Unfavorable Disease Research Articles

Utilization of radiotherapy for prostate cancer according to urologists’ practice patterns.

11 Background: Physician practices that offer ancillary medical services may refer their patients for such services, a process known as self-referral. Self-referral for radiation therapy according prostate cancer risk and cost of care is not known. We evaluated how utilization and cost of care differ for men diagnosed with prostate cancer in a self-referring urologic practice (SRP) compared to a traditional urologic practice. Methods: 17,982 men 66 years and older diagnosed with localized prostate cancer from 2006 to 2009 were identified from the Texas Cancer Registry. Disease was classified as favorable if low-grade and clinical T1 or T2. The diagnosing urologist was classified as being affiliated with a SRP if their practice owned a linear accelerator. Multilevel logistic regression models evaluated the odds of receiving a specific type of treatment adjusted for diagnosis year, age, comorbidities, race/ethnicity, income, education, clinical tumor stage, and tumor grade. Cost of care was calculated from Medicare expenditures within 12 months of diagnosis. Results: Diagnosis in a SRP increased from 2.2% of prostate cancers in 2004 to 24.5% in 2009 (p< 0.001). Men diagnosed in SRPs were more likely to receive upfront treatment (vs. watchful waiting/active surveillance) than men diagnosed by traditional practices (92.7% vs. 89%; AOR 1.61, p<0.001) and were more likely to be treated with external beam radiation (47.4% vs. 34.1%; AOR 1.59, P<0.001). This persisted for both favorable and unfavorable risk cancer. Men diagnosed in SRPs were more likely to receive upfront treatment (favorable: 92.9% vs. 87.1%; AOR 1.89, p<0.001; unfavorable: 97.9% vs. 95.0%; AOR 2.07, p=0.002) and more likely to be treated with EBRT (favorable: 41.2% vs. 31.1%; AOR 1.45, p=0.002; unfavorable: 49.0% vs. 38.1%; AOR 1.53, p<0.001). Median annual prostate cancer care cost was $2,460 (95% CI $1,663-$3,368) higher for men diagnosed by SRPs. Conclusions: Older men diagnosed with prostate cancer in SRPs are more likely to undergo upfront treatment and to receive radiation treatment. This may increase appropriate treatment of unfavorable disease but contribute to overtreatment of favorable disease.

FUNCTIONAL RE-MODELING INFLUENCE OF EPILEPS IN BRAIN TUMOR

Pathological electrical activity in proximity as well as distant cortical and subcortical zones induced by brain tumors alter the functioning of higher regulatory centers. These bioelectric changes in intricately connected brain functional zones lead to misbalances in compensatory mechanisms in turn influencing unfavorable disease outcome. Objective. This study is aimed at analyzing electroencephalographic (EEG) spectral peculiarities of as well as the peculiarities of cardiac rhythm variability in patients with epilepsy associated brain tumors. Materials and Methods. 72 patients participated in the survey aged from 22 to 83 years, divided into 2 groups: Brain tumor patients with epileptic seizures and brain tumor patients without seizures. The patients included in the study were those admitted to the neurosurgical department at Ryazan state regional hospital. Statistical, geometric and spectral parameters of heart rate variability as well as coherence and cross-correlational EEG analyses used to access the functional states of the patients. Results. The study revealed sympathetic predominance of the autonomic nervous system in patients with epilepsy associated brain tumors as opposed to parasympathetic predominance in non epilepsy associated brain tumors indicating significant stress to regulatory systems and depletion of subcortical reserves of the cardiovascular system, further more stretching the adaptation limits, ultimately leading to depression of autonomic regulatory mechanisms and predominance of central mechanisms of regulation and adaptation. Conclusion. Frequency-amplitude analysis of electroencephalogram and cardiointervalogram allow us to assess the degree of distress of different cortical and subcortical regulatory systems in patients with brain tumors, and is recommended as an additional method of investigation in these patients.

Monocentric study of bile aspiration associated with biliary brushing performed during endoscopic retrograde cholangiopancreatography in 239 patients with symptomatic biliary stricture.

