Risk of osteoporosis in testicular germ cell tumour survivors: A systematic review of the literature.

Context: Testicular germ cell tumour (TGCT) survivors are potentially at risk of developing osteoporosis, because of increased risk for disturbed bone remodelling associated with hypogonadism and anti-cancer treatment. A number of studies show bone loss and increased fracture risk in TGCT survivors, but data are scarce. There are no clinical guidelines or recommendations issued to address skeletal health in this group of patients potentially at high risk for osteoporosis. Objective: To conduct a systematic review of available literature addressing bone health in TGCT patients. Subgroup analysis was performed to identify risk factors for bone loss and increased fracture risk. Evidence Acquisition: Relevant databases, including MEDLINE, Embase and the Cochrane Library, including all English written comparative studies addressing bone health in TGCT patients, were searched up to December 2021 and a narrative synthesis was undertaken. Risk of bias (RoB) was assessed using Cochrane ROBINS-I tool. Evidence Synthesis: Ten studies (eight cross-sectional and two longitudinal), recruiting a total of 1997 unique TGCT patients, were identified and included in the analysis. Bone health was reported in various ways in different studies, and subgroups were defined heterogeneously, resulting in a widely varying prevalence of osteoporosis of up to 73.2% of patients. Six studies reported low BMD associated with higher luteinizing hormone levels and one study showed a correlation between follow up duration and bone loss. Conclusions: TGCT survivors are at risk of developing osteoporosis and sustaining fragility fractures. Chemotherapy, pituitary-gonadal axis dysfunction and ageing are key risk factors, although available data are scarce. With increasing survival of TGCT patients, a clear unmet need has been identified to systematically evaluate and monitor skeletal health in larger numbers of survivors in order to develop best clinical practice guidelines to manage the insidious but potentially preventable and treatable skeletal complications of TGCT.

Alternative prostate cancer grading systems incorporating percent pattern 4/5 (IQ-Gleason) and cribriform architecture (cGrade) improve prediction of outcome after radical prostatectomy.

Percentage Gleason pattern 4, invasive cribriform and/or intraductal carcinoma (IC/IDC) and minor pattern 5 are recognized as independent parameters for prostate cancer outcome, but are not incorporated in current grade groups (GGs). Two proof-of-principle studies have proposed alternative grading schemes based on percentage Gleason pattern 4/5 (integrated quantitative Gleason score; IQ-Gleason) and IC/IDC presence (cribriform grade; cGrade). Our objective was to compare the performance of GG, IQ-Gleason and cGrade for predicting biochemical recurrence and metastasis after radical prostatectomy (RP). RP specimens of 1064 patients were pathologically reviewed and graded according to the three schemes. Discriminative power for prediction of biochemical recurrence-free (BCRFS) and metastasis-free (MFS) survival was compared using Harrell's c-index. The GG distribution at RP was 207 (19.4%) GG1, 472 (44.4%) GG2, 126 (11.8%) GG3, 140 (13.2%) GG4 and 119 (11.2%) GG5. Grading according to 5-tier IQ-Gleason and cGrade systems led to categorical shifts in 49.8% and 29.7% of cases, respectively. Continuous IQ-Gleason had the best performance for predicting BCRFS (c-index 0.743, 95% confidence interval (CI) 0.715-0.771), followed by cGrade (c-index 0.738, 95%CI 0.712-0.759), 5-tier categorical IQ-Gleason (c-index 0.723, 95%CI 0.695-0.750) and GG (c-index 0.718, 95%CI 0.691-0.744). Continuous IQ-Gleason (c-index 0.834, 95%CI 0.802-0.863) and cGrade (c-index 0.834, 95%CI 0.808-0.866) both had better predictive value for MFS than categorical IQ-Gleason (c-index 0.823, 95%CI 0.788-0.857) and GG (c-index 0.806, 95%CI 0.777-0.839). In conclusion, the performance of prostate cancer grading can be improved by alternative grading schemes incorporating percent Gleason pattern 4/5 and IC/IDC.

Cribriform architecture outperforms Gleason pattern 4 percentage and tertiary Gleason pattern 5 in predicting the outcome of Grade Group 2 prostate cancer patients.

