Dissecting the Genome for Drug Response Prediction

The prediction of the cancer cell lines sensitivity to a specific treatment is one of the current challenges in precision medicine. With omics and pharmacogenomics data being available for over 1000 cancer cell lines, several machine learning and deep learning algorithms have been proposed for drug sensitivity prediction. However, deciding which omics data to use and which computational methods can efficiently incorporate data from different sources is the challenge which several research groups are working on. In this review, we summarize recent advances in the representative computational methods that have been developed in the last 2 years on three public datasets: COSMIC, CCLE, NCI-60. These methods aim to improve the prediction of the cancer cell lines sensitivity to a given treatment by incorporating drug's chemical information in the input or using a priori feature selection. Finally, we discuss the latest published method which aims to improve the prediction of clinical drug response of real patients starting from cancer cell line molecular profiles

2009

Design and Methods Patients The study cohort was constituted by 410 non-Down syndrome, non-T, Philadelphia chromosome-negative, B-cell precursor ALL patients consecutively enrolled in the AIEOP-BFM ALL2000 study in AIEOP Centers from February 2003 to July 2005, who were included in the previous study on CRLF2 alterations and for whom DNA was still available. 19 P2RY8-CRLF2 rearrangement was tested by reverse transcriptase polymerase chain reaction analysis in 372 (90.7%) patients. The project was approved by the AIEOP ALL Scientific Committee. Risk group definitions and treatment outlines have already been reported DNA copy number variations IKZF1 deletions, together with deletions in other genes (CDKN2A/B, PAX5, ETV6, BTG1, RB1 and EBF1) were investigated by multiplex ligation-dependent probe amplification (MLPA) using the Salsa MLPA P335-A3 ALL-IKZF1 kit (MRC-Holland, Amsterdam, the Netherlands) according to the manufacturer's instructions. Samples from pediatric ALL patients in complete remission were used as wild-type controls. Statistical analysis Event-free survival time was calculated from the date of diagnosis to the date of an event, which was resistance, relapse, death or second neoplasm, whichever occurred first. Patients were censored at last follow-up if no events occurred. Event-free survival was estimated according to Kaplan-Meier, and compared using the log-rank test. The cumulative incidence of relapse at 5 years was estimated by adjusting for competing risks of other events and compared using Gray's test. Results IKZF1 deletions at diagnosis IKZF1 deletions were detected in 54/410 cases (13.2%), in keeping with incidence data reported in the literature. The clinical characteristics of the patients are presented in Using the MLPA technique we further analyzed the presence of copy number variations of other genes frequently deleted in B-cell precursor ALL and known to be involved in lymphoid development (PAX5, ETV6, EBF1) or in cell cycle regulation (CDKN2A/B, BTG1, RB1). 10,20-22 We did not find statistically significant differences in the incidence of these genetic alterations in children positive or negative for IKZF1 deletions (Online Prognostic impact of IKZF1 deletions Compared to patients without a deletion of IKZF1, those with a deletion of part or all of this gene had an inferior event-free survival [70.2% (6.2) versus 85.2% (1.9) at 5 years, P=0.007] and a significantly higher cumulative incidence of relapse [24.2% (5.9) versus 13.1% (1.8) at 5 years, P= 0.049] ( These data are in accordance with those from other studies reported in the literature, in particular with those recently published by Dorge et al. who analyzed ALL patients enrolled in the AIEOP-BFM ALL2000 study in Germany [event-free survival 69% (5) versus 85% (1), P=<0.001 and cumulative incidence of relapse 21% (4) versus 10% © F e r r a t a S t o r t i F o u n d a t i o n N o c o m m e r c i a l u s e deleted patients. These events contributed to the statistical significance of the difference in the event-free survival. In both Cox model analyses, the P2RY8-CRLF2 aberration and risk group were significantly associated with outcome. Of note, when individually analyzed, the IKFZ1 deletion had a statistically significant effect on event-free survival and relapse, in keeping with results in We further analyzed the prognostic value of IKZF1 deletions within the subgroups according to protocol stratification. IKZF1 deletions were less frequent within the standard-risk group, being found in 8 out 117 standard-risk patients (6.8%), 42 out of 264 intermediate-risk patients (15.9%) and 4 out of 29 high-risk patients (13.8%) ( Discussion Previous studies Indeed, overall event-free survival for patients with IKZF1 deletions, after excluding the confounding effects of Down syndrome, T-immunophenotype and Philadelphia chromosome-positive patients, was around 70% at 5 years also in our experience. The three patients with IKZF1 deletions who were at high risk and relapsed had poor response to treatment (high minimal residual disease levels) and accordingly were all eligible for transplantation, thus identification of IKZF1 deletions would not have contributed to a better stratification. In the intermediate risk group, with a 5-year event-free survival of 70%, treatment intensification could be justified to improve results. In our context, the recent AIEOP-BFM ALL 2009 study, with a more intensive use of L-asparaginase, might already provide a benefit that reduces the impact of an IKZF1 deletion. This is especially true if we consider that in our study cohort the difference in the cumulative incidence of relapse was not so marked, being approximately 7% in the intermediate risk subgroup and 11% overall. This, as well as the lower number of events in the multivariate analysis, may explain why the presence of IKZF1 deletions is an independent prognostic factor for event-free survival but not for the hazard of relapse alone. In conclusion, based on our data, the suitability of IKZF1 deletions as an additional stratification marker for Philadelphia chromosome-negative, B-cell precursor ALL patients remains questionable, at least until new target therapy becomes available. (NoE-2011-261474). Acknowledgments The authors would like to thank Simona Songia, Lilia Corral, Eugenia Mella, Tiziana Villa (Monza), Elena Seganfreddo and Katia Polato (Padova) for AIEOP minimal residual disease monitoring and all medical doctors of the AIEOP centers. This work was supported by grants from: Fondazione Tettamanti (Monza), Fondazione Città della Speranza (Padova), Associazione Italiana Ricerca sul Cancro (AIRC) (to GB, AB, MGV, GteK and GC), MIUR (to GB and AB), Fondazione Cariplo (to AB, GC and GteK), and CARIPARO project of excellence (to GteK). This work was (partly) funded by the European Commission (FP7) under the contract ENCCA Authorship and Disclosure

