IKZF1 alterations are not associated with outcome in 498 adults with B-precursor ALL enrolled in the UKALL14 trial

IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1− B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420). Although patients with BCR-ABL1− ΔIKZF1 were more likely to have minimal residual disease at the end of induction, we did not find any impact of ΔIKZF1 (including subgroup analysis for DN or loss-of-function lesions) or the IKZF1plus genotype on event-free, overall survival, or relapse risk by univariable or multivariable analyses. Consistent with the technical approach, MLPA not only detected a wider range of deletions than PCR but also failed to detect some PCR-detected lesions. The main difference between our study and others reporting an association between ΔIKZF1 and outcome is the older age of participants in our population. The impact of ΔIKZF1 in ALL may be less marked in an older population of patients. Our study underscores the need for analyses in large, harmonized data sets. This trial was registered at www.clinicaltrials.gov as #NCT01085617

Erratum. Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 2014;63:3835–3845

The article to which this is the erratum is available in ORE at: http://hdl.handle.net/10871/17968In the article, there are two errors in the research design and methods section. In the section with the heading “Studies on Islet-Infiltrating Leukocytes,” the antibody listed as #M0701 should be attributed to Dako and not to Abcam and the Abcam rabbit anti-CD8 catalogue number should read #ab4055 and not #GR404-4. The online version reflects these changes

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

Utilization of focal therapy for patients discontinuing active surveillance of prostate cancer: Recommendations of an international Delphi consensus

BACKGROUND: With the advancement of imaging technology, focal therapy (FT) has been gaining acceptance for the treatment of select patients with localized prostate cancer (CaP). We aim to provide details of a formal physician consensus on the utilization of FT for patients with CaP who are discontinuing active surveillance (AS). METHODS: A 3-stage Delphi consensus on CaP and FT was conducted. Consensus was defined as agreement by ≥80% of physicians. An in-person meeting was attended by 17 panelists to formulate the consensus statement. RESULTS: Fifty-six respondents participated in this interdisciplinary consensus study (82% urologist, 16% radiologist, 2% radiation oncology). The participants confirmed that there is a role for FT in men discontinuing AS (48% strongly agree, 39% agree). The benefit of FT over radical therapy for men coming off AS is: less invasive (91%), has a greater likelihood to preserve erectile function (91%), has a greater likelihood to preserve urinary continence (91%), has fewer side effects (86%), and has early recovery post-treatment (80%). Patients will need to undergo mpMRI of the prostate and/or a saturation biopsy to determine if they are potential candidates for FT. Our limitations include respondent's biases and that the participants of this consensus may not represent the larger medical community. CONCLUSIONS: FT can be offered to men coming off AS between the age of 60 to 80 with grade group 2 localized cancer. This consensus from a multidisciplinary, multi-institutional, international expert panel provides a contemporary insight utilizing FT for CaP in select patients who are discontinuing AS

Enhanced upper genital tract pathologies by blocking Tim-3 and PD-L1 signaling pathways in mice intravaginally infected with Chlamydia muridarum

<p>Abstract</p> <p>Background</p> <p>Although Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated.</p> <p>Methods</p> <p>Neutralization antibodies targeting Tim-3 and PD-L1 were used to treat mice. Following an intravaginal infection with <it>C. muridarum </it>organisms, mice with or without the dual antibody treatment were compared for live chlamydial organism shedding from the lower genital tract and inflammatory pathology in the upper genital tract.</p> <p>Results</p> <p>Mice treated with anti-Tim-3 and anti-PD-L1 antibodies displayed a time course of live organism shedding similar to that of mice treated with equivalent amounts of isotype-matched IgG molecules. The combined antibody blocking failed to alter either the lower genital tract cytokine or systemic humoral and cellular adaptive responses to <it>C. muridarum </it>infection. However, the antibody blocking significantly enhanced <it>C. muridarum</it>-induced pathologies in the upper genital tract, including more significant hydrosalpinx and inflammatory infiltration in uterine horn and oviduct tissues.</p> <p>Conclusions</p> <p>The Tim-3 and PD-L1-mediated signaling can significantly reduce pathologies in the upper genital tract without suppressing immunity against chlamydial infection, suggesting that Tim-3 and PD-L1-mediated negative regulation may be manipulated to attenuate tubal pathologies in women persistently infected with <it>C. trachomatis </it>organisms.</p

Quadriceps force generation in patients with osteoarthritis of the knee and asymptomatic participants during patellar tendon reflex reactions: an exploratory cross-sectional study