The cytologic diagnosis obtained by brushing or biopsy in malignant biliary strictures is considered to be highly specific but poorly sensitive. The diagnostic association of biliary brushing and bile exfoliate cytology has been suggested but is rarely performed in clinical practice. The objective of this study was to assess the diagnostic performance of bile aspiration associated with biliary brushing during therapeutic endoscopic retrograde cholangiopancreatography (ERCP). From 2004 to 2009, 239 consecutive patients who underwent ERCP were included in the study. The biliary strictures were considered clinically benign in 26% of patients, uncertain in 25%, and malignant in 49%. The 298 cytologic samples collected were divided in 3 groups: bile aspiration alone (26%), biliary brushing alone (20%), and bile aspiration combined with brushing (54%). The definitive diagnosis of malignancy was obtained by biopsy, surgery, and fine-needle aspiration or was determined by an unfavorable disease course. The cytologic diagnoses were as follows: 149 samples were benign (50%), 114 were malignant (38%), 34 had atypia (12%), and 1 had no diagnostic value. The procedure output values were as follows: for bile aspiration alone, sensitivity was 56.4%, specificity was 93.9%, the positive predictive value (PPV) was 91.7%, and the negative predictive value (NPV) was 64.6%; for brushing alone, sensitivity was 62.5%, both specificity and the PPV were 100%, and the NPV was 73%; and, for bile aspiration and brushing combined, sensitivity was 81%, both specificity and the PPV were 100%, and the NPV was 75%. For patients who have symptomatic biliary stricture, bile aspiration during ERCP is a simple and safe procedure. Bile aspiration combined with brushing significantly increases the yield of cytology for malignant biliary tumors (sensitivity, 81%), particularly in cholangiocarcinomas. Cancer Cytopathol 2016;124:330-9. © 2015 American Cancer Society.

Addition of Mycophenolate Mofetil to Methotrexate and Tacrolimus Does Not Improve Gvhd Outcomes in Reduced Intensity Allogeneic Hematopoietic Cell Transplantation