Surgeons’ practice and preferences for the anal fissure treatment: results from an international survey

The best nonoperative or operative anal fissure (AF) treatment is not yet established, and several options have been proposed. Aim is to report the surgeons' practice for the AF treatment. Thirty-four multiple-choice questions were developed. Seven questions were about to participants' demographics and, 27 questions about their clinical practice. Based on the specialty (general surgeon and colorectal surgeon), obtained data were divided and compared between two groups. Five-hundred surgeons were included (321 general and 179 colorectal surgeons). For both groups, duration of symptoms for at least 6 weeks is the most important factor for AF diagnosis (30.6%). Type of AF (acute vs chronic) is the most important factor which guide the therapeutic plan (44.4%). The first treatment of choice for acute AF is ointment application for both groups (59.6%). For the treatment of chronic AF, this data is confirmed by colorectal surgeons (57%), but not by the general surgeons who prefer the lateral internal sphincterotomy (LIS) (31.8%) (p = 0.0001). Botulin toxin injection is most performed by colorectal surgeons (58.7%) in comparison to general surgeons (20.9%) (p = 0.0001). Anal flap is mostly performed by colorectal surgeons (37.4%) in comparison to general surgeons (28.3%) (p = 0.0001). Fissurectomy alone is statistically significantly most performed by general surgeons in comparison to colorectal surgeons (57.9% and 43.6%, respectively) (p = 0.0020). This analysis provides useful information about the clinical practice for the management of a debated topic such as AF treatment. Shared guidelines and consensus especially focused on operative management are required to standardize the treatment and to improve postoperative results