Real-World Treatment Patterns and Clinical Outcomes in Patients With Stage III NSCLC: Results of KINDLE, a Multicountry Observational Study.

INTRODUCTION: Stage III NSCLC is a heterogeneous disease requiring a multimodal management approach. We conducted a real-world, global study to characterize patients, treatment patterns, and their associated clinical outcomes for stage III NSCLC. METHODS: KINDLE was a retrospective study in patients with stage III NSCLC (American Joint Committee on Cancer, seventh edition) diagnosed between January 2013 and December 2017, with at least 9 months of documented follow-up since index diagnosis. In addition to descriptive statistics, Kaplan-Meier methodology evaluated survival estimates; two-sided 95% confidence interval was computed. Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: A total of 3151 patients from more than 100 centers across 19 countries from Asia, Middle East, Africa, and Latin America were enrolled. Median age was 63.0 years (range: 21.0-92.0); 76.5% were males, 69.2% had a smoking history, 53.7% had adenocarcinoma, and 21.4% underwent curative resection. Of greater than 25 treatment regimens, concurrent chemoradiotherapy was the most common (29.4%). The overall median progression-free survival (95% confidence interval) and median overall survival (mOS) were 12.5 months (12.06-13.14) and 34.9 months (32.00-38.01), respectively. Significant associations (p < 0.05) were observed for median progression-free survival and mOS with respect to sex, region, smoking status, stage, histology, and Eastern Cooperative Oncology Group status. In univariate and multivariate analyses, younger age, stage IIIA, better Eastern Cooperative Oncology Group status, concurrent chemoradiotherapy, and surgery as initial therapy predicted better mOS. CONCLUSIONS: KINDLE reveals the diversity in treatment practices and outcomes in stage III NSCLC in a real-world setting in the preimmuno-oncology era. There is a high unmet medical need, necessitating novel approaches to optimize outcomes.

Cancer cell detection device for the diagnosis of bladder cancer from urine.

Bladder cancer is common and has one of the highest recurrence rates. Cystoscopy, the current gold standard diagnosis approach, has recently benefited from the introduction of blue light assisted photodynamic diagnostic (PDD). While blue light cystoscopy improves diagnostic sensitivity, it remains a costly and invasive approach. Here, we present a microfluidic-based platform for non-invasive diagnosis which combines the principle of PDD with whole cell immunocapture technology to detect bladder cancer cells shed in patient urine ex vivo. Initially, we demonstrate with model cell lines that our non-invasive approach achieves highly specific capture rates of bladder cancer cells based on their Epithelial Cell Adhesion Molecule expression (>90%) and detection by the intensity levels of Hexaminolevulinic Acid-induced Protoporphyrin IX fluorescence. Then, we show in a pilot study that the biosensor platform successfully discriminates histopathologically diagnosed cancer patients (n = 10) from non-cancer controls (n = 25). Our platform can support the development of a novel non-invasive diagnostic device for post treatment surveillance in patients with bladder cancer and cancer detection in patients with suspected bladder cancer.

Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study.

OBJECTIVE: The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer. PATIENTS AND METHODS: In this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator's choice of 175 mg/m q3w or 80 mg/m weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety. RESULTS: Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1-50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7-27.6 months). CONCLUSION: Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT-ACS Trial.

BACKGROUND: The Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non-ST-Segment Elevation Myocardial Infarction (SELECT-ACS) trial suggested beneficial effects of inclacumab, a monoclonal antibody directed against P-selectin, on periprocedural myocardial damage. This study evaluated the effect of inclacumab on myocardial damage according to varying time intervals between study drug infusion and percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients (n=544) enrolled in the SELECT-ACS trial and randomized to receive 1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 hours before PCI) were divided according to the time interval between study drug infusion and PCI. The primary end point was the change in troponin I from baseline at 16 and 24 hours after PCI. In patients receiving inclacumab 20 mg/kg with a short (less than median) time interval between infusion and PCI, placebo-adjusted geometric mean percent changes in troponin I, creatine kinase-myocardial band, and peak troponin I at 24 hours were -45.6% (P=0.005), -30.7% (P=0.01), and -37.3% (P=0.02), respectively. No significant changes were observed in patients with a long (greater than median) time interval between infusion and PCI. Placebo-adjusted geometric mean percent changes in troponin I and creatine kinase-myocardial band were -43.5% (P=0.02) and -26.0% (P=0.07), respectively, when inclacumab 20 mg/kg was administered between 1 and 3 hours before PCI, whereas the drug had no effect with longer intervals. CONCLUSIONS: Inclacumab 20 mg/kg significantly reduces myocardial damage after PCI in patients with non-ST-segment elevation myocardial infarction, and benefits are larger when the infusion is administered <3 hours before PCI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01327183.

Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial.

