Reasons for lack of treatment in patients with locally advanced, unresectable or metastatic urothelial carcinoma.

BACKGROUND: The proportion of patients with locally advanced, unresectable or metastatic urothelial carcinoma that do not receive systemic anticancer treatment and the reasons for lack of treatment are largely unknown. The aim of this study was to investigate the prevalence and overall survival of this patient group and reasons for omission of treatment. MATERIAL AND METHODS: This retrospective, single-center cohort study from Rigshospitalet, Denmark included patients diagnosed with locally advanced, unresectable or metastatic urothelial carcinoma during the study period from 1 January 2010 to 31 March 2016 who did not receive systemic anticancer treatment. Patients were identified through the Danish Pathology Register and the electronic medical records. RESULTS: 100 patients were included, representing 34% of all patients diagnosed with locally advanced, unresectable or metastatic urothelial carcinoma at Rigshospitalet during the study period. Lack of treatment was most often due to poor physical condition (59%), decreased renal function (15%), or patient preferences (14%). Median overall survival was 1.9 months (95% CI: 1.6-2.8 months). CONCLUSION: One in three patients diagnosed with locally advanced, unresectable or metastatic urothelial carcinoma in the pre-immunotherapy era did not receive systemic anticancer treatment. Prompt identification of advanced disease and interventions to optimize these patients for treatment are essential. Our findings underscore the compelling need for novel, better tolerated treatment regimens in this frail patient group.

Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer-A population-based analysis of 2 national cohorts.

BACKGROUND: Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life-prolonging treatments have been introduced for patients with advanced PCa. On a populations-based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5-year mortality of men with de novo metastatic PCa. METHODS: Men diagnosed with PCa during the periods 1980 to 2011 and 1995 to 2011 were identified in the US Surveillance, Epidemiology, and End Results (SEER) program and the Danish Prostate Cancer Registry (DaPCaR), respectively, and stratified according to period of diagnosis. Age-standardized incidence rates were calculated. Five-year mortality rates for de novo metastatic PCa were analyzed using competing risk analysis. RESULTS: Totals of 426,266 and 47,024 men were identified in SEER and DaPCaR, respectively. Of these, 29,555 and 6874 had de novo metastatic PCa. The incidence of de novo metastatic PCa decreased (from 12.0 to 4.4 per 100,000 men) in the SEER cohort (1980-2011), whereas it increased (from 6.7 to 9.9 per 100,000 men) in the DaPCaR cohort (1995-2011). Five-year PCa mortality in the SEER cohort was stable for men diagnosed with de novo metastatic PCa from 1980 to 1994 and increased slightly in the latest periods studied (P < .0001), whereas it decreased by 16.6% (P < .0001) in the DaPCaR cohort. CONCLUSIONS: Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. © 2018 American Cancer Society.

Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study.

BACKGROUND: The risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. METHODS: Data were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. FINDINGS: Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8-8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0-79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7-26·5) versus 50·5% (47·5-53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9-6·5) versus 59·9% (55·2-64·6) for mortality from other causes. In men with PSA concentrations 10 µg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2-1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1-7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7-22·4) and for men with a PSA higher than 20 ng/mL (454 men). INTERPRETATION: The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. FUNDING: Capital Region of Denmark's Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersen's Foundation.

The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading - a matched-pair analysis.

OBJECTIVES: To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4). PATIENTS AND METHODS: A matched-pair analysis was conducted. In all, 215 patients with Gleason score 6 or 7 (3 + 4) prostate cancer on biopsy who underwent RP before 31 December 2005 (pre-ISUP group), were matched 1:1 by biopsy Gleason score, clinical tumour category, PSA level, and margin status to patients undergoing RP between 1 January 2008 and 31 December 2011 (post-ISUP group). Patients were followed until BCR defined as a PSA level of ≥0.2 ng/mL. Risk of BCR was analysed in a competing-risk model. RESULTS: The median follow-up was 9.5 years in the pre-ISUP group and 4.8 years in the post-ISUP group. The 5-year cumulative incidences of BCR were 34.0% and 13.9% in the pre-ISUP and post-ISUP groups, respectively (P < 0.001). The difference in cumulative incidence applied to both patients with Gleason score 6 (P < 0.001) and 7 (3 + 4) (P = 0.004). There was no difference in the 5-year cumulative incidence of BCR between patients with pre-ISUP Gleason score 6 and post-ISUP Gleason score 7 (3 + 4) (P = 0.34). In a multiple Cox-proportional hazard regression model, ISUP 2005 grading was a strong prognostic factor for BCR within 5 years of RP (hazard ratio 0.34; 95% confidence interval 0.22-0.54; P < 0.001). CONCLUSION: The revision of the Gleason grading system has reduced the risk of BCR after RP in patients with biopsy Gleason score 6 and 7 (3 + 4). This may have consequences when comparing outcomes across studies and historical periods and may affect future treatment recommendations.

