PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003.

HER2-HER3 Heterodimer Quantification by FRET-FLIM and Patient Subclass Analysis of the COIN Colorectal Trial.

BACKGROUND: The phase III MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. METHODS: HER2-HER3 dimerization was quantified by fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided. RESULTS: Latent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .02). A class prediction signature was formed and tested on an independent validation cohort (n = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (n = 1630) based on 10 baseline clinicopathological and genetic covariates. CONCLUSIONS: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.

Microdroplet digital PCR: detection and quantitation of biomarkers in archived tissue and serial plasma samples in patients with lung cancer.

INTRODUCTION: There is much interest in the use of noninvasive biomarkers in the management of lung cancer, particularly with respect to early diagnosis and monitoring the response to intervention. Cell-free tumor DNA in patients with cancer has been shown to hold potential as a noninvasive biomarker, in which the response to treatment may be evaluated using a blood test only. Multiple technologies have been suggested as being appropriate to measure cell-free tumor DNA. Microdroplet digital polymerase chain reaction (mdPCR) has a number of attributes that suggest it may be a useful tool for detecting clinically relevant genetic events. It offers precise and accurate quantitation of mutant alleles, including rare variants. METHODS: We evaluate the performance of mdPCR in the analysis of DNA extracted from reference standards, tumor biopsies, and patient plasma. RESULTS: The potential of mdPCR to detect clinically relevant mutations is demonstrated, in both formalin-fixed paraffin-embedded material and plasma. Furthermore, we show that mdPCR can be used to track changes in peripheral blood biomarkers in response to treatment and to detect the emergence of drug-resistant clones. CONCLUSIONS: MdPCR has potential as a tool to detect and quantify tumor-derived mutational events in cell-free DNA from patients with lung cancer.

Cardiobacterium hominis prosthetic valve endocarditis: an infrequent infection.

A case of prosthetic aortic valve endocarditis due to Cardiobacterium hominis in a 67-year-old woman is described. The diagnosis was confirmed by a positive blood culture and echocardiographic detection of aortic valve vegetations. The patient underwent replacement of the valve with a homograft, and received antibiotics postoperatively. She remained well after 12 months.

Blunt pulmonary contusion: admission computed tomography scan predicts mechanical ventilation.

BACKGROUND: Blunt pulmonary contusion (BPC) evolves over 12 to 24 hours, and the initial plain radiographs fail to reliably identify patients at risk of clinical deterioration. Admission computed tomography (CT) may offer accurate characterization of BPC and early prediction of the need for mechanical ventilation (MV). METHODS: This was a combination of a 5-year retrospective study (January 2002 to April 2007) and a 6-month prospective study (September 2007 to February 2008) of adult blunt trauma (BT) patients with thoracic injuries and a chest CT upon hospital arrival. The primary outcome was MV due to thoracic trauma. To ensure that MV was required for BPC and not for associated injuries, all patients with significant extrathoracic injuries (Abbreviated Injury Scale score >2) were excluded. The extent of BPC was measured by two scoring systems. RESULTS: Of 392 patients (67% males; age, 48 years ± 21 years; Abbreviated Injury Scale score chest, 3 ± 1; and Injury Severity Score [ISS], 13 ± 6), 243 (62%) had BPC. Twenty-five (6%) patients required MV and two (0.5%) died. The combination of Glasgow Coma Scale (GCS) score <14, BPC score >2, and >4 ribs fractured predicted MV in 100% of the cases, and the absence of all factors precluded MV in 100%. In the prospective period of 6 months, 55 patients had BPC and we confirmed our finding that the absence of the three factors precludes MV. CONCLUSION: A simple score derived by the initial chest CT, in combination with GCS and the number of fractured ribs, can predict the need for MV early. In the presence of these predictors, patients should be admitted to a high level of monitoring.