AIMS: Gleason pattern 4 (GP4) percentage, invasive cribriform and/or intraductal carcinoma (IC/IDC) and the presence of tertiary Gleason pattern 5 (TP5) in radical prostatectomy (RP) specimens all aid in the risk stratification of Grade Group (GG) 2 prostate cancer patients. However, it is unclear to what extent these pathological features are mutually related and what are their individual values if they are investigated simultaneously. The aims of this study were: (i) to determine the mutual relationships of the GP4 percentage, IC/IDC and TP5 in GG2 RP specimens; and (ii) to assess their prognostic value for biochemical recurrence-free survival (BCRFS). METHODS AND RESULTS: Of 1064 RP specimens, 472 (44.4%) showed GG2 prostate cancer. Patients with ≥25% GP4 more frequently had IC/IDC (67.0% versus 43.9%; P < 0.001) and TP5 (20.6% versus 5.8%; P < 0.001) than those with <25% GP4. In unadjusted analysis, an increased GP4 percentage [hazard ratio (HR) 1.3; 95% confidence interval (CI) 1.0-1.6; P = 0.04] and IC/IDC (log rank P < 0.001) were associated with shorter BCRFS, whereas TP5 (P = 0.12) and a dichotomised (<25%, ≥25%) GP4 percentage (P = 0.10) were not. In multivariable analysis, IC/IDC was an independent prognostic factor (HR 1.9; 95% CI 1.2-2.9; P = 0.005) for BCRFS, whereas a continuous or dichotomised GP4 percentage and TP5 were not independent prognostic factors. CONCLUSION: In conclusion, a higher GP4 percentage in RP specimens was associated with more frequent IC/IDC and TP5. IC/IDC was an independent predictor for BCRFS, whereas the GP4 percentage and TP5 were not. These findings underscore the importance of routinely including the presence of IC/IDC in RP pathology reports.

Real-life data on the impact of successful downstaging in patients with hepatocellular carcinoma: A Dutch Multicenter Study.

Patients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since they do not have extrahepatic spread or vascular invasion. Once successful, this can change the treatment strategy from palliative to curative intention. Although downstaging therapy is suggested in guidelines, it is still not widely accepted. Moreover, studies on downstaging are mainly performed in high-incidence HCC countries. Therefore, our aim was to gain insight in therapeutic strategies in patients with intermediate stage HCC and their impact on intention-to-treat survival in a real-life setting in a low-incidence HCC country. We retrospectively analyzed data from the national Dutch HCC registry. From this database, consisting of 1409 patients with a diagnosis of HCC between 2005-2013 in 5 Dutch tertiary referral centers, we identified 165 patients with intermediate stage HCC. Out of these patients, 63 (38%) were not offered LRT, whereas 102 (62%) did receive LRT. Subsequently, 50 (49%) of the 102 patients who received LRT were successfully downstaged. Eleven patients (22% of successfully downstaged patients) eventually underwent liver transplantation. Cox regression analysis showed that a lower MELD score, an AFP value <100 ng/ml, successful downstaging and liver transplantation (all ≤p = 0.01) were positively associated to overall survival. In conclusion, our results demonstrate that LRT is not routinely offered to intermediate stage HCC patients in the Netherlands. Nevertheless, we showed that patients with intermediate stage HCC who are successfully downstaged have a survival benefit compared to those who were not.

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer.

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels ≤9.1 mmol/L. Trough plasma concentrations of liposomal- and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t1/2 ~50 h for liposomal dexamethasone), trough concentrations of liposomal- and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow-up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715.

Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study.

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early- and intermediate-stage HCC. MATERIALS AND METHODS: Twenty-four patients with modified Child-Pugh class A early- and intermediate-stage HCC received neoadjuvant oral dovitinib 500 mg daily (5 days on/2 days off) for 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR-blockade, time to progression (TTP), and overall survival (OS). RESULTS: Modified RECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3-4 adverse events, most frequently (on-target) hypertension (54%), fatigue (25%), and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF-A, VEGF-D, and placental growth factor increased significantly, whereas sTie-2 decreased, consistent with VEGFR-blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (three early, four intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer-specific survival was not reached. CONCLUSION: Already after a short 4-week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC. IMPLICATIONS FOR PRACTICE: Orthotopic liver transplantation may cure early and intermediate-stage hepatocellular carcinoma. Considering the expected waiting time >6 months because of donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy, and may provide a novel treatment approach to improve patient outcomes if tolerability in patients with hepatocellular carcinoma can be improved by therapeutic drug monitoring and personalized dosing.

Comedonecrosis Gleason pattern 5 is associated with worse clinical outcome in operated prostate cancer patients.

