p53 and cyclooxygenase-2 expression are directly associated with cyclin D1 expression in radical prostatectomy specimens of patients with hormone-naïve prostate cancer.

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.

CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy.

INTRODUCTION: The cell surface endopeptidase CD10 (neutral endopeptidase) and nuclear factor-κB (NF-κB) have been independently associated with prostate cancer (PC) progression. We investigated the correlations between these two factors and their prognostic relevance in terms of biochemical (prostate-specific antigen, PSA) relapse after radical prostatectomy (RP) for localized PC. PATIENTS AND METHODS: The immunohistochemical expression of CD10 and NF-κB in samples from 70 patients who underwent RP for localized PC was correlated with the preoperative PSA level, Gleason score, pathological stage and time to PSA failure. RESULTS: CD10 expression was inversely associated with NF-κB expression (p < 0.001), stage (p = 0.03) and grade (p = 0.003), whereas NF-κB was directly related with stage (p = 0.006) and grade (p = 0.002). The median time to PSA failure was 56 months. CD10 and NF-κB were directly (p < 0.001) and inversely (p < 0.001) correlated with biochemical recurrence-free survival, respectively. CD10 expression (p = 0.022) and stage (p = 0.018) were independently associated with time to biochemical recurrence. CONCLUSION: Low CD10 expression is an adverse prognostic factor for biochemical relapse after RP in localized PC, which is also associated with high NF-κB expression. Decreased CD10 expression which would lead to increased neuropeptide signaling and NF-κB activity may be present in a subset of early PCs.

Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial 22991.

INTRODUCTION: This trial randomly assessed short-term adjuvant hormonal therapy added to radiotherapy (RT) for intermediate- and high-risk (UICC 1997 cT2a or cT1b-c with high PSA or Gleason score) localised prostate cancer. We report acute toxicity (CTCAE v2) assessed weekly during RT in relation to radiation parameters. PATIENTS AND METHODS: Centres selected the RT dose (70, 74 or 78Gy) and RT technique. Statistical significance is at 0.05. RESULTS: Of 791 patients, 652 received 3D-CRT (70Gy: 195, 74Gy: 376, 78Gy: 81) and 139 received IMRT (74Gy: 28, 78Gy: 111). During RT, grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were reported by 7 (0.8%) and 50 (6.3%) patients, respectively. No grade 4 was reported. The risk of grade 2 GI toxicity increased significantly with increasing D50%-rectum (p=0.004) and that of grade 2 GU toxicity correlated only to Dmax-bladder (p=0.051). 3D-RT technique, increasing total dose and V95% >400 cc increased D50% and Dmax. One month after RT, only 14 patients (1.8%) reported grade 3 toxicity. AST did not seem to influence the risk of GU or GI acute toxicity. CONCLUSION: RT up to 78Gy was well tolerated. Dmax-bladder and D50%-rectum influenced the risk of grade 2 GU toxicity and GI toxicity, respectively. Both were lower with IMRT but remained high for an irradiated RT volume>400 cc for 3D-RT and for a dose of 78Gy. Hormonal treatment did not influence acute toxicity.

Endorectal Magnetic Resonance Imaging and Spectroscopy Are Useful for Selecting Candidates for Biopsy among Patients with Persistently Elevated Prostate Specific Antigen

To evaluate the efficacy of endorectal Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spetroscopic Imaging (MRSI) combined with total prostate-specific antigen (tPSA) and free prostate-specific antigen (fPSA) in selecting candidates for biopsy. Subjects and Methods: 246 patients with elevated tPSA (median: 7.81 ng/ml) underwent endorectal MRI and MRSI before Transrectal Ultrasound (TRUS) biopsy (10 peripheral + 2 central cores); patients with positive biopsies were treated with radical intention; those with negative biopsies were followed up and underwent MRSI before each additional biopsy if tPSA rose persistently. Mean follow-up: 27.6 months. We compared MRI, MRSI, tPSA, and fPSA with histopathology by sextant and determined the association between the Gleason score and MRI and MRSI. We determined the most accurate combination to detect prostate cancer (PCa) using receiver operating curves; we estimated the odds ratios (OR) and calculated sensitivity, specificity, and positive and negative predictive values. Results: No difference in tPSA was found between patients with and without PCa (p = 0.551). In the peripheral zone, the risk of PCa increased with MRSI grade; patients with high-grade MRSI had the greatest risk of PCa over time (OR = 328.6); the model including MRI, MRSI, tPSA, and fPSA was more accurate (Area under Curve: AUC = 95.7%) than MRI alone (AUC = 85.1%) or fPSA alone (AUC = 78.1%), but not than MRSI alone (94.5%). In the transitional zone, the model was less accurate (AUC = 84.4%). The association (p = 0.005) between MRSI and Gleason score was significant in both zones. Conclusions: MRSI is useful in patients with elevated tPSA. High-grade MRSI lesions call for repeated biopsies. Men with negative MRSI may forgo further biopsies because a significantly high Gleason lesion is very unlikely

A prospective development study investigating focal irreversible electroporation in men with localised prostate cancer: Nanoknife Electroporation Ablation Trial (NEAT).

