 (CI: 1.12-2.00); 2.02 (CI: 1.30-3.13); and 2.93 (CI: 1.63-5.26) at <37, <35, and <32 weeks gestation, respectively, not dissimilar from the estimates for in vitro fertilization. Restricting the analysis to primiparas strengthened the association between treatment and preterm birth at the lower gestational endpoints. The increased risk persisted when the untreated group was used as the reference category, although the estimates were attenuated. CONCLUSION(S): In this large hospital-based cohort study, low-technology assisted reproduction appeared to be a moderately strong predictor of preterm birth, with similar associations observed in the high-technology treatment group. After adjusting for confounders, as well as the shared characteristics of infertile couples, associations were attenuated but remained significant, suggesting that part of the risk is likely attributable to the treatment.

Efficacy, safety, pharmacokinetics and biomarker findings in patients with HER2-positive advanced or metastatic breast cancer treated with lapatinib in combination with capecitabine: results from 51 Japanese patients treated in a clinical study.

BACKGROUND: The results from a phase III trial conducted outside of Japan demonstrated a significant improvement in time to progression (TTP) when lapatinib was combined with capecitabine compared with capecitabine alone in patients with HER2-positive advanced or metastatic breast cancer. In this clinical study of lapatinib in combination with capecitabine, efficacy, safety, pharmacokinetics (PK) and biomarkers were investigated in Japanese patients with HER2-positive advanced or metastatic breast cancer treated with prior trastuzumab. METHODS: Eligible women received lapatinib 1250 mg once daily and capecitabine 1000 mg/m(2) twice daily on days 1 through 14 of a 21-day cycle. The primary endpoint was the clinical benefit rate (CBR: complete response, partial response or stable disease for at least 24 weeks). RESULTS: Lapatinib in combination with capecitabine was well tolerated in the 51 patients enrolled in this study. CBR was 59 % (95 % CI 44.2, 72.4), and the median TTP in the Kaplan-Meier estimate was 36 weeks (95 % CI 27.1, 48.0). The majority of drug-related adverse events were mild to moderate (grade 1 or 2); the most common adverse events reported were palmar-plantar erythrodysesthesia syndrome (76 %), diarrhea (67 %) and stomatitis (41 %). CONCLUSIONS: Lapatinib in combination with capecitabine in Japanese HER2-positive breast cancer patients was well tolerated. Overall, our findings on the efficacy, safety and PK were similar to those reported from the overseas studies.

Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial.

PURPOSE: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. RESULTS: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. CONCLUSIONS: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC.

Perspectives of obstetricians on labour and delivery after abdominal or laparoscopic myomectomy.

OBJECTIVE: Because of concerns about uterine rupture, many obstetricians recommend elective Caesarean section for women with a prior myomectomy. This practice has led to an increased rate of elective CS and subsequently of repeat Caesarean sections. The purpose of this study was to evaluate the perspectives of obstetricians on labour and delivery after abdominal or laparoscopic myomectomy. METHODS: We conducted a survey of 49 practising obstetricians from July 2012 to January 2013, using a standard questionnaire. This included questions on labour and delivery after myomectomy by laparotomy or laparoscopy. RESULTS: Overall, the inter-respondent agreement was fair (kappa 0.3; P < 0.001). There was no significant difference in the likelihood that respondents would allow vaginal delivery after myomectomy by laparotomy and by laparoscopy (27% and 14% if the uterine cavity was entered and 76% and 71% if the uterine cavity was not entered, respectively). However, the likelihood that respondents would allow vaginal delivery was significantly reduced if the uterine cavity was entered, regardless of the surgical approach (P < 0.001). Entry into the uterine cavity during myomectomy also significantly increased the likelihood that obstetricians would recommend elective CS rather than induction of labour. There was no significant difference in practice regarding the use of oxytocin with amniotomy, oxytocin infusion, or prostaglandins. CONCLUSION: Despite a lack of evidence, obstetricians consider entry into the uterine cavity at myomectomy to be an important factor in determining the method of delivery, the use of oxytocin, and delivery by elective Caesarean section. This was independent of the myomectomy approach.

Objectif : En raison de préoccupations au sujet de la rupture utérine, de nombreux obstétriciens recommandent la tenue d'une césarienne planifiée pour ce qui est des femmes ayant déjà subi une myomectomie. Cette pratique a mené à la hausse du taux de césarienne planifiée et, subséquemment, à celle du taux de césarienne itérative. Cette étude avait pour objectif d'évaluer les points de vue des obstétriciens en ce qui concerne le travail et l'accouchement à la suite d'une myomectomie abdominale ou laparoscopique. Méthodes : Nous avons mené un sondage auprès de 49 obstétriciens praticiens, entre juillet 2012 et janvier 2013, au moyen d'un questionnaire standard. Ce dernier comptait des questions sur le travail et l'accouchement à la suite d'une myomectomie menée par laparotomie ou par laparoscopie. Résultats : De façon globale, le consensus inter-répondants était assez bon (kappa 0,3; P < 0,001). Aucune différence significative n'a été constatée en ce qui concerne la probabilité que les répondants permettent la tenue d'un accouchement vaginal à la suite d'une myomectomie menée par laparotomie ou par laparoscopie (27 % et 14 %, si la cavité utérine avait été pénétrée, et 76 % et 71 %, si la cavité utérine n'avait pas été pénétrée, respectivement). Cependant, la probabilité que les répondants permettent la tenue d'un accouchement vaginal était considérablement atténuée lorsque la cavité utérine avait été pénétrée, peu importe l'approche chirurgicale utilisée (P < 0,001). La probabilité que les obstétriciens recommandent la tenue d'une césarienne planifiée, plutôt que celle d'un déclenchement du travail, connaissait également une hausse significative lorsque la cavité utérine avait été pénétrée au cours de la myomectomie. Aucune différence significative n'a été constatée au niveau de la pratique en ce qui concerne l'utilisation d'oxytocine conjointement avec une amniotomie, d'oxytocine en perfusion ou de prostaglandines. Conclusion : Malgré le manque de données sur le sujet, les obstétriciens considèrent que la pénétration de la cavité utérine pendant la myomectomie (et ce, peu importe l'approche chirurgicale utilisée dans le cadre de cette dernière) constitue un facteur important au moment de prendre des décisions quant au mode d'accouchement, à l'utilisation d'oxytocine et au recours à une césarienne planifiée.

The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma.

PURPOSE: Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking. EXPERIMENTAL DESIGN: We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent. RESULTS: The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib. CONCLUSIONS: In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.

Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436).

PURPOSE: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib. EXPERIMENTAL DESIGN: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available. RESULTS: All baseline patient samples had BRAF(V600E/K) confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1-24.3) vs. 32.1 weeks (95% CI, 24.1-33), P=0.059]. Higher copy number of CCND1 (P=0.009) and lower copy number of CDKN2A (P=0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors. CONCLUSIONS: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients.

Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer.

PURPOSE: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. PATIENTS AND METHODS: Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥ 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. RESULTS: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment. CONCLUSION: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer.

RETIRED: Cancer chemotherapy and pregnancy.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.