OBJECTIVES: The study aimed to evaluate inclacumab for the reduction of myocardial damage during a percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation myocardial infarction. BACKGROUND: P-selectin is an adhesion molecule involved in interactions between endothelial cells, platelets, and leukocytes. Inclacumab is a recombinant monoclonal antibody against P-selectin, with potential anti-inflammatory, antithrombotic, and antiatherogenic properties. METHODS: Patients (N = 544) with non-ST-segment elevation myocardial infarction scheduled for coronary angiography and possible ad hoc PCI were randomized to receive 1 pre-procedural infusion of inclacumab 5 or 20 mg/kg or placebo. The primary endpoint, evaluated in patients who underwent PCI, received study medication, and had available efficacy data (n = 322), was the change in troponin I from baseline at 16 and 24 h after PCI. RESULTS: There was no effect of inclacumab 5 mg/kg. Placebo-adjusted geometric mean percent changes in troponin I with inclacumab 20 mg/kg were -24.4% at 24 h (p = 0.05) and -22.4% at 16 h (p = 0.07). Peak troponin I was reduced by 23.8% (p = 0.05) and area under the curve over 24 h by 33.9% (p = 0.08). Creatine kinase-myocardial band yielded similar results, with changes of -17.4% at 24 h (p = 0.06) and -16.3% at 16 h (p = 0.09). The incidence of creatine kinase-myocardial band increases >3 times the upper limit of normal within 24 h was 18.3% and 8.9% in the placebo and inclacumab 20-mg/kg groups, respectively (p = 0.05). Placebo-adjusted changes in soluble P-selectin level were -9.5% (p = 0.25) and -22.0% (p < 0.01) with inclacumab 5 and 20 mg/kg. There was no significant difference in adverse events between groups. CONCLUSIONS: Inclacumab appears to reduce myocardial damage after PCI in patients with non-ST-segment elevation myocardial infarction. (A Study of RO4905417 in Patients With Non ST-Elevation Myocardial Infarction [Non-STEMI] Undergoing Percutaneous Coronary Intervention; NCT01327183).

The index of microcirculatory resistance measured acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: This study investigated the relationship between the index of microcirculatory resistance (IMR) with myocardial injury and microvascular obstruction (MVO) assessed by contrast-enhanced cardiac magnetic resonance (ceCMR) imaging in a broad range of ST-segment elevation myocardial infarction (STEMI) patients undergoing emergency percutaneous coronary intervention (PCI). BACKGROUND: Contrast-enhanced cardiac magnetic resonance imaging is the gold standard for assessment of microvascular obstruction (MVO), left ventricular (LV) ejection fraction, and infarct volumes in ST-segment elevation myocardial infarction (STEMI). However, ceCMR is not available acutely. The index of microcirculatory resistance is a simple invasive measure of microvascular function available at the time of emergency PCI. We investigated the relationship between IMR with myocardial injury and MVO assessed by ceCMR in STEMI patients undergoing emergency PCI. METHODS: Fifty-seven patients with STEMI were included and 53 (93%) and 47 (82%) patients had complete ceCMR scans 2 days and 3 months following MI, respectively. Microvascular obstruction was defined as a dark core of hypoenhancement within the area of hyperenhanced infarct tissue 10 to 15 min following intravenous gadolinium (0.1 mmol/kg). RESULTS: The median IMR (interquartile range [IQR]) was 35 (24 to 63) U. Twenty-seven patients (46%) had MVO. We found that IMR (median [IQR]) was higher in patients with MVO (38 [29 to 55] U) than in patients without MVO (27 [18 to 36] U); p = 0.003). The index of microcirculatory resistance was a negative multivariable predictor of LV ejection fraction, (p < or = 0.001) and infarct volume (p = 0.01) on the ceCMR scan 2 days after MI, and IMR was a multivariable predictor of LV ejection fraction (p = 0.028) and infarct volume (p = 0.048) at 3 months. CONCLUSIONS: The index of microcirculatory resistance measured acutely was higher in patients with MVO on ceCMR, and IMR independently predicted LV function and infarct volume. This easily measured physiological parameter provides important prognostic information at the time of emergency PCI.

Declining renal function after myocardial infarction predicts poorer long-term outcome.

INTRODUCTION: In-hospital decline in renal function during the immediate post myocardial infarction (MI) period is known to predict poorer outcome; subsequent chronic change in renal function is less well reported. This study sought to track long-term change in renal function after MI, and assess its correlation with the outcome. METHODS AND RESULTS: Individuals who had sustained a first validated MI in the preceding 2.5-11.5 years were identified from the monitoring of trends and determinants in cardiovascular disease (MONICA) register and were invited to undergo a screening process in 1995, and again in 1998. All deaths were recorded up to the end of 2006. Change in renal function between 1995 and 1998 was available for 500 individuals (mean age 61.6+/-7.3 years, 74.8% men). Change in (Delta) calculated estimated glomerular filtration rate (eGFR) was normally distributed, with a mean crude fall in eGFR of 1.91+/-9.47 ml/min per 1.73 m. This corresponded to a -1.9+/-13.3% change in eGFR, or -0.8+/-3.6 ml/min/1.73 m2 per year. Delta eGFR correlated negatively with baseline eGFR (r=l-0.307, P<0.001). The first tertile (with the largest decline in eGFR) had an adjusted hazard ratios of 1.86 (1.14-3.03) for all cause mortality and 2.06 (1.13-3.74) for cardiovascular death, compared to the third tertile. A rise in creatinine of greater than 0.3 mg/dl carried adjusted hazard ratios of 2.27 (1.13-4.57) and 3.61 (1.73-7.54) for all cause mortality and cardiovascular death, respectively. CONCLUSION: Chronic change in renal function after MI is predictive of long-term prognosis.

