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

Suitability of PSA-detected localised prostate cancers for focal therapy: Experience from the ProtecT study

This article is available through a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Copyright @ 2011 Cancer Research UK.Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. Methods: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. Results: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. Conclusion: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.National Institute for Health Researc

Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

<p>Abstract</p> <p>Background</p> <p>Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors.</p> <p>Methods</p> <p>A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP) in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC), 13 papillary (pRCC), 10 chromophobe (chRCC), and 10 oncocytomas) and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters.</p> <p>Results</p> <p>Significant differences in methylation levels among the four subtypes of renal tumors were found for <it>CDH1 </it>(<it>p </it>= 0.0007), <it>PTGS2 </it>(<it>p </it>= 0.002), and <it>RASSF1A </it>(<it>p </it>= 0.0001). <it>CDH1 </it>hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (<it>p </it>= 0.00016 and <it>p </it>= 0.0034, respectively), whereas <it>PTGS2 </it>methylation levels were significantly higher in ccRCC compared to pRCC (<it>p </it>= 0.004). <it>RASSF1A </it>methylation levels were significantly higher in pRCC than in normal tissue (<it>p </it>= 0.035). In pRCC, <it>CDH1 </it>and <it>RASSF1A </it>methylation levels were inversely correlated with tumor stage (<it>p </it>= 0.031) and nuclear grade (<it>p </it>= 0.022), respectively.</p> <p>Conclusion</p> <p>The major subtypes of renal epithelial neoplasms display differential aberrant <it>CDH1</it>, <it>PTGS2</it>, and <it>RASSF1A </it>promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.</p

JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA)

12-0-tetradecanoylphorbol-13-acetate (TPA) stimulates protein kinase C (PKC) which mediates apoptosis in androgen-sensitive LNCaP human prostate cancer cells. The downstream signals of PKC that mediate TPA-induced apoptosis in LNCaP cells are unclear. In this study, we found that TPA activates the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 pathway. To explore the possible role that the JNK/c-Jun/AP-1 signal pathway has on TPA-induced apoptosis in LNCaP cells, we stably transfected the scaffold protein, JNK interacting protein 1 (JIP-1), which binds to JNK inhibiting its ability to phosphorylate c-Jun. TPA (10(-9)-10(-7) mol l(-1)) caused phosphorylation of JNK in both wild-type and JIP-1-transfected (LNCaP-JIP-1) cells. It resulted in phosphorylation and upregulation of expression of c-Jun protein in the wild-type LNCaP cells, but not in the JIP-1-transfected LNCaP cells. In addition, upregulation of AP-1 reporter activity by TPA (10(-9) mol l(-1)) occurred in LNCaP cells but was abrogated in LNCaP-JIP-1 cells. Thus, TPA stimulated c-Jun through JNK, and JIP-1 effectively blocked JNK. TPA (10(-12)-10(-8) mol l(-1)) treatment of LNCaP cells caused their growth inhibition, cell cycle arrest, upregulation of p53 and p21waf1, and induction of apoptosis. All of these effects were significantly attenuated when LNCaP-JIP-1 cells were similarly treated with TPA. A previous study showed that c-Jun/AP-1 blocked androgen receptor (AR) signaling by inhibiting AR binding to AR response elements (AREs) of target genes including prostate-specific antigen (PSA). Therefore, we hypothesised that TPA would not be able to disrupt the AR signal pathway in LNCaP-JIP-1 cells. Contrary to expectation, TPA (10(-9)-10(-8) mol l(-1)) inhibited DHT-induced AREs reporter activity and decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, TPA, probably by stimulation of PKC, phosphorylates JNK, which phosphorylates and increases expression of c-Jun leading to AP-1 activity. Growth control of prostate cancer cells can be mediated through the JNK/c-Jun pathway, but androgen responsiveness of these cells can be independent of this pathway, suggesting that androgen independence in progressive prostate cancer may not occur through activation of this pathway

Focal Therapy: Patients, Interventions, and Outcomes-A Report from a Consensus Meeting.

Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field

Deletion of chromosome 4q predicts outcome in Stage II colon cancer patients

Background: Around 30% of all stage II colon cancer patients will relapse and die of their disease. At present no objective parameters to identify high-risk stage II colon cancer patients, who will benefit from adjuvant chemotherapy, have been established. With traditional histopathological features definition of high-risk stage II colon cancer patients is inaccurate. Therefore more objective and robust markers for prediction of relapse are needed. DNA copy number aberrations have proven to be robust prognostic markers, but have not yet been investigated for this specific group of patients. The aim of the present study was to identify chromosomal aberrations that can predict relapse of tumor in patients with stage II colon cancer