Introduction: The introduction of reduced intensity conditioning (RIC) regimens, associated with less NRM, has significantly broadened transplant eligibility to older patients. However, graft-versus-host disease (GVHD) continues to be a major problem, even with RIC allo-HCTs. At our institution, we have been routinely adding mycophenolate mofetil (MMF) to the standard methotrexate (MTX) plus Tacrolimus combination in the majority of RIC allo-HCT recipients from unrelated donors. However, there is a paucity of data on whether this approach further decreases GVHD rates without increasing NRM and risk of relapse. To answer these questions, we retrospectively analyzed data from 177 patients who received MMF, MTX and Tacrolimus (MMF + Tac/MTX) as part of their GVHD prophylaxis and compared their outcomes to those of 117 patients who received MTX and Tacrolimus alone (Tac/MTX).Patients and methods: The study included a total of 294 consecutive patients who underwent RIC allo-HCT at Washington University Medical Center between January 2006 and December 2013. The data was analyzed for patients who received GVHD prophylaxis with either tacrolimus/methotrexate (Tac/MTX) or tacrolimus/mycophenolate mofetil/methotrexate (MMF+Tac/MTX). Cumulative incidence of relapse was estimated treating death in remission as competing risk event. Cumulative incidence of NRM was calculated considering death in relapse as competing risk event. Univariate analysis was performed to evaluate variables, and multivariate Cox models with a backward selection procedure were done to assess whether GVHD prophylaxis was an independent predictor after adjusting other factors significant in the univariate analysis. All analyses were two-sided, and significance was set at a p-value of 0.05. Statistical analyses were performed using library cmprsk in statistical package R for competing risk analysis and SAS 9.4 (SAS Institutes, Cary, NC) for all other analyses.Results: 177 patients (60.2%) received MMF+Tac/MTX whereas 117 patients (39.8%) received Tac/MTX. Median age was 61 years in the MMF+Tac/MTX group and 58 years in the Tac/MTX group, and the most common diagnosis was AML(31%) followed by NHL (26%) and MDS (19%) in the MMF+Tac/MTX group vs. AML (45%) followed by MDS (14%) and NHL (13%) in the Tac/MTX group. There were more transplants from unrelated and mismatched donors, higher intermediate ASMBT RFI risk group patients and more frequent use of conditioning with Flu/Bu/Thymo regimen in the MMF+Tac/MTX cohort. In particular 160 (90.4%) patients in MMF+Tac/MTX group received thymoglobulin as part of their conditioning, compared to 64 (54.7%) patients in the Tac/MTX group (p < 0.001).The cumulative incidence of grade 2-4 aGVHD at day 100 was 31.0% in the MMF+Tac/MTX group vs. 36.2% in the Tac/MTX group (p=0.191) while as grade 3-4 aGVHD at day 100 and 1 year were 16.8% and 25.9% in the Tac/MTX group compared to 8.0% and 12.4% in the MMF+Tac/MTX group, respectively (p=0.010). However, after adjusting for the thymoglobin use there was no significant difference in the incidence of grade 3-4 aGVHD in these two groups (p=0.129). To eliminate the confounding effect of thymoglobulin, we performed a subgroup analysis of patients without thymoglobulin. Given the small number of samples (n=17 in MMF+Tac/MTX and n=53 in Tac/MTX), propensity score matching was used and the results again showed no significant difference in severe aGVHD between two groups (p=0.219).The incidence of cGVHD at 1 year was 15.3% and 21.6% in MMF+Tac/MTX and Tac/MTX, respectively (p=0.645). Although patients in the MMF+Tac/MTX group had more unfavorable disease risk, the cumulative incidence of relapse at 3 years was not significantly different: 40.8% in the MMF+Tac/MTX group and 39.8% in the Tac/MTX group (p=0.941). 5-year OS was 33.7% in the MMF+Tac/MTX group, compared to 35.1% in the Tac/MTX group (p=0.769).Conclusion: Here we report transplant outcomes of RIC allo-HCT patients who received MMF in addition to Tac/MTX for GVHD prophylaxis. Interestingly we did not see any increase in NRM or relapse rates with additional immune-suppression from adding MMF in these patients. However, addition of MMF to the Tac/MTX regimen did not result in any significant improvement in acute or chronic GVHD outcomes in our patients. Based on these results we do not recommend adding MMF to Tac/MTX regimen for GVHD prophylaxis in RIC allo-HCT patients. DisclosuresUy:Novartis: Research Funding. Schroeder:Incyte: Consultancy; Celgene: Other: Azacitidine provided for this trial by Celgene. Abboud:Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy. Cashen:Celgene: Speakers Bureau.

Is supplemental external beam radiation therapy essential to maximize brachytherapy outcomes in patients with unfavorable intermediate-risk disease?

To evaluate whether supplemental external beam radiotherapy (EBRT) is essential to maximize Pd-103 brachytherapy outcomes in patients with unfavorable intermediate-risk (IR) disease. A total of 630 patients were assessed from two prospective randomized brachytherapy trials evaluating the role of supplemental EBRT in patients with higher risk features. Patients were stratified into unfavorable IR (primary Gleason pattern 4, ≥50% positive biopsies, or ≥2 IR features), favorable IR, and high-risk (HR) cohorts. Median follow-up was 7.5years. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure (BF) was defined as a prostate-specific antigen >0.40ng/mL after nadir. Patients with metastatic prostate cancer or nonmetastatic castrate-resistant disease who died of any cause were classified as dead of prostate cancer. Multiple parameters were evaluated for effect on outcomes. The 10-year BF for favorable IR, unfavorable IR, and HR was 1.7%, 6.6%, and 15.5% (p < 0.001). At 10years, prostate cancer-specific mortality (PCSM) and overall mortality (OM) were 0% and 20.4%, 2.1% and 23.2%, and 4.3% and 42.4% for favorable IR, unfavorable IR, and HR. Although unfavorable IR patients had a greater incidence of BF, PCSM, and OM when compared with favorable IR, neither the addition nor dose of supplemental EBRT influenced outcome. Outcomes for favorable IR were superior to those with unfavorable IR. Within the confines of this study, neither the addition nor dose of supplemental EBRT influenced BF, PCSM, or OM in patients with IR disease.

Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence

Aquaporin 5 (AQP5) is an androgen-regulated member of a family of small hydrophobic integral transmembrane water channel proteins regulating cellular water homeostasis and growth signaling. To evaluate its clinical impact and relationship with key genomic alterations in prostate cancer, AQP5 expression was analyzed by immunohistochemistry on a tissue microarray containing 12427 prostate cancers. The analysis revealed weak to moderate immunostaining in normal prostate epithelium. In prostate cancers AQP5 staining levels were more variable and also included completely negative and highly overexpressing cases. Negative, weak, moderate, and strong AQP5 staining was found in 25.0%, 32.5%, 32.5%, and 10.0% of 10239 interpretable tumors. Comparison of AQP5 expression levels with tumor characteristics showed a dichotomous pattern with both high and low staining levels being linked to unfavorable tumor phenotype. AQP5 was negative in 28%, 23%, 24%, and 35% of tumors with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4, while the rate of strongly positive cases continuously increased from 7.0% over 10.0% and 12.0% to 13.0% in cancers with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4. AQP5 expression was also related to ERG positivity and phosphatase and tensin homolog (PTEN) deletion (P < .0001 each). Strong AQP5 positivity was seen in 15.5% of ERG-positive and 5.8% of ERG-negative cancers (P < .0001) as well as in 14.7% of cancers with PTEN deletion and 9.4% of cancers without PTEN deletion. Remarkably, both negativity and strong positivity of AQP5 were linked to unfavorable disease outcome. This was however only seen in subgroups defined by TMPRSS2-ERG fusion and/or PTEN deletion. In summary, AQP5 can be both overexpressed and lost in subgroups of prostate cancers. Both alterations are linked to unfavorable outcome in molecularly defined cancer subgroups. It is hypothesized that this dichotomous role of AQP5 is due to two highly different mechanisms as to how the protein can influence cancer cells, that is, hydraulic motility regulation and Ras/MAPK pathway activation.

Organizing pneumonia/non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression

BackgroundOverlapping forms of interstitial pneumonia have been recognized, but are likely underappreciated, and their clinical, radiologic, and histologic characteristics are not well-defined. MethodsWe identified 38 patients with surgical lung biopsy demonstrating histologic organizing pneumonia (OP) or histologic organizing pneumonia/non-specific interstitial pneumonia overlap (OP/NSIP) who met established multi-disciplinary clinical-radiologic-histologic criteria for OP. For each patient, radiologic and co-histologic findings were assessed, and clinical outcome was characterized as disease resolution (complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms) or unfavorable disease progression (death due to respiratory failure or forced vital capacity < 70% predicted > six months from diagnosis). ResultsSeven of 38 patients had clinical-radiologic-histologic focal OP. Focal OP was associated with histologic OP (p = 0.019), and all seven patients demonstrated disease resolution. In the remaining 31 patients with cryptogenic or autoimmune-associated OP, 21 patients had histologic OP/NSIP, and 10 had histologic OP. Histologic OP/NSIP was associated with ground glass opacity (GGO, p = 0.012), reticulation (p = 0.029), traction bronchiectasis (p = 0.029), reactive pneumocytes (p = 0.013), and unfavorable disease progression (p < 0.0001). Histologic OP was associated with consolidation (p = 0.028) and disease resolution (p < 0.0001). Multivariate analysis demonstrated histologic OP/NSIP (p < 0.001) and radiologic GGO (p = 0.041) to be independently associated with unfavorable disease progression. ConclusionsOP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and should therefore be recognized as a characteristic clinical-radiologic-histologic entity.