INTRODUCTION: Focal therapy may reduce the toxicity of current radical treatments while maintaining the oncological benefit. Irreversible electroporation (IRE) has been proposed to be tissue selective and so might have favourable characteristics compared to the currently used prostate ablative technologies. The aim of this trial is to determine the adverse events, genito-urinary side effects and early histological outcomes of focal IRE in men with localised prostate cancer. METHODS: This is a single centre prospective development (stage 2a) study following the IDEAL recommendations for evaluating new surgical procedures. Twenty men who have MRI-visible disease localised in the anterior part of the prostate will be recruited. The sample size permits a precision estimate around key functional outcomes. Inclusion criteria include PSA ≤ 15 ng/ml, Gleason score ≤ 4 + 3, stage T2N0M0 and absence of clinically significant disease outside the treatment area. Treatment delivery will be changed in an adaptive iterative manner so as to allow optimisation of the IRE protocol. After focal IRE, men will be followed during 12 months using validated patient reported outcome measures (IPSS, IIEF-15, UCLA-EPIC, EQ-5D, FACT-P, MAX-PC). Early disease control will be evaluated by mpMRI and targeted transperineal biopsy of the treated area at 6 months. DISCUSSION: The NEAT trial will assess the early functional and disease control outcome of focal IRE using an adaptive design. Our protocol can provide guidance for designing an adaptive trial to assess new surgical technologies in the challenging landscape of health technology assessment in prostate cancer treatment.

Sooty blotch and flyspeck control with fungicide applications based on calendar, local IPM, and warning system

The objective of this work was to compare fungicide application timing for the control of sooty blotch and flyspeck (SBFS) of 'Fuji' apples in Rio Grande do Sul state, Brazil. The following treatments were evaluated in two growing seasons: two warning system-based (modified version of the Brown-Sutton-Hartmann system) spray of captan plus thiophanate methyl, with or without summer pruning; two calendar/rain-based spray of captan or a mixture of captan plus thiophanate methyl; fungicide spray timing based on a local integrated pest management (IPM) for the control of summer diseases; and a check without spraying. Sooty blotch and flyspeck incidence over time and their severity at harvest were evaluated. The highest number of spray was required by calendar/rain-based treatments (eight and seven sprays in the sequential years). The warning system recommended five and three sprays, in the sequential years, which led to the highest SBFS control efficacy expressed by the reduced initial inoculum and disease progress rate. Summer pruning enhanced SBFS control efficacy, especially by suppressing SBFS signs which tended to be restrained to the peduncle region of the fruit. Sooty blotch and flyspeck can be managed both with calendar and the grower-based IPM practices in Brazil, but a reduced number of sprays is required when the warning system is used.

Acute toxicity of curative radiotherapy for intermediate risk localized prostate cancer in the EORTC trial 22991