Individual growth patterns and cribriform architecture are increasingly considered in risk stratification and clinical decision-making in men with prostate cancer. Our objective was to establish the prognostic value of individual Gleason 5 patterns in a radical prostatectomy (RP) cohort. We reviewed 1064 RPs and recorded Grade Group (GG), pT-stage, surgical margin status, Gleason 4 and 5 growth patterns as well as intraductal carcinoma. The clinical endpoints were biochemical recurrence and post-operative distant metastasis. Gleason pattern 5 was present in 339 (31.9%) RPs, of which 47 (4.4%) presented as primary, 166 (15.6%) as secondary, and 126 (11.8%) as tertiary pattern. Single cells/cords were present in 321 (94.7%) tumors with Gleason pattern 5, solid fields in 90 (26.5%), and comedonecrosis in invasive carcinoma in 32 (9.4%) tumors. Solid fields demonstrated either a small nested morphology (n = 50, 14.7%) or medium to large solid fields (n = 61, 18.0%). Cribriform architecture was present in 568 (53.4%) RPs. Medium to large solid fields and comedonecrosis coincided with cribriform architecture in all specimens, and were not observed in cribriform-negative cases. In multivariable analysis adjusted for Prostate-Specific Antigen, pT-stage, GG, surgical margin status and lymph node metastases, cribriform architecture (Hazard Ratio (HR) 9.9; 95% Confidence Interval (CI) 3.9-25.5, P < 0.001) and comedonecrosis (HR 2.1, 95% CI 1.2-3.7, P = 0.01) were independent predictors for metastasis-free survival, while single cells/cords (HR 1.2; 95% CI 0.7-1.8, P = 0.55) and medium to large solid fields (HR 1.6, 95% CI 0.9-2.7, P = 0.09) were not. In conclusion, comedonecrosis in invasive carcinoma is an independent prognostic Gleason 5 pattern for metastasis-free survival after RP. These data support the current recommendations to routinely include cribriform pattern in pathology reports and indicate that comedonecrosis should also be commented on.

Cribriform architecture in radical prostatectomies predicts oncological outcome in Gleason score 8 prostate cancer patients.

The Gleason score is an important parameter for clinical outcome in prostate cancer patients. Gleason score 8 is a heterogeneous disease including Gleason score 3 + 5, 4 + 4, and 5 + 3 tumors, and encompasses a broad range of tumor growth patterns. Our objective was to characterize individual growth patterns and identify prognostic parameters in Gleason score 8 prostate cancer patients. We reviewed 1064 radical prostatectomy specimens, recorded individual Gleason 4 and 5 growth patterns as well as presence of intraductal carcinoma, and evaluated biochemical recurrence- and metastasis-free survival. Gleason score 8 disease was identified in 140 (13%) patients, of whom 76 (54%) had Gleason score 3 + 5, 46 (33%) 4 + 4, and 18 (13%) 5 + 3 disease. Invasive cribriform and/or intraductal carcinoma (n = 87, 62%) was observed more frequently in Gleason score 4 + 4 (93%) than 3 + 5 (47%; P < 0.001) and 5 + 3 (44%; P < 0.001) patients. Gleason pattern 5 was present in 110 (79%) men: as single cells and/or cords in 99 (90%) and solid fields in 32 (29%) cases. Solid field pattern 5 coexisted with cribriform architecture (23/32, 72%) more frequently than nonsolid pattern 5 cases (36/78, 46%, P = 0.02). In multivariable analysis including age, prostate-specific antigen, pT-stage, surgical margin status, and lymph node metastases, presence of cribriform architecture was an independent parameter for biochemical recurrence-free (hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.0-3.7; P = 0.04) and metastasis-free (HR 3.5, 95% CI 1.0-12.3; P = 0.05) survival. In conclusion, invasive cribriform and/or intraductal carcinoma occurs more frequently in Gleason score 4 + 4 prostate cancer patients than in Gleason score 3 + 5 and 5 + 3, and is an independent parameter for biochemical recurrence and metastasis. Therefore, cribriform architecture has added value in risk stratification of Gleason score 8 prostate cancer patients.

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands: An Analysis of Toxicity, Efficacy, and Predictive Markers.

BACKGROUND: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population. PATIENTS AND METHODS: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated. RESULTS: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non-clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P = .038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P = .000). On-treatment increase in eosinophils by week 8 predicted improved OS (P = .003), PFS (P = .000), and TTF (P = .014), whereas a decrease of neutrophils was associated with significantly better TTF (P = .023). CONCLUSIONS: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation.

Neoadjuvant and adjuvant treatments in muscle-invasive bladder cancer: Where are we?