Evaluation of the prognostic benefit of identifying the probable primary site in cancer of unknown primary

Abstract With the development of site-specific cancer therapy, identifying the primary origin allows the oncologist to personalise therapy for patients with the cancer of unknown primaries (CUPs). At present, immunohistochemistry (IHC) screening is the standard method used to postulate the primary site in CUP. In this retrospective study, we evaluated the prognostic benefit of identifying the primary site in CUP. All 84 patients who presented with suspected CUP to the Royal Stoke University Hospital between 2011 and 2012 were included in our study. Forty-eight percent (40/84) of these patients were unable to undergo necessary investigations to identify primary sites because of poor performance status. IHC screening was able to postulate the primary site in 59% (26/44) of the remaining patients with confirmed CUP. Therefore, the primary site was not identified in a significant proportion of patients with CUP. The median survival of confirmed CUP with probable primary site was 2.0 months (95% confidence interval (CI): 1.2 to 2.9 months), whereas the median survival of confirmed CUP with no probable primary site was 4.1 months (95% CI: 1.5 to 9.7 months). This difference in survival time was statistically significant. In addition, using the Cox regression model, we found that patients with confirmed CUP with primary sites had prognostically unfavourable diseases with a shorter median survival, regardless of the age of disease onset, gender, sites of metastases or number of metastases. One approach to improve the survival would be to start systemic therapy at the earliest possible opportunity rather than waiting for all investigation results, such as IHC.

Case Discussion: Intermediate-risk Prostate Cancer: The Case for Radical Treatment

any urologists will be familiar with this interesting case. As 66-yr-old man, the patient has good life expectancy, which, sing Australian data [1], I estimate to be around 16 yr. He ppears to have little sexual or urinary dysfunction, and his ather had a good outcome from prostate cancer (PCa) reatment, so I assume this man is expecting cure if possible. is cancer appears to be confined to the prostate on adiologic and statistical grounds, but his tumour has leason pattern 4 elements, and maybe the 1-mm biopsy selected men with Gleason 3 + 4 PCa may have lower risk disease than others. Gandaglia et al. [6] demonstrated that patients with organ-confined Gleason 3 + 4 PCa did not have poorer outcomes compared with counterparts with Gleason 3 + 3 disease, and they defined unfavourable disease as Gleason 4 + 3 or non–organ-confined disease on final pathology. Moreover, Ploussard et al. [7] calculated the risk of missing such clinically significant disease in patients with biopsy-proven Gleason 3 + 4 PCa. When applying very strict selection criteria (PSA 10 ng/ml, PSA density 0.15 ng/ml per gram, 2 cores positive for T1c, and age 70 yr), this risk is reduced to < 20%. This compares with a reclassification rate of 28% in patients in the Prostate Cancer Research International Active Surveillance study [4]. In any case, an important message for all men considering AS for localised PCa is that the possibility of understaging and undergrading must always be considered, but in the case of already established intermediate-risk disease, additional caution is warranted because the safety of AS in such patients has not E U R O P E A N U R O L O G Y F O C U S 1 ( 2 0 1 5 ) 2 0 7 – 2 1 1 10

BCRP and P-gp relay overexpression in triple negative basal-like breast cancer cell line: a prospective role in resistance to Olaparib.

The triple negative basal-like (TNBL) breast carcinoma is an aggressive and unfavorable prognosis disease. Inhibitors of poly(ADP-ribose) polymerase such as Olaparib could represent a promising targeted therapy but their sensitivity against Multidrug Resistance proteins (MDR), which causes resistance, is not well defined. Thus, our work focused on the analysis of P-gp and BCRP coexpression in the SUM1315 TNBL human cell line, in correlation with Olaparib intracellular concentration. Western blot analyses showed a clear coexpression of P-gp and BCRP in SUM1315 cells. A low cytotoxic Olaparib treatment clearly led to an increased expression of both BCRP and P-gp in these cells. Indeed, after 1.5 h of treatment, BCRP expression was increased with a 1.8 fold increase rate. Then, P-gp took over from 3 h to 15 h with an average increase rate of 1.8 fold, and finally returned to control value at 24 h. HPLC-UV analyses showed that, in the same treatment conditions, the intracellular Olaparib concentration increased from 1 h to 3 h and remained relatively stable until 24 h. Results suggest that the resistance mechanism induced by Olaparib in TNBL SUM1315 cell line may be overpassed if a cytotoxic and stable intracellular level of the drug can be maintained.