Introduction: EORTC trial 22991 randomly assessed the addition of concomitant and adjuvant short-term hormonal therapy to curative conformal/intensity-modulated radiotherapy (RT) for intermediate risk localized prostate cancer. We report the acute toxicity (assessed weekly during RT) for the organs at risk (genito-urinary (GU) and gastro-intestinal (GI)) in relation to radiation parameters. Material and Methods: Eligibility criteria were age _80 years, PSA _ 50 ng/ml, N0M0 and either tumour stage cT2a (1997 UICC TNM) or cT1b-c combined with PSA_10 ng/ml and/or Gleason score _7. We report toxicity for all eligible patients who received the planned RT with documented acute toxicity (CTCAEv.2) and RT-quality assurance parameters. The RT dose (70 Gy, 74 Gy or 78 Gy) and technique (3DCRT vs IRMT) were per institution choice, the randomization was stratified for institution. Statistical significance was set at 0.05. (ClinicalTrials.gov: NCT00021450) Results: Of 819 randomized patients, 28 were excluded from the analysis (3 with <60 Gy RT, 25 with missing information). Of the 791 analysed patients, 652 (82.4%) were treated with 3D-CRT, 139 with IMRT. In the 3DCRT group, 195 patients (29.9%) were treated with a total prescribed dose of 70 Gy; 376 (57.7%) with 74 Gy and 81 (12.4%) with 78 Gy. In the IMRT group, 28 (20.1%) were treated to a total dose of 74 Gy and 111 (79.9%) with 78 Gy. Overall, only 7 of 791 patients (0.9%) had grade 3 GI toxicity during RT: diarrhea (N = 6), rectal bleeding (N = 1) and proctitis (N = 1). Fifty patients (6.3%) had grade 3 GU toxicity: urinary frequency (N = 38, 4.6%), dysuria (N = 14, 1.7%), urinary retention (N = 11, 1.3%), urinary incontinence (N = 2) and hematuria (N = 1). No grade 4 toxicity was reported. Hormonal treatment did not influence the risk of side effects (p>0.05). The risk of grade _2 GI toxicity significantly correlated to D50%-rectum (p = 0.004) with a cut-of value of 44 Gy. The risk of grade _2 GU toxicity was moderately affected by Dmax-bladder (p = 0.051). Overall, only 14 patients (1.8%) had residual grade 3 toxicities one month after RT. Conclusion: 3D-CRT and IMRT up to 78 Gy is well tolerated. Dmaxbladder and D50%-rectum were related to the risk of grade_2 GU and GI toxicity, respectively. IMRT lowered D50% rectum and Dmax-bladder. An irradiated volume >400 cc for 3D-RT and a dose of 78 Gy, even for IMRT, negatively affected those parameters and increased the risk for toxicity.

Image-Based Coral Reef Classification and Thematic Mapping

This paper presents a novel image classification scheme for benthic coral reef images that can be applied to both single image and composite mosaic datasets. The proposed method can be configured to the characteristics (e.g., the size of the dataset, number of classes, resolution of the samples, color information availability, class types, etc.) of individual datasets. The proposed method uses completed local binary pattern (CLBP), grey level co-occurrence matrix (GLCM), Gabor filter response, and opponent angle and hue channel color histograms as feature descriptors. For classification, either k-nearest neighbor (KNN), neural network (NN), support vector machine (SVM) or probability density weighted mean distance (PDWMD) is used. The combination of features and classifiers that attains the best results is presented together with the guidelines for selection. The accuracy and efficiency of our proposed method are compared with other state-of-the-art techniques using three benthic and three texture datasets. The proposed method achieves the highest overall classification accuracy of any of the tested methods and has moderate execution time. Finally, the proposed classification scheme is applied to a large-scale image mosaic of the Red Sea to create a completely classified thematic map of the reef benthos

Identifying the index lesion with template prostate mapping biopsies.

PURPOSE: The natural history of prostate cancer might be driven by the index lesion. We determined the percent of men in whom the index lesion could be defined using transperineal template prostate mapping biopsies. MATERIALS AND METHODS: Included in study were consecutive men undergoing transperineal template prostate mapping biopsies with biopsies grouped into 20 zones. Men with clinically significant disease in only 1 prostate area were considered to have an identifiable index lesion. We evaluated the impact of using 2 definitions of clinically significant disease (Gleason grade pattern 4 and/or lesion volume 0.5 cc or greater) and 2 clustering rules (stringent and tolerant) to define the index lesion. RESULTS: Included in study were 391 men with a median age of 62 years (IQR 58-67) and a median prostate specific antigen of 6.9 ng/ml (IQR 4.8-10.0). Of the men 269 (69%) were previously diagnosed with prostate cancer. By deploying a median of 1.2 cores per ml (IQR 0.9-1.7) cancer was diagnosed in 82.9% of the men (324 of 391) with a median of 6 positive cores (IQR 2-9), a median maximum cancer core length of 5 mm (IQR 3-8) and a total cancer core length per zone of 7 mm (IQR 3-13). Insignificant disease was found in 26.3% to 42.9% of cases. When a stringent spatial relationship was used to define individual lesions, 44.4% to 54.6% of patients had 1 index lesion and 12.7% to 19.1% had more than 1 area with clinically significant disease. These proportions changed to 46.6% to 59.2% and 10.5% to 14.5%, respectively, when less stringent spatial clustering was applied. CONCLUSIONS: Transperineal template prostate mapping biopsies enable the index lesion to be localized in most men with clinically significant disease. This information may be important to select appropriate candidates for targeted therapy and to plan a tailored treatment strategy in men undergoing radical therapy.

