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PubMed | Fondazione Irccs Instituto Of Ricovero E Cura A Carattere Scientifico Instituto Nazionale Tumori Int, Cancer Research Initiatives Foundation, Japan National Institute of Radiological Sciences, University of Cologne and 71 more.
Type: Journal Article | Journal: Breast cancer research : BCR | Year: 2016

Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3%). Cases were defined as TH, and controls were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 controls carried a BRCA1 mutation found in the TH case. Matched SH2 controls carried a BRCA2 mutation found in the TH case. After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.The majority of TH (45.2%) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p=0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p=0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p=0.231), but was on average 4.5years younger in TH than in SH2 (p<0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p=0.010) or progesterone receptor (PR) positive (p=0.013) than in SH1, but less likely to be ER positive (p<0.001) or PR positive (p=0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.


Vickers A.J.,Memorial Sloane Kettering Cancer Center | Thompson I.M.,University of Texas Health Science Center at San Antonio | Klein E.,Cleveland Clinic | Carroll P.R.,University of California at San Francisco | Scardino P.T.,Memorial Sloane Kettering Cancer Center
Urology | Year: 2014

Although the value of prostate-specific antigen (PSA) velocity or doubling time has never been seriously questioned for aiding the clinical management of recurrent or advanced cancer, there has historically been considerable uncertainty about PSA kinetics for decisions about biopsy and initial treatment. Recent studies, including analyses of cohorts from all the major randomized trials of localized prostate cancer, have failed to find any evidence that PSA velocity and application of PSA cutpoints are of benefit in this setting. Given current data on PSA velocity and doubling time, we propose the following "take home" messages for the practicing urologist: (1) High PSA velocity is not an indication for biopsy; (2) for men with a low total PSA but a high PSA velocity, consideration should be given to having PSA taken at a shorter interval; (3) men with an indication for biopsy should be biopsied irrespective of PSA velocity; (4) changes in PSA after negative biopsy findings do not determine the need for repeat biopsy; (5) monitoring PSA over time can aid judgment in decisions about biopsy, as informed by the clinical context; (6) PSA velocity is uninformative of risk at diagnosis; (7) high PSA velocity is not an indication for treatment in men on active surveillance; (8) PSA velocity at the time of recurrence should be entered into prediction models (or "nomograms") to aid patient counseling; (9) PSA changes after treatment for advanced disease can help indicate therapeutic response.


Osterwalder U.,BASF | Herzog B.,BASF | Wang S.Q.,Memorial Sloane Kettering Cancer Center
Expert Review of Dermatology | Year: 2011

The availability of potent and broad-spectrum sunscreens can protect the skin from harmful effects induced by UV radiation. Aside from avoiding sunburn, modern-day sunscreen also has the potential to prevent skin cancer and slow photoaging, if it is used appropriately. This article traces through the evolution of sunscreens and highlights the clinical benefits, specifically in preventing skin cancers. Besides improved UV filter technology, development of UVA assessment methods and the regulatory standards are instrumental in the advancement of sunscreen efficacy. Lastly, compliance remains the most crucial factor for optimal sun protection. Sunscreen is often applied in too little amount, too late or not at all. Compliance may not improve if users do not change their behaviors and habits. © 2011 Expert Reviews Ltd.


Fielding A.K.,University College London | Rowe J.M.,Rambam Medical Center | Buck G.,Clinical Trial Service Unit | Foroni L.,Imperial College London | And 11 more authors.
Blood | Year: 2014

The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukemia (ALL) enrolled 266 patients between 1993 and 2003 (preimatinib cohort). In 2003 imatinib was introduced as a single-agent course following induction (N 5 86, late imatinib). In 2005 imatinib was added to the second phase of induction (N 5 89, early imatinib). The complete remission (CR) rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P 5 .004). At 4 years, the overall survival (OS) of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P 5 .003). The magnitude of the difference between the preimatinib and imatinib cohorts in event-free survival (EFS), OS, and relapse-free survival (RFS) seen in univariate analysis was even greater in the multivariate analysis. In the preimatinib cohort, 31% of those starting treatment achieved hematopoietic stem cell transplant (alloHSCT) compared with 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS 5 0.64, 95% confidence interval 0.44-0.93, P 5 .02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This trial was registered at clinicaltrials.gov as NCT00002514. © 2014 by The American Society of Hematology.