Definition and Validation of “Favorable High-Risk Prostate Cancer”: Implications for Personalizing Treatment of Radiation-Managed Patients

To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease. We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer-specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268). Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.

Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease—the Role of Functional Imaging.

Early-stage classical Hodgkin lymphoma (CHL) is a highly curable malignancy. Historically, extended-field radiotherapy (EFRT) alone showed excellent cure rates, but the risk of radiotherapy (RT)-associated toxicities led to combined modality therapy (CMT) replacing RT alone. RT has subsequently evolved further with significant reductions of dose and field size, and is currently restricted to involved sites only (ISRT). Contemporary CMT yields cure rates in excess of 85%, and most studies do not have adequate follow-up required to evaluate the risk reduction in late effects. In an effort to avoid RT altogether, response-adapted treatment approaches utilizing results of interim [(18)F]fluorodeoxyglucose (FDG) positron emission tomography with fused computed tomography (PET/CT) imaging have been studied. Results from two studies in favorable-risk (UK RAPID and EORTC H10F) and one in unfavorable-risk patients (EORTC H10U) suggest that omission of RT in patients with a negative interim PET/CT response (Deauville score ≤2) yields slightly inferior progression-free survival (PFS) compared to conventional CMT, but with no difference in overall survival (OS) albeit with short-term follow-up. In order to extrapolate results to daily practice, it is critical to understand the selection of patients entered on trials since definitions of favorable and unfavorable disease vary between study groups. Currently, CMT continues to be the standard of care for the vast majority of patients with early-stage CHL and RT is an integral part of therapy in patients with bulky disease. However, for selected patients with favorable characteristics, emerging data suggest that a chemotherapy-alone approach is reasonable.

Climatic anomalies, food systems, and subsistence crises in medieval Novgorod and Ladoga

Climatic factors have affected subsistence strategies throughout human history. In northern Europe and Russia, short-term climatic anomalies and weather extremes are commonly thought to underlie famines in the Middle Ages. However, medieval subsistence crises were not just natural disasters and medieval people were not passive victims of climatic anomalies. In addition, the capacity to cope with climatic anomalies has varied temporally and spatially throughout the Middle Ages. Yet only a few studies have explored the climatic impact on regional medieval food systems comprehensively. This article examines the significance of climate variability on subsistence crises in medieval Novgorod and Ladoga (Russia), focusing on the relationship between short-term climate anomalies and crop cultivation. In addition, this paper evaluates the impact of crop failures, frosts, and other weather phenomena on the food system. The materials are drawn from medieval sources, paleoclimatological reconstructions, and archaeological evidence. The results show that short-term climatic anomalies alone rarely lead to severe subsistence crises, and during every famine period there is evidence of other contributing factors, such as unfavourable weather phenomena, disease, or social unrest. The variety of cultivated crops and agricultural techniques is shown to increase the region’s resilience to climatic anomalies and to crop failures.