The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study.

OBJECTIVES: To determine the diagnostic accuracy of the measurement of plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTproBNP) in patients referred by their general practitioners (GPs) with symptoms suggestive of heart failure. Additionally, to compare the diagnostic accuracy of the resting 12-lead electrocardiogram (ECG) with that of the peptides. DESIGN: A diagnostic accuracy study. SETTING: Rapid-access heart failure clinics in five hospitals. PARTICIPANTS: 306 patients referred by their GPs with suspected heart failure. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and positive and negative likelihood ratios for BNP, NTproBNP and the ECG for the diagnosis of heart failure. Area under the receiver operating characteristics (ROC) curves for the two natriuretic peptides. RESULTS: The diagnosis of heart failure was confirmed in 104 (34%) patients. The area under the ROC curve was 0.84 [95% CI 0.79-0.89] for BNP and 0.85 [0.81-0.90] for NTproBNP. At the manufacturers' recommended decision cut-points, NTproBNP provided a higher NPV (0.97) than BNP (0.87), but at lower PPV (0.44 versus 0.59). An abnormal ECG did not add any further predictive value to that of NTproBNP. CONCLUSIONS: We have confirmed the value of the measurement of plasma BNP or NTproBNP as a 'rule-out' test for heart failure in patients currently referred by GPs to rapid access diagnostic clinics. A simple classification of the 12-lead ECG into 'normal' or 'abnormal' adds little value to ruling out heart failure in these circumstances. Further work is necessary to establish the best decision cut-points for use in clinical practice.

Patient differences related to management in general practice and the hospital: a cross-sectional study of heart failure in the community.

AIM: To compare patients treated for heart failure in relation to the management in general practices versus hospital admission. METHODS AND RESULTS: Twelve randomly selected general practices (GP) were screened for patients receiving ACE-inhibitor, digoxin, or loop diuretic treatment. The first 500 volunteers of 959 potential subjects were invited to a cardiac examination after exclusion of 235 frail, physically or mentally disabled patients. A diagnosis of heart failure during hospital admission (Hospital-HF, n = 102) was more related (p < 0.05) to male sex (45% vs. 21%), advanced age (73 vs. 70 years), breathlessness (75% vs. 62%), LV systolic dysfunction (47% vs. 20%), objective cardiac abnormality (92% vs. 65%) and higher 4-year mortality (33% vs. 15%) than patients taking loop diuretics due to signs and symptoms of heart failure in GP (GP-HF). Patients without clinical heart failure (n = 301) had the same survival but less symptoms and cardiac abnormalities than GP-HF patients. CONCLUSION: A surplus morbidity and mortality was related to a hospital-based rather than a GP based diagnosis of HF. Patients managed in GP were different from patients entering previous clinical trials of heart failure. We estimate that the pool of patients hospitalised with systolic heart failure would be increased from 1.3 to 1.4 more if all patients from primary care were included.

Retrospective analysis of the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic dysfunction in the general population.

OBJECTIVES: We sought to assess the cost-effectiveness of using plasma brain natriuretic peptide (BNP) as a pre-echocardiographic screening test for left ventricular systolic dysfunction (LVSD) in the general population. BACKGROUND: We hypothesized that plasma BNP and simple clinical parameters would reduce the number of echocardiograms needed and cost when screening for LVSD in the general population. METHODS: A random sample of 1,257 community subjects (age 25 to 74 years) was examined. Three risk groups were formed: one group with symptomatic ischemic heart disease (IHD); a second group with blood pressure >160/95 mm Hg and/or an abnormal electrocardiogram (high risk); and a group with none of these risk factors (low risk). The BNP assay was adjusted to give a high sensitivity. RESULTS: Left ventricular systolic dysfunction was prevalent in 0.7% (6/823), 6% (16/269), and 19% (26/140) of low-risk and high-risk subjects and IHD subjects, respectively. Raised BNP concentrations (>8 pg/ml) occurred in 41%, 64%, and 71%. Sensitivities of BNP for detecting LVSD were 83% (5/6), 94% (15/16), and 92% (24/26); and the negative predictive values were 99.8%, 99.0%, and 95.1%. Brain natriuretic peptide was not associated with LVSD in low-risk subjects (p = 0.087), but in IHD subjects (p = 0.015) and high-risk subjects (p = 0.023). Screening high-risk subjects by BNP before echocardiography could have reduced the cost per detected case of LVSD by 26% for the cost ratio of 1/20 (BNP/echocardiogram). CONCLUSIONS: Subjects at low and high risk of LVSD can be identified by simple clinical parameters, and BNP testing further reduces the number of echocardiograms needed and the costs of screening in subjects at risk <75 years of age in the general population.