BACKGROUND: It has been postulated that muscle contraction is slower in patients with osteoarthritis of the knee than asymptomatic individuals, a factor that could theoretically impair joint protection mechanisms. This study investigated whether patients with osteoarthritis of the knee took longer than asymptomatic participants to generate force during reflex quadriceps muscle contraction. This was an exploratory study to inform sample size for future studies. METHODS: An exploratory observational cross sectional study was carried out. Two subject groups were tested, asymptomatic participants (n = 17), mean (SD) 56.7 (8.6) years, and patients with osteoarthritis of the knee, diagnosed by an orthopaedic surgeon, (n = 16), age 65.9 (7.8) years. Patellar tendon reflex responses were elicited from participants and measured with a load cell. Force latency, contraction time, and force of the reflex response were determined from digitally stored data. The Mann-Whitney U test was used for the between group comparisons in these variables. Bland and Altman within-subject standard deviation values were calculated to evaluate the measurement error or precision of force latency and contraction time. RESULTS: No significant differences were found between the groups for force latency (p = 0.47), contraction time (p = 0.91), or force (p = 0.72). The two standard deviation measurement error values for force latency were 27.9 ms for asymptomatic participants and 16.4 ms for OA knee patients. For contraction time, these values were 29.3 ms for asymptomatic participants and 28.1 ms for OA knee patients. Post hoc calculations revealed that the study was adequately powered (80%) to detect a difference between the groups of 30 ms in force latency. However it was inadequately powered (59%) to detect this same difference in contraction time, and 28 participants would be required in each group to reach 80% power. CONCLUSION: Patients with osteoarthritis of the knee do not appear to have compromised temporal parameters or magnitude of force generation during patellar tendon reflex reactions when compared to a group of asymptomatic participants. However, these results suggest that larger studies are carried out to investigate this area further

Surgical and conservative treatment of patients with congenital scoliosis: α search for long-term results

<p>Abstract</p> <p>Background</p> <p>In view of the limited data available on the conservative treatment of patients with congenital scoliosis (CS), early surgery is suggested in mild cases with formation failures. Patients with segmentation failures will not benefit from conservative treatment. The purpose of this review is to identify the mid- or long-term results of spinal fusion surgery in patients with congenital scoliosis.</p> <p>Methods</p> <p>Retrospective and prospective studies were included, reporting on the outcome of surgery in patients with congenital scoliosis. Studies concerning a small numbers of cases treated conservatively were included too. We analyzed mid-term (5 to 7 years) and long-term results (7 years or more), both as regards the maintenance of the correction of scoliosis and the safety of instrumentation, the early and late complications of surgery and their effect on quality of life.</p> <p>Results</p> <p>A small number of studies of surgically treated patients were found, contained follow-up periods of 4-6 years that in the most cases, skeletal maturity was not yet reached, and few with follow-up of 36-44 years. The results of bracing in children with congenital scoliosis, mainly in cases with failure of formation, were also studied.</p> <p>Discussion</p> <p>Spinal surgery in patients with congenital scoliosis is regarded in short as a safe procedure and should be performed. On the other hand, early and late complications are also described, concerning not only intraoperative and immediate postoperative problems, but also the safety and efficacy of the spinal instrumentation and the possibility of developing neurological disorders and the long-term effect these may have on both lung function and the quality of life of children.</p> <p>Conclusions</p> <p>Few cases indicate the long-term results of surgical techniques, in the natural progression of scoliosis. Similarly, few cases have been reported on the influence of conservative treatment.</p> <p>In conclusion, patients with segmentation failures should be treated surgically early, according to the rate of deformity formation and certainly before the pubertal growth spurt to try to avoid cor- pulmonale, even though there is lack of evidence for that in the long-term. Furthermore, in patients with formation failures, further investigation is needed to document where a conservative approach would be necessary.</p

Expression signatures of TP53 mutations in serous ovarian cancers

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>TP53 </it>gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease.</p> <p>Methods</p> <p>The <it>TP53 </it>coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage.</p> <p>Results</p> <p>Missense or chain terminating (null) mutations in <it>TP53 </it>were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict <it>TP53 </it>status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers.</p> <p>Conclusions</p> <p>This represents the first attempt to define a genomic signature of <it>TP53 </it>mutation in ovarian cancer. Patterns of gene expression characteristic of <it>TP53 </it>mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of <it>TP53 </it>mutation in breast cancer.</p