DaPeCa-3: promising results of sentinel node biopsy combined with (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in clinically lymph node-negative patients with penile cancer - a national study from Denmark.

OBJECTIVES: To estimate the diagnostic accuracy of sentinel node biopsy (SNB) combined with preoperative (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for inguinal lymph node (LN) evaluation in patients with invasive penile squamous cell carcinoma (PSCC) with no clinical evidence of inguinal metastases (cN0) at two tertiary centres with complete clinical follow-up. PATIENTS AND METHODS: From April 2010 in Centre one and from January 2013 in Centre two, we prospectively enrolled patients diagnosed with invasive PSCC and scheduled for SNB at the only two university centres treating penile cancer in Denmark. All patients had FDG PET/CT before SNB. The sentinel LNs were preoperatively located by planar lymphoscintigraphy in 134 groins (68 patients) and by single-photon emission CT/CT in 120 groins (61 patients). The primary endpoints were the sensitivity, specificity, and false-negative rate of SNB combined with FDG PET/CT. The secondary endpoint was SNB-related morbidity. RESULTS: We examined 254 groins in 129 patients by SNB combined with FDG PET/CT. The median (interquartile range, IQR) follow-up of survivors was 23 (14-35) months. Of 201 LN-negative groins, two were false negatives, and despite radio-chemotherapy treatment, both patients died from penile cancer. Four of 23 radiotracer-silent groins, had a FDG PET/CT-positive LNs and were surgically explored. In one of four of the explored groins, a positive LN was found. Combined FDG PET/CT-SNB sensitivity was 94.4% (95% confidence interval [CI] 81-99%) per groin. The false-negative rate was 5.6% (95% CI 1-19%) per groin. In 15 patients (11.6%) there were 25 SNB-related complications of Clavien-Dindo grades I-IIIa. The only Clavien-Dindo IIIa complication was an inguinal lymphocele treated by aspiration. CONCLUSION: In this study, we present a favourable SNB false-negative rate of 5.6% in a national cohort of clinically LN-negative patients with invasive PSCC with a pre-SNB FDG PET/CT scan. The combination of FDG PET/CT and SNB seems to be a promising diagnostic approach. Even so, a false-negative SNB was fatal in two of two cases and we are determined to continue the development of our SNB technique. The SNB-related morbidity was limited.

DaPeCa-1: diagnostic accuracy of sentinel lymph node biopsy in 222 patients with penile cancer at four tertiary referral centres - a national study from Denmark.

OBJECTIVES: To estimate the diagnostic accuracy of sentinel lymph node biopsy (SNB) in patients with penile cancer and assess SNB complications in a national multicentre setting. PATIENTS AND METHODS: Retrospectively data were collected from records in four university centres by one medical doctor covering all SNBs performed in Denmark between 1 January 2000 and 31 December 2010. Patients had either impalpable lymph nodes (LNs) in one or both groins, or had a palpable inguinal mass from which aspiration cytology failed to reveal malignancy. Patients were injected with nanocolloid technetium and had a scintigram recorded before the SNB. The primary endpoint was LN recurrence on follow-up. The secondary endpoint was complications after SNB. Diagnostic accuracy was computed. RESULTS: In all, 409 groins in 222 patients were examined by SNB. The median (interquartile range) follow-up of patients who survived was 6.6 (5-10) years. Of 343 negative groins, eight were false negatives. The sensitivity was 89.2% (95% confidence interval 79.8-95.2%) per groin. Interestingly, four of 67 T1G1 patients had a positive SNB. In all, 28 of 222 (13%) patients had complications of Clavien-Dindo grade I-IIIa. CONCLUSION: Penile cancer SNB with a close follow-up stages LN involvement reliably and has few complications in a national multicentre setting. Inguinal LN dissection was avoided in 76% of patients.

Use of Risk Factors To Select Adjuvant Therapy Versus Surveillance for Testicular Nonseminoma and Seminoma Germ Cell Tumors.

New risk factors associated with relapse of stage I testicular cancer have been identified. These new factors reflect the risk of recurrence much better than previous parameters and can be used to assess the possible effect of adjuvant chemotherapy.

The use of transrectal ultrasound-guided biopsy following the introduction of prostate-specific antigen testing in Denmark: a population-based analysis.