Localized prostate cancer in Norway, the United States, and Spain: between-country differences of variables before treatment among patients eligible for curative treatment

Between-country differences in medical and sociodemographic variables, and patient-related outcomes (PROs) before treatment might explain published variations of side effects after radical prostatecomy (RP) or radiotherapy (RAD) for prostate cancer (PCa). This hypothesis was tested among 1908 patients from the United States, Spain, and Norway. Significant between-country differences were observed for most factors investigated before treatment. The observations should be considered in comparison of the frequency and severity of internationally published studies. Background: In men with PCa, large variations of PROs after RP or high-dose RAD might be related to betweencountry differences of medical and sociodemographic variables, and differences in PROs before treatment in the sexual and urinary domains. Patients and Methods: In 1908 patients with localized PCa from Norway, the United States, or Spain, the relation between medical (prostate-specific antigen, Gleason score, cT-category) and sociodemographic variables (age, education, marital status) before treatment was investigated. Using the Expanded Prostate Cancer Index Composite questionnaire, PROs before treatment within the sexual and urinary domains were also considered. Results: Compared with the European patients, American patients were younger, fewer had comorbid conditions, and more had a high education level. Fifty-three percent of the US men eligible for RP had low-risk tumors compared with 42% and 31% among the Norwegian and the Spanish patients, respectively. Among the Spanish RAD patients, 54% had had low-risk tumors compared with 34% of the American and 21% of the Norwegian men planned for RAD, respectively. Compared with the European patients, significantly fewer US patients reported moderate or severe sexual dysfunction and related problems. In most subgroups, the number of patients with sexual or urinary dysfunction exceeded that of patients with bother related to the reported dysfunction. Conclusion: Statistically significant between-country differences were observed in medical and sociodemographic variables, and in PROs before treatment within the sexual and urinary domains. Large differences between reported dysfunction and related problems within the sexual and urinary domains indicate that dysfunction and bother should be reported separately in addition to calculation of summary scores. The documented differences, not at least regarding PROs, might in part explain the large variation of side effects after treatment evident in the medical literature

Multi-institutional validation of the prognostic value of Ki-67 labeling index in patients treated with radical prostatectomy.

OBJECTIVE: Several smaller single-center studies have reported a prognostic role for Ki-67 labeling index in prostate cancer. Our aim was to test whether Ki-67 is an independent prognostic marker of biochemical recurrence (BCR) in a large international cohort of patients treated with radical prostatectomy (RP). METHODS: Ki-67 immunohistochemical staining on prostatectomy specimens from 3,123 patients who underwent RP for prostate cancer was retrospectively performed. Univariable and multivariable Cox regression models were used to assess the association of Ki-67 status with BCR. RESULTS: Ki-67 positive status was observed in 762 (24.4 %) patients and was associated with lymph node involvement (LNI) (p = 0.039). Six hundred and twenty-one (19.9 %) patients experienced BCR. The estimated 3-year biochemical-free survivals were 85 % for patients with negative Ki-67 status and 82.1 % for patients with positive Ki-67 status (log-rank test, p = 0.014). In multivariable analysis that adjusted for the effects of age, preoperative PSA, RP Gleason sum, seminal vesicle invasion, extracapsular extension, positive surgical margins, lymphovascular invasion, and LNI, Ki-67 was significantly associated with BCR (HR = 1.19; p = 0.019). Subgroup analysis revealed that Ki-67 is associated with BCR in patients without LNI (p = 0.004), those with RP Gleason sum 7 (p = 0.015), and those with negative surgical margins (p = 0.047). CONCLUSION: We confirmed Ki-67 as an independent predictor of BCR after RP. Ki-67 could be particularly informative in patients with favorable pathologic characteristics to help in the clinical decision-making regarding adjuvant therapy and optimized follow-up scheduling.

Avaliação da resposta bioquímica no câncer inicial de próstata: experiência uninstitucional comparando teleterapia exclusiva ou associada à braquiterapia de alta taxa de dose