PROGNOSTIC SIGNIFICANCE OF MDM2 GENE EXPRESSION IN CHILDHOOD NEUROBLASTOMA

To investigate the association of MDM2 expression at the mRNA levels in neuroblastoma with clinical features and unfavorable disease factors to determine the possibility of it usage as a prognostic marker of neuroblastoma. Total RNA and DNA were extracted from tumor tissue samples of total 91 neuroblastoma patients (mean age: 39.45 ± 4.81 months). MDM2 mRNA levels were detected with Q-PCR. TP53 gene deletion was detected with FISH method. MYCN amplification was detected with -Q-PCR analysis in fresh tumor samples and FISH in FFPE samples. We investigated the association of MDM2 mRNA expression with clinical outcome in neuroblastoma patients (n = 91). Kaplan - Meier curves showed a significant association of high MDM2 expression with poor event-free survival (p < 0.001). Clinical outcome of patients without MYCN amplification with low MDM2 expression was associated with better event-free survival than with high MDM2 expression (p < 0.001). Overexpression of MDM2 can be used as significant prognostic marker for patient stratification on risk groups and treatment optimization. Our results showed that the high expression of MDM2 at mRNA levels is an important factor of neuroblastoma prognosis. It may be a valuable additional molecular marker in guiding specific therapy in MYCN non-amplified NB patients without TP53 gene deletion.

The biopsy Gleason score 3+4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy Gleason score 3+3: looking for larger selection criteria for active surveillance candidates

To assess whether the addition of clinical Gleason score (Gs) 3+4 to the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria affects pathologic results in patients who are potentially suitable for active surveillance (AS) and to identify possible clinical predictors of unfavourable outcome. Three hundred and twenty-nine men who underwent radical prostatectomy with complete clinical and follow-up data and who would have fulfilled the inclusion criteria of the PRIAS protocol at the time of biopsy except for the addition of biopsy Gs=3+4 and with at least 10 cores taken have been evaluated. One experienced genitourinary pathologist selected those with real Gs=3+3 and 3+4 in only one core according to the 2005 International Society of Urological Pathology criteria. The primary end point was the proportion of unfavourable outcome (nonorgan confined disease or Gs⩾4+3). Logistic regressions explored the association between preoperative characteristics and the primary end point. Two hundred and four patients were evaluated and 46 (22.5%) patients harboured unfavourable disease at final pathology. After a median follow-up of 73.5 months, there was no cancer-specific death, and 4 (2.0%) patients had biochemical relapse. There were no significant differences in terms of high Gs, locally advanced disease, unfavourable disease and biochemical relapse-free survival among patients with clinical Gs=3+3 vs Gs=3+4. At multivariable analysis, the presence of atypical small acinar proliferation (ASAP) and lower number of core taken were independently associated with a higher risk of unfavourable disease. The inclusion of Gs=3+4 in patients suitable to AS does not enhance the risk of unfavourable disease after radical prostatectomy. Additional factors such as number of cores taken and the presence of ASAP should be considered in patients suitable for AS.

Performance of biopsy factors in predicting unfavorable disease in patients eligible for active surveillance according to the PRIAS criteria

To assess the added value of biopsy factors, like maximum cancer length in a core (MCL), cumulative cancer length (CCL), cumulative length of positive cores (CLPC), percentage of cancer involvement in positive cores (CIPC) and the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria in patients who underwent radical prostatectomy (RP) but eligible for active surveillance (AS). From January 2002 to December 2007, 750 consecutive subjects underwent RP. We identified 147 (19.07%) patients who were eligible for AS based on PRIAS criteria: clinical stage T1c or T2, PSA level of ⩽ 10 ng ml(-1), Gleason score ⩽ 6, PSA-D of <0.2 ng ml(-2) and one or two positive biopsy cores. We calculated the diagnostic accuracy of biopsy factors in determining pathological confirmed unfavorable disease. Decision curve analysis (DCA) were performed. Of all subjects, 95 patients (66.43%) had favorable whereas 48 had (33.57%) unfavorable disease. On multivariate analyses, the inclusion of MCL, CCL, CLPC and CIPC significantly increased the accuracy of the base multivariate model in predicting unfavorable disease. The gain in predictive accuracy for MCL in a core, CCL, CLPC and CIPC ranged from 13 to 27%. The DCA shows that adding MCL, CCL, CLPC and CIPC resulted in a greater net benefit when the probability of ranges between 15 and 50%. The models can be applied at the cost of missing not more than 16.83% of unfavorable disease. Our findings suggested that the addition of these biopsy factors to PRIAS criteria has the potential to significantly increase the ability to detect unfavorable disease.