OBJECTIVE: Incidence rates of prostate cancer in Denmark resemble those of countries that endorse prostate-specific antigen (PSA) screening. So far, no studies have described the consequences of PSA testing on diagnostic activity on a population level. The aim of this study was to describe the frequency of systematic transrectal ultrasound-guided biopsy (TRUS-gb) activity, including rebiopsy rates, in Denmark between 1995 and 2011. MATERIALS AND METHODS: All men who underwent TRUS-gb during the period were identified in the Danish Prostate Cancer Registry. In total, 83,041 biopsy sets from 64,430 individuals were identified. The diagnostic rate and the frequency of rebiopsy were analyzed. Age, histology and PSA were compared at the time of biopsy. RESULTS: The number of TRUS-gb per 100,000 men per year increased 4.6-fold. The mean number of TRUS-gb procedures per individual increased from 1.08 in 1995 to 1.46 in 2011 (p = .0001), and the proportion of men with negative initial biopsy sets who underwent rebiopsy increased from 22% in 1995 to 41% in 2004, later decreasing to 31% in 2009. CONCLUSIONS: The diagnostic activity in Denmark and the rebiopsy rates in men with initial negative TRUS-gb have increased substantially, and guidelines for the management of men with a negative initial biopsy are highly warranted.

Novel germline c-MET mutation in a family with hereditary papillary renal carcinoma.

Hereditary papillary renal carcinoma (HPRC) is a highly penetrant hereditary renal cancer syndrome caused by germline missense mutations in the c-MET proto-oncogene. HPRC is clinically characterized by multiple bilateral papillary renal-cell carcinomas. Here we report a family with a novel missense mutation in c-MET. The original pathology report of four primary kidney cancers (1988-1997) revealed renal-cell carcinoma. A revised report described multiple adenomas and papillary renal-cell carcinomas with focal clear cells and a mixture of type 1 and type 2 pattern, emphasizing the importance of revised pathology examinations in possible hereditary renal-cell carcinomas especially when described before 1997.

A histopathological score on baseline biopsies from elderly donors predicts outcome 1 year after renal transplantation.

Kidneys from elderly deceased patients and otherwise marginal donors may be considered for transplantation and a pretransplantation histopathological score for prediction of postoperative outcome is warranted. In a retrospective design, 29 baseline renal needle biopsies from elderly deceased donors (age: 63 ± 4 years; mean ± SD) were evaluated independently by three pathologists and with ten or more glomeruli and one artery present the biopsy was histopathologically scored (numeric score: 0-12) according to the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis and increased wall thickness of arteries and/or arterioles. Nineteen renal baseline biopsies from 15 donors (age: 64 ± 10 years) were included and following consensus the histopathological score was 4.3 ± 2.1 (intraclass correlation coefficient: 0.81; confidence interval: 0.66-0.92). The donor organs were used for single renal transplantation (recipient age: 47 ± 3 years). Two grafts were lost after the transplantation. In the remaining 17 recipients the 1-year creatinine clearance (54 ± 6 mL/min) correlated to the baseline histopathological score (r(2) = 0.59; p < 0.01). This study demonstrates that in elderly Danish donors a histopathological score on baseline renal needle biopsies, with at least ten glomeruli and one artery present, predicts graft function 1 year after transplantation.

Effect of smoking, smoking cessation, and nicotine patch on wound dimension, vitamin C, and systemic markers of collagen metabolism.

BACKGROUND: Postoperative wound disruption and tissue-destructive disorders are more frequent in smokers than in nonsmokers. Impaired wound healing and altered connective tissue turnover are suggested mechanisms, but exact details remain unknown. METHODS: Full-thickness, 5-mm punch biopsy wounds were made lateral to the sacrum in 48 smokers and were randomized double-blinded to continuous smoking, abstinence with transdermal nicotine patch (TNP), or abstinence with placebo patch and 30 never smokers. At 1, 4, 8, and 12 weeks, the wounds were excised and fixed for wound measurement, and blood was collected for measurement of vitamin C, procollagen I N-propeptide (PINP), matrix metalloproteinase 8 (MMP), MMP-9, neutrophils, and eosinophils. RESULTS: One week after wounding, smokers' wounds were 3.1 ± 0.1 mm (mean, standard error of the mean) wide and were 1.3 ± 0.1 mm deep compared with the never smokers' wounds, measuring 3.7 ± 0.1 mm wide and 1.5 ± 0.1 mm deep (P < .01, respectively). Abstinent smokers' wounds were 3.3 ± 0.1 mm wide (NS) and were 1.4 ± 0.1 mm deep (P = .02 compared with smokers). In smokers, vitamin C and PINP were 50.5 ± 9.0 µmol/L and were 52.7 ± 6.6 ng/mL, respectively, compared with 68.8 ± 14.5 µmolL and 64.7 ± 4.7 ng/mL in never smokers (P < .001 and P = .07). Both increased significantly after smoking cessation. Plasma MMP-8 and MMP-9 were correlated with neutrophil blood count, which significantly was affected by smoking status. No effect of TNP was found. CONCLUSION: Smokers have smaller, more superficial wounds and lesser blood levels of vitamin C and PINP. Smoking cessation resulted in increased wound depth, vitamin C, and PINP as well as a decreased neutrophil blood count. These findings suggest that wound contraction and collagen metabolism are affected by a smoking-induced alteration in vitamin C turnover and by a change in inflammatory cell response.