Mulhall J.P.,Memorial Sloane Kettering Cancer Center | Parker M.,Loyola University | Waters B.W.,Loyola University | Flanigan R.,Loyola University
BJU International | Year: 2010

OBJECTIVE To define if erectile function (EF) outcomes were better in men with early institution of penile rehabilitation after radical prostatectomy (RP), as one of the mechanisms by which patients fail to recover EF after RP is collagenization of corporal smooth muscle with subsequent venous leak development, and rehabilitation is aimed at preventing these structural alterations. PATIENTS AND METHODS The study population comprised patients who: (i) had clinically organ-confined prostate cancer; (ii) had fully functional erections, corroborated by the partner; (iii) had bilateral nerve-sparing RP; and (iv) committed to pharmacological penile rehabilitation. Patients completed the International Index of Erectile Function (IIEF) serially after RP. Patients were instructed to obtain three erections/week using initially sildenafil, and if unsuccessful, then intracavernous injections. Patients were subdivided into those starting rehabilitation at <6 months after RP (early) and those starting at ≥6 months after RP (delayed). RESULTS There were 48 patients in the early group and 36 in the delayed group; patients in both groups were matched for age, comorbidity status and baseline EF. The mean duration after RP at the time of starting penile rehabilitation was 2 and 7 months in the early and delayed groups, respectively (P < 0.01). At 2 years after surgery there was a highly statistically significant difference in IIEF EF domain score between the early and delayed groups (22 vs 16, P < 0.001). There were also statistically significant differences between the groups in the percentage of men at 2 years after RP who had unassisted functional erections and sildenafil-assisted functional erections (58% vs 30%, P < 0.01; 86% vs 45%, P < 0.01, respectively). CONCLUSIONS These data suggest that delaying the start of penile rehabilitation after RP is associated with poorer outcomes for EF. © 2009 BJU International.


Kale A.,Yeshiva University | Li W.,Yeshiva University | Li W.,Memorial Sloane Kettering Cancer Center | Lee C.-H.,Yeshiva University | Baker N.E.,Yeshiva University
Cell Death and Differentiation | Year: 2015

Heterozygosity for mutations in ribosomal protein genes frequently leads to a dominant phenotype of retarded growth and small adult bristles in Drosophila (the Minute phenotype). Cells with Minute genotypes are subject to cell competition, characterized by their selective apoptosis and removal in mosaic tissues that contain wild-type cells. Competitive apoptosis was found to depend on the pro-apoptotic reaper, grim and head involution defective genes but was independent of p53. Rp/+ cells are protected by anti-apoptotic baculovirus p35 expression but lacked the usual hallmarks of 'undead' cells. They lacked Dronc activity, and neither expression of dominant-negative Dronc nor dronc knockdown by dsRNA prevented competitive apoptosis, which also continued in dronc null mutant cells or in the absence of the initiator caspases dredd and dream/strica. Only simultaneous knockdown of dronc and dream/strica by dsRNA was sufficient to protect Rp/+ cells from competition. By contrast, Rp/Rp cells were also protected by baculovirus p35, but Rp/Rp death was dronc-dependent, and undead Rp/Rp cells exhibited typical dronc-dependent expression of Wingless. Independence of p53 and unusual dependence on Dream/Strica distinguish competitive cell death from noncompetitive apoptosis of Rp/Rp cells and from many other examples of cell death. © 2015 Macmillan Publishers Limited.


Chambers S.K.,Griffith University | Chambers S.K.,Prostate Cancer Foundation of Australia | Chambers S.K.,Edith Cowan University | Zajdlewicz L.,Cancer Council Queensland | And 4 more authors.
Psycho-Oncology | Year: 2014

Background The Distress Thermometer (DT) is widely recommended for screening for distress after cancer. However, the validity of the DT in men with prostate cancer and over differing time points from diagnosis has not been well examined. Method Receiver operating characteristics analyses were used to evaluate the diagnostic accuracy of the DT compared with three commonly used standardised scales in two prospective and one cross-sectional survey of men with prostate cancer (n = 740, 189 and 463, respectively). Comparison scales included the Impact of Event Scale - Revised (IES-R, Study 1), the Hospital Anxiety and Depression Scale (HADS, Study 2) and the Brief Symptom Inventory-18 (BSI-18, Study 3). Results Study 1: the DT showed good accuracy against the IES-R at all time points (area under curves (AUCs) ranging from 0.84 to 0.88) and sensitivity was high (>85%). Study 2: the DT performed well against both the anxiety and depression subscales for HADS at baseline (AUC = 0.84 and 0.82, respectively), but sensitivity decreased substantially after 12 months. Study 3: validity was high for the anxiety (AUC = 0.90, sensitivity = 90%) and depression (AUC = 0.85, sensitivity = 74%) subscales of the BSI-18 but was poorer for somatization (AUC = 0.67, sensitivity = 52%). A DT cut-off between ≥3 and ≥6 maximised sensitivity and specificity across analyses. Conclusions The DT is a valid tool to detect cancer-specific distress, anxiety and depression among prostate cancer patients, particularly close to diagnosis. A cut-off of ≥4 may be optimal soon after diagnosis, and for longer-term assessments, ≥3 was supported. © 2013 The Authors. Psycho-Oncology published by John Wiley & Sons, Ltd. © 2013 The Authors. Psycho-Oncology published by John Wiley & Sons, Ltd.


