Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra®, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours

This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1–7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m−2 and cisplatin 75 mg m−2. Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m−2 and cisplatin 75 mg m−2. This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting

Assessment of algorithms for mitosis detection in breast cancer histopathology images

The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues. In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists

Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor

Contains fulltext : 69595.pdf (publisher's version ) (Closed access)PURPOSE: In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. METHODS: Three intravenous cisplatin-regimens, given concurrently with radiation, were studied: daily low-dose (6 mg/m(2)) cisplatin, weekly 40 mg/m(2), three-weekly 100 mg/m(2). A (32)P-postlabeling technique was used to quantify adducts in normal tissue [white blood cells (WBC) and buccal cells] and tumor. RESULTS: Normal tissue samples for adduct determination were obtained from 63 patients and tumor biopsies from 23 of these patients. Linear relationships and high correlations were observed between the levels of two guanosine- and adenosine-guanosine-adducts in normal and tumor tissue. Adduct levels in tumors were two to five times higher than those in WBC (P<0.001). No significant correlations were found between adduct levels in normal tissues and primary tumor biopsies, nor between WBC and buccal cells. CONCLUSIONS: In concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumors were significantly higher than in normal tissues (WBC). No evidence of a correlation was found between adduct levels in normal tissues and primary tumor biopsies. This lack of correlation may, to some extent, explain the inconsistencies in the literature regarding whether or not cisplatin-DNA adducts can be used as a predictive test in anticancer platinum therapy

Assessment of left ventricular function: visual or quantitative?

Cardiovascular Aspects of Radiolog

From endurance to power athletes: The changing shape of successful male professional tennis players.

The aim of the present study was to identify whether the relative shape and size characteristics of elite male tennis players have changed over time, and in addition whether any anthropometric parameters characterise the more successful players in Grand Slam tournaments. The height and body mass of the players qualifying for the first round in all four Grand Slam tennis tournaments during the period 1982-2011 was obtained, and successful players defined arbitrarily as those reaching round 3 or beyond. Body mass index (BMI) and the reciprocal ponderal index (RPI) were used as our measures of body shape. Multilevel modelling was used to explore the trend over time using non-linear polynomials. The results suggest that the body shape of elite tennis players has changed over time, with a non-linear (cubic polynomial regression model) increase in BMI and a similar non-linear decline in the RPI. BMI, reflecting greater muscle mass rather than greater adiposity, has emerged as an important factor associated with success, identified by a significantly positive (steeper) "successful player"-by-"year" interaction term. The evidence that the RPI of elite tennis players has also decreased over time, together with a significantly negative "successful player"-by-"year" interaction term, suggests that a more linear (ectomorphic) body shape is a less important factor in terms of success. These results suggest that elite male tennis players are becoming more power trained athletes as opposed to endurance athletes, with greater muscle mass being an important factor associated with success in all Grand Slam tournaments