Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of salvage radiotherapy (RT) for persistent or rising PSA after radical prostatectomy and to determine prognostic factors identifying patients who may benefit from salvage RT.</p> <p>Methods</p> <p>Between 1990 and 2003, 59 patients underwent RT for PSA recurrence after radical prostatectomy. Patients received a median of 66 Gy to the prostate bed with 3D or 2D RT. The main end point was biochemical failure after salvage RT, defined as an increase of the serum PSA value >0.2 ng/ml confirmed by a second elevation.</p> <p>Results</p> <p>Median follow-up was 38 months. The 3-year and 5-year bDFS rates were 56.1% and 41.2% respectively. According to multivariate analysis, only preRT PSA ≥1 ng/ml was associated with biochemical relapse.</p> <p>Conclusion</p> <p>When delivered early, RT is an effective treatment after radical prostatectomy. Only preRT PSA ≥1 ng/ml predicted relapse.</p

MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea

Background:Methylating agents such as N-methyl-N-nitrosourea (MNU) can cause cell cycle arrest and death either via caspase-dependent apoptosis or via a poly(ADP-ribose) polymerase (PARP)-dependent form of apoptosis. We wished to investigate the possible role of MLH1 in signalling cell death through PARP.Methods:Fibroblasts are particularly dependent on a PARP-mediated cell death response to methylating agents. We used hTERT-immortalised normal human fibroblasts (WT) to generate isogenic MLH1-depleted cells, confirmed by quantitative PCR and western blotting. Drug resistance was measured by clonogenic and cell viability assays and effects on the cell cycle by cell sorting. Damage signalling was additionally investigated using immunostaining.Results:MLH1-depleted cells were more resistant to MNU, as expected. Despite having an intact G2/M checkpoint, the WT cells did not initially undergo cell cycle arrest but instead triggered cell death directly by PARP overactivation and nuclear translocation of apoptosis-inducing factor (AIF). The MLH1-depleted cells showed defects in this pathway, with decreased staining for phosphorylated H2AX, altered PARP activity and reduced AIF translocation. Inhibitors of PARP, but not of caspases, blocked AIF translocation and greatly decreased short-term cell death in both WT and MLH1-depleted cells. This MLH1-dependent response to MNU was not blocked by inhibitors of ATM/ATR or p53.Conclusion:These novel data indicate an important role for MLH1 in signalling PARP-dependent cell death in response to the methylating agent MNU

Analysis of variants in DNA damage signalling genes in bladder cancer

<p>Abstract</p> <p>Background</p> <p>Chemicals from occupational exposure and components of cigarette smoke can cause DNA damage in bladder urothelium. Failure to repair DNA damage by DNA repair proteins may result in mutations leading to genetic instability and the development of bladder cancer. Immunohistochemistry studies have shown DNA damage signal activation in precancerous bladder lesions which is lost on progression, suggesting that the damage signalling mechanism acts as a brake to further tumorigenesis. Single nucleotide polymorphisms (SNPs) in DSB signalling genes may alter protein function. We hypothesized that SNPs in DSB signalling genes may modulate predisposition to bladder cancer and influence the effects of environmental exposures.</p> <p>Methods</p> <p>We recruited 771 cases and 800 controls (573 hospital-based and 227 population-based from a previous case-control study) and interviewed them regarding their smoking habits and occupational history. DNA was extracted from a peripheral blood sample and genotyping of 24 SNPs in <it>MRE11, NBS1, RAD50, H2AX </it>and <it>ATM </it>was undertaken using an allelic discrimination method (Taqman).</p> <p>Results</p> <p>Smoking and occupational dye exposure were strongly associated with bladder cancer risk. Using logistic regression adjusting for age, sex, smoking and occupational dye exposure, there was a marginal increase in risk of bladder cancer for an <it>MRE11 </it>3'UTR SNP (rs2155209, adjusted odds ratio 1.54 95% CI (1.13–2.08, p = 0.01) for individuals homozygous for the rare allele compared to those carrying the common homozygous or heterozygous genotype). However, in the hospital-based controls, the genotype distribution for this SNP deviated from Hardy-Weinberg equilibrium. None of the other SNPs showed an association with bladder cancer and we did not find any significant interaction between any of these polymorphisms and exposure to smoking or dye exposure.</p> <p>Conclusion</p> <p>Apart from a possible effect for one MRE11 3'UTR SNP, our study does not support the hypothesis that SNPs in DSB signaling genes modulate predisposition to bladder cancer.</p

Optimisation de la prise en charge du cancer de la vessie chez les patients âgés

International audienceAim: To define and present potential improvements for the management of bladder cancer in older patients.Method: Bibliographical search was performed from the Medline bibliographic database (NLM Pubmed tool) and Embase focused on: bladder cancer, treatment, BCG, chemotherapy, cystectomy, and elderly.Results: The oncological principles of medico-surgical management of bladder cancer do not differ according to age. On the other hand, the patient comorbidities have been likely to alter the tolerance of these treatments. At the NMIBC stages, no adaptation of the standard treatment has demonstrated any interest. At the MIBC stages, the prognosis was improved by geriatric multidisciplinary perioperative management.Conclusion: The indications and principles of surgical treatments must be identical regardless of the patient age. At the NMIBC stages, adjuvant therapy, including BCG therapy, should not be questioned because of the age of the patient. On the other hand, at the localized MIBC stages, neoadjuvant and adjuvant chemotherapy should not be considered as a standard and their indications assessed individually after geriatric assessment

