Discovery of Molecular DNA Methylation-Based Biomarkers through Genome-Wide Analysis of Response Patterns to BCG for Bladder Cancer

Background: Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. Methods: To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip. Results: Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes GPR158, KLF8, C12orf42, WDR44, FLT1, and CHST11, were internally validated by bisulfite-sequencing. GPR158 promoter hypermethylation was the best predictor of BCG failure with an AUC of 0.809 (p-value < 0.001). Conclusions: Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts

Impact of gastrointestinal side effects on patients’ reported quality of life trajectories after radiotherapy for prostate cancer: Data from the prospective, observational pros-it CNR study

Radiotherapy (RT) represents an important therapeutic option for the treatment of localized prostate cancer. The aim of the current study is to examine trajectories in patients’ reported quality of life (QoL) aspects related to bowel function and bother, considering data from the PROState cancer monitoring in ITaly from the National Research Council (Pros-IT CNR) study, analyzed with growth mixture models. Data for patients who underwent RT, either associated or not associated with androgen deprivation therapy, were considered. QoL outcomes were assessed over a 2-year period from the diagnosis, using the Italian version of the University of California Los Angeles-Prostate Cancer Index (Italian-UCLA-PCI). Three trajectories were identified for the bowel function; having three or more comorbidities and the use of 3D-CRT technique for RT were associated with the worst trajectory (OR = 3.80, 95% CI 2.04–7.08; OR = 2.17, 95% CI 1.22–3.87, respectively). Two trajectories were identified for the bowel bother scores; diabetes and the non-Image guided RT method were associated with being in the worst bowel bother trajectory group (OR = 1.69, 95% CI 1.06–2.67; OR = 2.57, 95% CI 1.70–3.86, respectively). The findings from this study suggest that the absence of comorbidities and the use of intensity modulated RT techniques with image guidance are related with a better tolerance to RT in terms of bowel side effects

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: The Pros-IT CNR study

Background: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. Methods: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). Results: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Conclusions: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

Abstract BACKGROUND: One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. METHODS/DESIGN: The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. DISCUSSION: The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia

Einfluss der Komorbidität auf die Mortalität und Morbidität bei der radikalen Zystektomie

Radical cystectomy (RC) with bilateral pelvic lymph node dissection constitutes the gold standard treatment for muscle-invasive and high-risk non-muscle-invasive urothelial carcinoma of the bladder refractory to instillation therapy. Although radical cystectomy is performed with curative intent, the overall 5-year survival has been reported to be as low as 62 % in the current literature. Various clinico-pathological parameters determine post-RC outcome, but besides these, the role of comorbidity has gained increasing attention and can be quantified with various comorbidity scores. We here review the most recent data on comorbidity scores and performance indices, which have been assessed in patients, undergoing RC and highlight their clinical implications

Returns of Hatchery-Reared Lake Trout in Southern Lake Superior, 1955–62

Experimental plantings of fin-clipped lake trout (Salvelinus namaycush) of various ages have been made in southern Lake Superior since 1952. The catch of planted lake trout by the commercial fishery was used to measure the success of stocking. Estimates of total returns were based on samples of 8.2 to 21.2% of the Wisconsin catches in 1955–62 and 36.4 to 46.8% of the Michigan catches in 1959–62. Marked lake trout were assigned to various plantings according to the fin mark, length of fish, readings of age from scales, and locations of capture.Estimated returns from Wisconsin plantings of 9-month-old lake trout varied from 2.1 to 6.4%. Wisconsin releases of 16-month-old fish yielded returns of 5.7 to 37.3%. Returns from plantings in Michigan were 0.3% for 9-month-old fish and 1.5 to 3.8% for 16-month-old fish. The ratios of the returns from plantings of 16-month-old fish to those of 9-month-old fish were 3.9:1 for Wisconsin releases and 6.7:1 for Michigan releases. Lake trout planted in Wisconsin generally survived better than those released in Michigan. Returns from fish planted at ages of 17 to 40 months in Michigan in 1958–59 were far greater than those from 16-month-old fish released in Michigan, but were not as high as from the most successful plantings of 16-month-old fish in Wisconsin. Lake trout released in 1960 from shore and from boats survived equally well.Average size of lake trout at release was more closely related to survival than any other factor. All except 1 of 10 highly successful releases were of fish larger than 22 per lb, and all 6 poor releases were of fish smaller than 34 per lb. Fish that ran 22 to 33 per lb survived only moderately well. A size of 17 to 20 fish per lb appears to be close to optimum.Abundance of native lake trout, American smelt (Osmerus mordax), and sea lampreys (Petromyzon marinus) all appeared to be unrelated to stocking success. The only apparent method of rapidly improving the success of stocking is to rear all lake trout to an average size of 17 to 20 per lb. </jats:p

Movements of Hatchery-Reared Lake Trout in Lake Superior

The history of stocking of lake trout (Salvelinus namaycush) in the Great Lakes is reviewed.The study of movements is based on capture of 24,275 fin-clipped lake trout taken in experimental gill nets and trawls and commercial gill nets.Yearling lake trout planted from shore dispersed to 15-fath (27-m) depths in [Formula: see text]. Most fish remained within 2 miles (3.2 km) of the planting site 2 months, but within 4 months some fish had moved as much as 17 miles (27 km). The highest abundance of planted lake trout was in areas 2–4 miles (3.2–6.4 km) from the planting site even 3 years after release. Distance moved and size of fish were not correlated.Dispersal of lake trout begins at planting and probably continues until the fish are mature. Most movement was eastward in southern Lake Superior and followed the counterclockwise surface currents. Movement is most rapid in areas of strong currents and slowest in areas of weak currents or eddies. Movement to areas west of the Keweenaw Peninsula was insignificant from plantings in Keweenaw Bay and nil from other plantings farther east. Lake trout planted in the eastern third of the lake dispersed more randomly than those planted farther west. Few fish moved farther offshore than the 50-fath (91-m) contour. Lake trout planted in Canadian waters made insignificant contributions to populations in US waters. </jats:p