OBJECTIVES: Fifty percent of muscle-invasive bladder cancer (MIBC) patients succumb from metastatic disease despite radical cystectomy (RC). Neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (ACT) randomized clinical trials (RCT) investigated whether peri-operative chemotherapy improves survival. More recently, immune checkpoint inhibitors (ICI) are explored as peri-operative single agent, ICI-ICI or ICI-chemotherapy combinations. Our goal is to provide the status of neoadjuvant and adjuvant treatment in MIBC. METHODS: The literature on NAC and ACT trials in MIBC was reviewed. RESULTS: Since the 1980s, NAC RCTs were performed in cisplatin-fit patients, mainly using cisplatin combination chemotherapy. Meta-analyses indicated a small, but significant 5% improvement in overall survival in T2-T4N0M0 MIBC patients. Mostly MVAC or gemcitabine-cisplatin (GC) regimens were used without clear benefit of one regimen over the other. NAC value in N+MIBC is not established and predictive value of associated~25-40% complete downstaging (pathologically confirmed complete regression, pCR) not unequivocally demonstrated. Adjuvant cisplatin-based chemotherapy RCTs were smaller, some prematurely stopped for poor accrual, and underpowered to demonstrate clear statistical evidence for a 5% overall survival advantage in pT3-T4N1-3M0 MIBC. Novel neoadjuvant immune checkpoint inhibitors, alone or with chemotherapy, phase 2 trials demonstrate down staging and encouraging clinical results. CONCLUSIONS: Neoadjuvant MVAC or GC in cT2-T4N0 MIBC patients fit for cisplatin is still recommended based on OS benefit shown in meta-analyses, butreal-world adherence to NAC is low as ~40-50% ofpatients are unfit for cisplatin. The value of neoadjuvant treatment in node-positive MIBC is not clearly demonstrated requiring more accurate clinical staging and prospective studies. Adjuvant cisplatin-based chemotherapy may be considered in selected, chemo-naïve pT3-T4N+patients. Results from prospective checkpoint inhibitor immunotherapy RCTs are needed before immunotherapy becomes a recommended alternative for peri-operative treatment. Molecular tumour subtyping will support selecting novel agents for neoadjuvant or adjuvant strategies.

OBJETIVOS: El 50% de los tumores vesicales invasivos acaban siendo metastáticos todos y con la cistectomía radical. Los ensayos prospectivos randomizados de quimioterapia neoadyuvante y adyuvante investigaron si la quimioterapia perioperatoria mejoraba la supervivencia. Recientemente, los inhibidores de checkpoint han sido estudiados como única terapia perioperatoria o en combinaciones con quimioterapia. Nuestro objetivo es determinar el estado del tratamiento neoadyuvante y adyuvante en cáncer de vejiga musculo invasivo.MÉTODOS: Se revisó la literatura en quimioterapia neoadyuvante y adyuvante para cáncer de vejiga músculoinfiltrante. RESULTADOS: Desde 1980, los ensayos de quimioterapia neoadyuvante se realizaron en pacientes que podían tolerar cisplatino usando combinaciones de quimioterapia de cisplatino. Un metanálisis indicó una pequeña pero significante ventaja del 5% en supervivencia global para pacientes T2-4 N-M0 con cáncer de vejiga músculo invasivo. Principalmente los regímenes MVAC oGC han sido utilizados, sin demostrar beneficio de un régimen sobre otro. El valor de la quimioterapia neoadyuvante en pacientes con ganglios positivos no esta establecido pero una infragradación del 25 al 40% se ha demostrado. Los ensayos de quimioterapia adyuvante fueron mas pequeños, algunos terminaron antes de finalizar el reclutamiento y con poca potencia estadística para demostrar un 5% de ventaja de supervivencia global en pT3-T4N1-3M0. Los nuevos immunomoduladores neoadyuvantes, solos o en combinación con quimioterapia han demostrado resultados esperanzadores en términos de infragradación. CONCLUSIONES: La quimioterapia neoadyuvante con MVAC o GC en cT2-4N0 de vejiga en pacientes que pueden recibir cisplatino se recomienda en base a un beneficio en supervivencia global demostrado en un metanálisis, pero la adherencia en el mundo real a la quimioterapia neoadyuvante es tan baja como que del 40-50% de los pacientes no puede recibir cisplatino. El valor de la quimioterapia neoadyuvante en pacientes con ganglios positivos y cáncer de vejiga musculoinvasivo no esta claramente demostrado; requiere un estadiaje clínico mas eficaz y estudio prospectivos. La quimioterapia adyuvante se puede considerar en pacientes seleccionados, sobretodo los que no han recibido quimioterapia previa pT3-4 N+. Los resultados de estudios prospectivos con inmunoterapia son necesarios antes de que se pueda recomendar la quimioterapia como alternativa en el tratamiento perioperatorio. La clasificación molecular nos ayudara a seleccionar los pacientes que pueden beneficiarse de terapias neoadyuvantes y adyuvantes.