Évaluation du patient âge présentant un cancer

International audienceurpose: To explain the notion of frailty, then to explain how crucial is the detection of frailty detection in the elderly patient, and, in cases of suspected frailty, how crucial is the need for geriatric assessment. To describe (i) how this assessment of the elderly cancer patient is performed, (ii) how the results of this geriatric assessment must drive the decision making, and (iii) the role of the geriatrician in the care pathway.Method: Bibliographic research from the Medline bibliographic database (NLM Pubmed tool) and Embase, as well as on the websites of scientific geriatric societies, from the National Cancer Institute using the following keywords: elderly, geriatrics, cancer, frailty, assessment, decision making.Results: The goal of frailty detection is to optimize care, to maintain the independence and the survival of the patient. The prevalence of frailty increases with the age and the diagnosis of cancer. Detection of frailty in the elderly patient with cancer is performed using the G8 questionnaire recommended by the INCa. In case of anomaly or clinical justification, the patient receives a geriatric assessment, which is a multidimensional and multidisciplinary procedure. The clinician can call on the UCOG of the region in which he practices. The relevance of medical decisions will be based on the results of this geriatric assessment. The geriatrician plays a crucial role and will be involved throughout the care.Conclusion: The detection of frailty in the elderly patient with cancer is obligatory. Consecutive geriatric assessment can be performed by the UCOG of the region. The results of the geriatric assessment must serve as a basis for any therapeutic decision making and the preservation of the independence of the patient must remain the priority

Spécificités épidémiologiques, pathologiques et pronostiques du cancer de la vessie chez les patients âgés

International audienceAim: To define and present explanations for the epidemiological, pathological and prognostic differences in bladder cancer in elderly patients.Method: Bibliographical search was performed from the Medline bibliographic database (NLM Pubmed tool) and Embase focused on: bladder cancer, carcinogenesis, elderly, epidemiology, prognosis.Results: Bladder cancer is a growing concern for the elderly first and foremost and with an impact, mainly those who are consumers or former users of tobacco, whose therefore frequently have comorbidities associated with this consumption. The initiated carcinogenesis extends with the life length of patients, increasing the prevalence of bladder cancer. Aging promotes carcinogenesis by both potentiating its genetic abnormalities and reducing the immune system performance of the aged host to destroy cancer cells. The delay in the diagnosis of bladder cancer in elderly patients is explained and make up for the time could improve the prognosis.Conclusion: Regardless of variations in therapeutic effect and morbidity and mortality of treatments, aging promotes the occurrence and aggressiveness of bladder cancer. The incentive to stop exposure to carcinogens and the search for bladder cancer in patients with hematuria should not reduce with advanced age but instead be promoted in order to improve the prognosis

Spécificité de la prise en charge du cancer du rein métastatique chez le patient âgé

International audienceAim: To define the necessary arrangements of medical treatment with anti-angiogenics, mTOR inhibitor or systemic immunotherapies in the management of metastatic renal cell carcinoma in elderly patients.Method: Bibliographical search was performed from the Medline bibliographic database (NLM Pubmed tool) and Embase focused on: metastatic renal cell carcinoma, elderly, treatment.Results: The selection criteria for the medical treatment of metastatic renal cell carcinoma in elderly patients are the IMDC score, necessarily complemented by performance status, the tolerability profile of treatments, more frequent drug interactions, treatment adherence, management capacity of side effects, and patient preference. Each of these criteria is detailed in critical ways.Conclusion: The efficacy and tolerability of medical treatments for metastatic renal cancer have not been reported as different depending on age. No dosage adjustment is recommended in principle. However, prevention and early treatment of side effects of treatment should be strengthened in elderly patients

Spécificités gériatriques du cancer de la prostate

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Spécificités gériatriques du cancer du rein localisé

International audiencePurpose: To describe the epidemiology of renal cell carcinoma (RCC) and its natural history in the elderly patient. To propose adaptations of geriatric evaluation specific to RCC. Recall therapeutic options and the treatment options specific to elderly patients.Method: Bibliographic research from the Medline bibliographic database (NLM Pubmed tool) and Embase, as well as on the websites of scientific societies of geriatrics, from the National Cancer Institute using the following keywords: elderly, geriatrics, renal cell carcinoma, small renal mass, diagnosis, treatment.Results: The incidence of RCC increases in France and peaks between 70 and 80 years. This increase in incidence is mainly due to the diagnosis of small renal masses (SMR). The specific mortality of RCC increases with age (at least between 75 and 95 years). Tumor biopsy, especially of SMR, should be considered in the elderly patient. The geriatric assessment of patients with CaR has no specificity apart from specific evaluation of renal function and operative risk. There is no prospective therapeutic trials dedicated to elderly patients with localized RCC. Surgical treatment requires the use of fast track protocol (the modalities of which are being elaborated) in which geriatricians play a key role throughout the process. The role of percutaneous ablative treatment should be better defined in elderly patients. However, given their low specific mortality, surveillance of SRM (at least initially) is probably an interesting option, certainly under-used, although its impact on quality of life remains to be clarified. The overarching goal of geriatric oncology must guide the decisions of care in the older patient with CaR: first, the respect of patient-specific expectations and secondly the search for an overall clinical benefit; objectives that have no reason to be restricted to elderly patients.Conclusion: RCC is becoming a predominantly elderly cancer. It responds to the current general diagnostic and therapeutic guidelines. It is desirable that clinical research help to better define the respective roles of percutaneous biopsy and treatment of localized RCC