OBJETIVO: Análise comparativa da resposta bioquímica em pacientes submetidos à teleterapia exclusiva ou associada à braquiterapia de alta taxa de dose para tumores localizados da próstata. MATERIAIS E MÉTODOS: De novembro de 1997 a janeiro de 2000, 74 pacientes foram submetidos à teleterapia com 45 Gy e reforço com braquiterapia de alta taxa de dose com irídio-192 e dose de 16 Gy em quatro inserções (BT). Estes foram comparados a 29 pacientes submetidos à teleterapia com 45 Gy e reforço com arcoterapia e dose mediana de 24 Gy (RT) entre outubro de 1996 e fevereiro de 2000. Nos dois grupos houve associação ocasional de hormonioterapia neoadjuvante. Sobrevida atuarial livre de doença em três anos (SB3) e fatores prognósticos pré-tratamento da resposta bioquímica, como o antígeno prostático-específico inicial (PSAi), escore de Gleason da biópsia de próstata (EG) e estádio clínico (EC), foram analisados. RESULTADOS: O seguimento mediano foi de 25 meses para o grupo RT e 37 meses para o BT. Na análise atuarial, a SB3 foi de 51% e 73% (p = 0,032) para RT e BT, respectivamente. Na análise estratificada pelo PSAi, a SB3 para RT e BT foi de 85,7% e 79,1% (p = 0,76) para PSAi < 10 ng/mL e de 38% e 68% (p = 0,023) para PSAi > 10 ng/mL, respectivamente. Quando estratificado pelo EG, a SB3 para RT e BT foi de 37% e 80% (p = 0,001) para EG < 6 e 78% e 55% para EG > 6 (p = 0,58); estratificando-se pelo EC, a SB3 para RT e BT foi de 36% e 74% (p = 0,018) para EC < T2a e 73% e 69% para EC > T2a (p = 0,692), respectivamente. O risco relativo bruto de recidiva bioquímica foi de 2,3 (95% IC: 1,0-5,1) para os pacientes tratados com RT, em relação à BT; quando ajustado pelo PSAi e EG, o risco relativo de recidiva bioquímica foi de 2,4 (95% IC: 1,0-5,7). CONCLUSÃO: A modalidade de tratamento foi fator prognóstico independente de recidiva bioquímica, com maior controle bioquímico associado à BT. Nossos resultados preliminares sugerem que o maior benefício com BT foi obtido nos pacientes com PSAi > 10 ng/mL, EC < T2a e EG < 6.

Braquiterapia de alta taxa de dose no tratamento do carcinoma da próstata: análise da toxicidade aguda e do comportamento bioquímico

OBJETIVO: Analisar a resposta bioquímica nas variáveis volume prostático, valor do antígeno prostático específico (PSA), escores de Gleason, estádio, risco da doença e hormonioterapia. MATERIAIS E MÉTODOS: No período de fevereiro de 1998 a julho de 2001, 46 pacientes com câncer de próstata foram tratados com radioterapia, numa combinação de teleterapia e braquiterapia de alta taxa de dose (BATD). A idade variou de 51 a 79 anos (média de 66,4 anos). O estádio T1c foi o mais freqüente: 30 (65%). O escore de Gleason era abaixo de 7 em 78% dos pacientes. O PSA variou de 3,4 a 33,3, estando abaixo de 10 em 39% das vezes. O volume prostático médio foi de 32,3 cc. Um total de 28% dos pacientes recebeu hormonioterapia. A dose de teleterapia variou de 45 a 50,4 Gy, associada a quatro frações de BATD de 4 Gy. RESULTADOS: O seguimento variou de 6 a 43 meses. Quatro pacientes perderam seguimento e quatro morreram (um por doença). Dos 39 pacientes analisados, 76% apresentaram PSA menor que 1,5. Nenhuma das variáveis analisadas foi estatisticamente significante (p > 0,05) com relação ao controle bioquímico. CONCLUSÃO: A utilização de BATD foi eficiente no tratamento do câncer de próstata e, neste estudo, as variáveis consideradas como fatores prognósticos não interferiram no controle bioquímico.

O papel atual da ultra-sonografia transretal da próstata na detecção precoce do câncer prostático

OBJETIVO: Determinar o papel real que a ultra-sonografia da próstata, notadamente com a associação do Doppler colorido, desempenha no diagnóstico de lesões malignas na próstata. MATERIAIS E MÉTODOS: Foram estudados, prospectivamente, 84 pacientes submetidos a biópsia guiada por ultra-sonografia transretal. Em todos os pacientes foram feitos estudo com Doppler colorido, à procura de focos de hipervascularização, e o exame ultra-sonográfico habitual. Os resultados foram comparados com os diagnósticos histopatológicos obtidos. RESULTADOS: A ultra-sonografia transretal habitual (escala de cinza) apresentou sensibilidade de 67,7%, especificidade de 52,8%, valor preditivo positivo de 45,6% e valor preditivo negativo de 73,6%. A adição do estudo com Doppler colorido ocasionou aumento importante da especificidade (de 52,8% para 79,2%) e do valor preditivo positivo (de 45,6% para 62,0%), porém causou queda na sensibilidade (de 67,7% para 58,0%). Além disso, houve perda de 32,2% dos cânceres, que não foram diagnosticados por nenhum dos dois métodos, e esses pacientes, apesar de possuírem cânceres menos extensos, eram todos clinicamente significativos (Gleason 6 ou mais). CONCLUSÃO: Mesmo com a associação do Doppler colorido, a ultra-sonografia transretal não possui capacidade suficiente para definir, através dos seus achados, quais pacientes devem ou não realizar biópsia.