Krestin G.P.,Rotterdam University | Grenier P.A.,Service de Radiologie Polyvalente Diagnostique et Interventionnelle | Hricak H.,Memorial Sloane Kettering Cancer Center | Jackson V.P.,Indiana University | And 5 more authors.
European Radiology | Year: 2012

The International Society for Strategic Studies in Radiology held its 9th biennial meeting in August 2011. The focus of the programme was integrated diagnostics and massive computing. Participants discussed the opportunities, challenges, and consequences for the discipline of radiology that will likely arise from the integration of diagnostic technologies. Diagnostic technologies are increasing in scope, including advanced imaging techniques, new molecular imaging agents, and sophisticated point-of-use devices. Advanced information technology (IT), which is increasingly influencing the practice of medicine, will aid clinical communication and the development of "population images" that represent the phenotype of particular diseases, which will aid the development of diagnostic algorithms. Integrated diagnostics offer increased operational efficiency and benefits to patients through quicker and more accurate diagnoses. As physicians with the most expertise in IT, radiologists are well placed to take the lead in introducing IT solutions and cloud computing to promote integrated diagnostics. To achieve this, radiologists must adapt to include quantitative data on biomarkers in their reports. Radiologists must also increase their role as participating physicians, collaborating with other medical specialties, not only to avoid being sidelined by other specialties but also to better prepare as leaders in the selection and sequence of diagnostic procedures. Key Points • New diagnostic technologies are yielding unprecedented amounts of diagnostic information. • Advanced IT/cloud computing will aid integration and analysis of diagnostic data. • Better diagnostic algorithms will lead to faster diagnosis and more rapid treatment. © European Society of Radiology 2012.


Dunn J.,Griffith University | Dunn J.,University of Queensland | Ng S.K.,Griffith University | Breitbart W.,Memorial Sloane Kettering Cancer Center | And 8 more authors.
Health and Quality of Life Outcomes | Year: 2013

Background: This longitudinal study describes the five year trajectories of health-related quality of life (HR-QOL) and life satisfaction in long term colorectal cancer survivors.Patients and methods: A population-based sample of 1966 colorectal cancer survivors were surveyed at six time points from five months to five years post-diagnosis. Predictor variables were: socio-demographic variables, optimism; cancer threat appraisal; perceived social support. Quality of life was assessed with the Functional Assessment of Cancer Therapy-Colorectal (HR-QOL); and the Satisfaction with Life Scale. Growth mixture models were applied to identify trajectory classes and their predictors.Results: Distinct adjustment trajectories were identified for HR-QOL and life satisfaction. Lower optimism, poorer social support, a more negative cognitive appraisal, and younger age were associated with poorer life satisfaction, while survivors with less than 8 years of education had higher life satisfaction. This pattern was similar for overall HR-QOL except that educational level was not a significant predictor and later stage disease and female gender emerged as related to poorer outcomes. One in five survivors reported poorer constant HR-QOL (19.2%) and a small group had poor life satisfaction (7.2%); 26.2% reported constant high HR-QOL and 48.8% had high constant life satisfaction. Socioeconomic disadvantage and remoteness of residence uniquely predicted poorer outcomes in the colorectal cancer specific HR-QOL sub domain.Conclusion: Although HR-QOL and subjective cognitive QOL share similar antecedents their trajectory patterns suggested they are distinct adjustment outcomes; with life satisfaction emerging as temporally stable phenomenon. Unique patterns of risk support suggest the need to account for heterogeneity in adjustment in longitudinal QOL studies with cancer survivors. © 2013 Dunn et al.; licensee BioMed Central Ltd.


PubMed | University of Michigan, University of Wisconsin - Madison, Montefiore Medical Center, Dana-Farber Cancer Institute and 9 more.
Type: Clinical Trial, Phase II | Journal: British journal of haematology | Year: 2016

Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10d of AZA (50mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P=0008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6months, respectively. The novel 50*10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.

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