Survival outcome according to KRAS mutation status in newly diagnosed patients with stage IV non-small cell lung cancer treated with platinum doublet chemotherapy

Introduction

Mutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20–25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear.

Methods

We undertook a single-institution retrospective analysis of 93 consecutive patients with stage IV NSCLC adenocarcinoma with known KRAS and EGFR MT status to determine the association of KRAS MT with survival. All patients were treated between January 1, 2008 and December 31, 2011 with standard platinum based chemotherapy at the University of Pennsylvania. Overall and progression free survival were analyzed using Kaplan-Meier and Cox proportional hazard methods.

Results

All patients in this series received platinum doublet chemotherapy, and 42 (45%) received bevacizumab. Overall survival and progression free survival for patients with KRAS MT was no worse than for patients with wild type KRAS. Median overall survival for patients with KRAS MT was 19 months (mo) vs. 15.6 mo for KRAS WT, p = 0.34, and progression-free survival was 6.2 mo in patients with KRAS MT vs. 7mo in patients with KRAS WT, p = 0.51. In multivariable analysis including age, race, gender, and ECOG PS, KRAS MT was not associated with overall survival (HR 1.12, 95% CI 0.58–2.16, p = 0.74) or progression free survival (HR 0.80, 95% CI 0.48–1.34, p = 41). Of note, receipt of bevacizumab was associated with improved overall survival only in KRAS WT patients (HR 0.34, p = 0.01).

Conclusions

KRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy.     

VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

Aim

VE1 is a monoclonal antibody detecting mutant BRAF^V600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients.

Methods

Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks).

Results

Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks.

Conclusion

VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays.     

Sonographische Funktionsbeurteilung von H?modialysefisteln

Zusammenfassung Hintergrund und Ziel:   Für die Hämodialyse und verwandte Verfahren wird ein stabiler Gefäßzugang benötigt, wobei die Brescia-Cimino-Fistel am nicht dominierenden Unterarm die beste Form darstellt. Die apparative Diagnostik von Fisteldysfunktionen erfolgt heute in erster Linie mit der farbkodierten Duplexsonographie. Der Wert der dopplersonographischen Widerstandsindex-( RI-)Messung am zuführenden Gefäß für die Vorhersage des Stromzeitvolumens der Fistel sollte beurteilt werden. Patienten und Methodik:   Bei 47 Patienten mit Dialysefisteln wurden morphologische und funktionelle Untersuchungen des Fistelarms einschließlich Stromzeitvolumenbestimmung mittels farbkodierter Duplexsonographie durchgeführt. Es erfolgten RI-Messungen proximal und distal der Fistel sowie am kontralateralen Arm an den gleichen Ableitorten mit Hilfe der bidirektionalen CW-Doppler-Sonographie. Die systolischen Fingerarteriendrücke am zweiten und dritten Finger beider Hände wurden dopplersonographisch ermittelt. Es wurden Untersuchungen zur Feststellung eines Zusammenhangs zwischen dem proximalen RI und dem Stromzeitvolumen durchgeführt. Ergebnisse:   Am Fistelarm lagen proximal und distal niedrigere RI-Werte vor als am kontralateralen Arm. Die systolischen Fingerarteriendrücke waren am Fistelarm niedriger. Die Stromzeitvolumina waren bei Oberarmfisteln höher als bei Unterarmfisteln, bedingt durch die größeren Gefäßdurchmesser. Eine lineare Korrelation zwischen dem proximalen RI und dem Stromzeitvolumen der Fistel ließ sich nicht belegen. 50% der Unterarmfisteln mit einem proximalen RI 0,53 wiesen ein Stromzeitvolumen < 400 ml/min auf. Schlussfolgerung:   Die Bestimmung des RI an der fistelspeisenden Arterie bei Unterarmfisteln eignet sich zur Identifizierung von Unterarmfisteln mit für eine effektive Hämodialyse zu geringen Stromzeitvolumina. In diesen Fällen ist eine weitere Untersuchung der betreffenden Fisteln indiziert. Viele Einflüsse, vor allem auf die Bestimmung der Stromzeitvolumina, sind zu beachten. Empfehlenswert sind intraindividuelle Längsschnittuntersuchungen mit der CW-Doppler-Sonographie zur Evaluation der Dynamik der Dialysefisteln, um bessere Möglichkeiten für die Überwachung der funktionstüchtigen Fisteln zur Verfügung zu haben.     

Diagnosis of bacterial infection in the ICU: General principles

Diagnosis and treatment of infection is a common procedure in the clinical management of patients in the ICU. Infection in the ICU is an important area for study, but requires well-defined and proven diagnostic criteria. The diagnosis of infection, like any diagnosis, is based on probability, and diagnostic criteria are therefore selected according to the physician's objectives and the acceptable margin of error. It is easier to diagnose correctly a full-blown, severe bacterial infection than one that is just beginning, and the same criteria cannot be used to identify accurately both conditions. We should diagnose an infectious complication at the time it needs treatment, but there is often a lack of clear objectives in the diagnostic process, and up to now, few reliable criteria have been available. Before considering the sensitivity and specificity of single diagnostic procedures it is important to trace the evolution of the infection. The problem may be approached in two steps, by describing or defining (i) the minimum level of severity of a probable infection which requires/justifies specific treatment as the first end-point of the diagnosis, and (ii) the ways the diagnosis may be confirmed using the best available procedure (which might not be always available or applicable in all cases in the short term).     

Definition and Prioritization of Data Elements for Cohort Studies and Clinical Trials on Patients with Unruptured Intracranial Aneurysms: Proposal of a Multidisciplinary Research Group

Introduction

Variability in usage and definition of data characteristics in previous cohort studies on unruptured intracranial aneurysms (UIA) complicated pooling and proper interpretation of these data. The aim of the National Institute of Health/National Institute of Neurological Disorders and Stroke UIA and Subarachnoid Hemorrhage (SAH) Common Data Elements (CDE) Project was to provide a common structure for data collection in future research on UIA and SAH.

Methods

This paper describes the development and summarization of the recommendations of the working groups (WGs) on UIAs, which consisted of an international and multidisciplinary panel of cerebrovascular specialists on research and treatment of UIAs. Consensus recommendations were developed by review of previously published CDEs for other neurological diseases and the literature on UIAs. Recommendations for CDEs were classified by priority into ‘Core,’ ‘Supplemental—Highly Recommended,’ ‘Supplemental,’ and ‘Exploratory.’

Results

Ninety-one CDEs were compiled; 69 were newly created and 22 were existing CDEs. The CDEs were assigned to eight subcategories and were classified as Core (8), Supplemental—Highly Recommended (23), Supplemental (25), and Exploratory (35) elements. Additionally, the WG developed and agreed on a classification for aneurysm morphology.

Conclusion

The proposed CDEs have been distilled from a broad pool of characteristics, measures, or outcomes. The usage of these CDEs will facilitate pooling of data from cohort studies or clinical trials on patients with UIAs.