Health Care Delivery Practices in Huntington's Disease Specialty Clinics : An International Survey

The CHDI Foundation, Inc. funds Enroll-HD and the activities of the Enroll-HD Care Improvement Committee, including the present survey. We would like to acknowledge the Enroll-HD and REGISTRY administrative staff that assisted in the recruitment of sites and sites that completed the survey.Peer reviewedPublisher PD

iRFP is a real time marker for transformation based assays in high content screening

Anchorage independent growth is one of the hallmarks of oncogenic transformation. Here we show that infrared fluorescent protein (iRFP) based assays allow accurate and unbiased determination of colony formation and anchorage independent growth over time. This protocol is particularly compatible with high throughput systems, in contrast to traditional methods which are often labor-intensive, subjective to bias and do not allow further analysis using the same cells. Transformation in a single layer soft agar assay could be documented as early as 2 to 3 days in a 96 well format, which can be easily combined with standard transfection, infection and compound screening setups to allow for high throughput screening to identify therapeutic targets

A phase 1 study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumors.

Background: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours. Methods: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1–14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles. Results: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1–7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade greater than or equal to3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml−1 min−1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers. Conclusions: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190)

A Survey of Attitudes towards the Clinical Application of Systemic Inflammation Based Prognostic Scores in Cancer

Introduction. The systemic inflammatory response (SIR) plays a key role in determining nutritional status and survival of patients with cancer. A number of objective scoring systems have been shown to have prognostic value; however, their application in routine clinical practice is not clear. The aim of the present survey was to examine the range of opinions internationally on the routine use of these scoring systems. Methods. An online survey was distributed to a target group consisting of individuals worldwide who have reported an interest in systemic inflammation in patients with cancer. Results. Of those invited by the survey ( = 238), 65% routinely measured the SIR, mainly for research and prognostication purposes and clinically for allocation of adjuvant therapy or palliative chemotherapy. 40% reported that they currently used the Glasgow Prognostic Score/modified Glasgow Prognostic Score (GPS/mGPS) and 81% reported that a measure of systemic inflammation should be incorporated into clinical guidelines, such as the definition of cachexia. Conclusions. The majority of respondents routinely measured the SIR in patients with cancer, mainly using the GPS/mGPS for research and prognostication purposes. The majority reported that a measure of the SIR should be adopted into clinical guidelines

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer : a study protocol of a randomised phase II trial (PRIME-RT)

Acknowledgements We are grateful to Mr George Davidson and Ms Monica Jeffers for their input with writing the PRIME-RT protocol and patient information sheet. This study is co-sponsored by the University of Glasgow and NHS Greater Glasgow and Clyde. Funding PRIME-RT is funded by Astrazeneca and receives core funding from CRUK Clinical Trials Unit Glasgow for the purposes of trial set-up and data collection. The trial is co-sponsored by the University Of Glasgow and NHS Greater Glasgow and Clyde.Peer reviewedPublisher PD

Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer

Histological ‘phenotypic subtypes’ that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I–III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I–III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease‐free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II–III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893‐patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146‐patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (pinteraction = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy

The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study

<p>Abstract</p> <p>Background</p> <p>We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (<it>LRRK2</it>)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen <it>LRRK2 </it>mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of <it>LRRK2 </it>mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.</p> <p>Methods</p> <p>A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different <it>LRRK2 </it>mutations. Penetrance was estimated in families of <it>LRRK2 </it>carriers with consideration of the inherent bias towards increased penetrance in a familial sample.</p> <p>Results</p> <p>Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 <it>LRRK2 </it>mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the <it>LRRK2 </it>mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-<it>LRRK2</it>-related PD families.</p> <p>Conclusion</p> <p>Lifetime penetrance of <it>LRRK2 </it>estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained <it>LRRK2 </it>cases, suggesting that inherited susceptibility factors may modify the penetrance of <it>LRRK2 </it>mutations. In addition, the presence of nine PD phenocopies in the <it>LRRK2 </it>families suggests that these susceptibility factors may also increase the risk of non-<it>LRRK2</it>-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for <it>LRRK2 </it>carriers are independent of the factors which increase PD prevalence in men.</p