Neoadjuvant and adjuvant treatments in muscle-invasive bladder cancer: Where are we? / Tratamientos neoadyuvantes y adyuvantes en cáncer de vejiga músculo invasivo: ¿dónde nos encontramos?

OBJECTIVES: Fifty percent of muscle-invasive bladder cancer (MIBC) patients succumb from metastatic disease despite radical cystectomy (RC). Neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (ACT) randomized clinical trials (RCT) investigated whether peri-operative chemotherapy improves survival. More recently, immune checkpoint inhibitors (ICI) are explored as peri-operative single agent, ICI-ICI or ICI-chemotherapy combinations. Our goal is to provide the status of neoadjuvant and adjuvant treatment in MIBC. METHODS: The literature on NAC and ACT trials in MIBC was reviewed. RESULTS: Since the 1980s, NAC RCTs were performed in cisplatin-fit patients, mainly using cisplatin combination chemotherapy. Meta-analyses indicated a small, but significant 5% improvement in overall survival in T2-T4N0M0 MIBC patients. Mostly MVAC or gemcitabine-cisplatin (GC) regimens were used without clear benefit of one regimen over the other. NAC value in N+ MIBC is not established and predictive value of associated ~25-40% complete downstaging (pathologically confirmed complete regression, pCR) not unequivocally demonstrated. Adjuvant cisplatin-based chemotherapy RCTs were smaller, some prematurely stopped for poor accrual, and underpowered to demonstrate clear statistical evidence for a 5% overall survival advantage in pT3-T4N1-3M0 MIBC. Novel neoadjuvant immune checkpoint inhibitors, alone or with chemotherapy, phase 2 trials demonstrate downstaging and encouraging clinical results. CONCLUSIONS: Neoadjuvant MVAC or GC in cT2-T4N0 MIBC patients fit for cisplatin is still recommended based on OS benefit shown in meta-analyses, but real-world adherence to NAC is low as ~40-50% of patients are unfit for cisplatin. The value of neoadjuvant treatment in node-positive MIBC is not clearly demonstrated requiring more accurate clinical staging and prospective studies. Adjuvant cisplatin-based chemotherapy may be considered in selected, chemo-naïve pT3-T4N+ patients. Results from prospective checkpoint inhibitor immunotherapy RCTs are needed before immunotherapy becomes a recommended alternative for peri-operative treatment. Molecular tumour subtyping will support selecting novel agents for neoadjuvant or adjuvant strategies

OBJETIVOS: El 50% de los tumores vesicales invasivos acaban siendo metastáticos todos y con la cistectomía radical. Los ensayos prospectivos randomizados de quimioterapia neoadyuvante y adyuvante investigaron si la quimioterapia perioperatoria mejoraba la supervivencia. Recientemente, los inhibidores de checkpoint han sido estudiados como única terapia perioperatoria o en combinaciones con quimioterapia. Nuestro objetivo es determinar el estado del tratamiento neoadyuvante y adyuvante en cáncer de vejiga musculoinvasivo. MÉTODOS: Se revisó la literatura en quimioterapia neoadyuvante y adyuvante para cáncer de vejiga músculo infiltrante. RESULTADOS: Desde 1980, los ensayos de quimioterapia neoadyuvante se realizaron en pacientes que podían tolerar cisplatino usando combinaciones de quimioterapia de cisplatino. Un metanálisis indicó una pequeña pero significante ventaja del 5% en supervivencia global para pacientes T2-4 N-M0 con cáncer de vejiga músculo invasivo. Principalmente los regímenes MVAC o GC han sido utilizados, sin demostrar beneficio de un régimen sobre otro. El valor de la quimioterapia neoadyuvante en pacientes con ganglios positivos no está establecido pero una infragradación del 25 al 40% se ha demostrado. Los ensayos de quimioterapia adyuvante fueron más pequeños, algunos terminaron antes de finalizar el reclutamiento y con poca potencia estadística para demostrar un 5% de ventaja de supervivencia global en pT3-T4N1-3M0. Los nuevos inmunomoduladores neoadyuvantes, solos o en combinación con quimioterapia han demostrado resultados esperanzadores en términos de infragradación. CONCLUSIONES: La quimioterapia neoadyuvante con MVAC o GC en cT2-4N0 de vejiga en pacientes que pueden recibir cisplatino se recomienda en base a un beneficio en supervivencia global demostrado en un metanálisis, pero la adherencia en el mundo real a la quimioterapia neoadyuvante es tan baja como que del 40-50% de los pacientes no puede recibir cisplatino. El valor de la quimioterapia neoadyuvante en pacientes con ganglios positivos y cáncer de vejiga musculo invasivo no está claramente demostrado; requiere un estadiaje clínico más eficaz y estudio prospectivos. La quimioterapia adyuvante se puede considerar en pacientes seleccionados, sobretodo los que no han recibido quimioterapia previa pT3-4 N+. Los resultados de estudios prospectivos con inmunoterapia son necesarios antes de que se pueda recomendar la quimioterapia como alternativa en el tratamiento perioperatorio. La clasificación molecular nos ayudara a seleccionar los pacientes que pueden beneficiarse de terapias neoadyuvantes y adyuvantes