221 Influence of nutritional status of children with cystic fibrosis on disease outcome

Objectives To establish the influence of nutritional status of children with CF, who are in critical condition, on disease outcome. Methods This is a retrospective study of children with CF admitted to the pediatric ICU of St. George University Hospital, Plovdiv, from January 2004 to June 2013. Children were admitted because of respiratory failure, heart failure or dehydration. We analyzed patients' weight, height, BMI, severity of the disease based on the Shwachman-Kulczycki score, colonization with P. aeruginosa, length of hospital stay and disease outcome. Results 23 children are included in the study – 12 boys and 11 girls. The mean age of the patients is 63.7 months (1–214 months). The main reason for admission to ICU was respiratory infection (78.3%). Two of the children had severe dehydration and one had arrhythmia. Five of the patients died in ICU (21.7%). There is a positive correlation between the nutrition deficit on one side, low Shwachman-Kulczycki score, longer hospital stay and unfavourable disease outcome on the other. Children without nutritional deficit had a significantly shorter hospital stay and higher Shwachman-Kulczycki score on admission. We did not establish a statistically significant correlation between the degree of nutritional deficit and colonization with P. aeruginosa . Conclusion Children with nutritional deficit and low Shwachman-Kulczycki score have a longer hospital stay and are at a higher risk of unfavorable disease outcome. If the nutritional deficit is diagnosed early and actively corrected, this could lead to shorter hospital stay and reduced disease severity while on ICU.

Androgen deprivation therapy and the risk of death from prostate cancer among men with favorable or unfavorable intermediate-risk disease.

Radiotherapy (RT), short-course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate-risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC-specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate-risk PC is unknown. The authors assessed PCSM risk after commonly used treatments. The cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate-risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing-risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors. After a median follow-up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13-0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18-2.57 [P =.56]). Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.

Circulating Tumor Cells as Potential Biomarkers in Bladder Cancer

We explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing. A total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFlux™ System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing. Median circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low-fewer than 10, medium-11 to 30 and high-greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch® showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity. This study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells.

Adverse Pathologic Features at Radical Prostatectomy: Effect of Preoperative Risk on Oncologic Outcomes

BackgroundUp to 30% of patients with low-risk prostate cancer (PCa) are found to have features of aggressive disease at radical prostatectomy (RP). Several predictive nomograms and novel genomic markers have been developed to estimate the risk of adverse pathology in men eligible for active surveillance (AS). However, oncologic risk associated with these findings remains unknown. ObjectiveTo determine if the presence of adverse pathologic features at RP in patients eligible for AS is prognostic of poor oncologic outcome independent of pretreatment risk status. Design, setting, and participantsA total of 2660 patients underwent immediate RP at our institution between 1998 and 2008. Patients were stratified as low, intermediate, or high risk according to the D’Amico clinical risk criteria. Outcome measurements and statistical analysisThe rates of adverse pathology were reported, and the 5-yr risk of biochemical recurrence (BCR) was calculated in the presence of aggressive disease. Results and limitationsThe 5-yr risk of BCR in patients with extracapsular extension (n=937) was 43% (95% confidence interval [CI], 40–46) overall but only 15% (95% CI, 11–22) for those who met the criteria for low risk (n=181). For the 473 patients with pathologic Gleason score 4+3, the risk of recurrence at 5 yr was 41% (95% CI, 37–46) overall, 13% (95% CI, 5–27) for low-risk men (n=41), 41% (95% CI, 35–47) for intermediate-risk men (n=287), and 51% (95% CI, 43–60) for high-risk men (n=145). Limitations include use of BCR as the study end point and surrogate for oncologic outcome in men who received curative treatment. ConclusionsThe presence of pathologically unfavorable disease in patients eligible for AS is not informative as to the safety of this treatment modality. We question the relevance of adverse pathology as the end point for predictive tools designed to guide treatment decisions in low-risk PCa. Patient summaryThe risk of biochemical recurrence associated with adverse pathologic findings at prostatectomy is reduced by approximately 50% in men with clinically low-risk prostate cancer.