Clinicopathological characteristics of glomeruloid architecture in prostate cancer.

Glomeruloid architecture is the least common Gleason 4 growth pattern in prostate adenocarcinoma. Its clinicopathological features and relation with cribriform architecture, which has been recognized as an adverse feature, remains to be established. Our objective was to investigate clinicopathological features of glomeruloid architecture in radical prostatectomies. We reviewed 1064 radical prostatectomy specimens and recorded Grade Group, pT-stage, margin status, Gleason pattern percentages, and growth patterns. Simple and complex glomerulations were distinguished by gland size and intraluminal cribriform protrusions. Clinical endpoint was biochemical recurrence-free survival. Glomerulations were identified in 365 (34%) specimens. In 472 Grade Group 2 patients, 210 (44%) had simple and 92 (19%) complex glomerulations. Complex glomerulations coincided with cribriform architecture more often than simple glomerulations (67% versus 52%; P = 0.01). Men with simple glomerulations had significantly lower prostate specific antigen (PSA) levels (9.7 versus 12.1 ng/ml; P = 0.03), percentage Gleason pattern 4 (19% versus 25%; P = 0.001), extra-prostatic extension (34% versus 50%; P = 0.01), and positive surgical margins (25% versus 39%; P = 0.04) than those with cribriform architecture. Extra-prostatic extension (37%) and positive surgical margins (30%) in men with complex glomerulations resembled those with simple glomeruloid rather than those with cribriform architecture. In multivariate Cox regression analysis adjusted for PSA, pT-stage, margin status, and lymph node metastases, cribriform architecture had independent predictive value for biochemical recurrence-free survival (hazard ratio (HR)) 1.9; 95% confidence interval (CI) 1.2-2.9; P = 0.004), while simple (HR 0.8; 95% CI 0.5-1.2; P = 0.26) and complex (HR 0.9; 95% CI 0.5-1.6; P = 0.67) glomerulations did not. Both simple and complex glomeruloid architecture are associated with better outcome than cribriform architecture in Grade Group 2 prostate cancer patients. Therefore, glomeruloid pattern and particularly complex glomerulations should not be classified as a cribriform growth pattern variant in radical prostatectomy specimens.

Lifetime Transfusion Burden and Transfusion-Related Iron Overload in Adult Survivors of Solid Malignancies.

BACKGROUND: Limited data exist on transfusion burden and transfusion-related iron overload in adult survivors of solid malignancies. METHODS: Hospital-specific cancer registry data of patients with solid tumor receiving systemic anticancer treatment between January 2008 and September 2009 at the Oncology Department of the Leiden University Medical Center (The Netherlands) were retrieved and cross-referenced with red blood cell (RBC) transfusion records. Individual lifetime transfusion burden was captured in April 2015. Multitransfused long-term survivors with serum ferritin >500 µg/L were subsequently screened for hepatic and cardiac iron overload using 1.5 Tesla magnetic resonance imaging. RESULTS: The study population consisted of 775 adult patients with solid cancer (45.2% male; median age, 58 years; >75% chemotherapy-treated), 423 (54.6%) of whom were transfused with a median of 6.0 RBC units (range 1-67). Transfusion triggers were symptomatic anemia or hemoglobin <8.1-8.9 g/dL prior to each myelosuppressive chemotherapy cycle. We identified 123 (15.9%) patients across all tumor types with a lifetime transfusion burden of ≥10 RBC units. In the absence of a hemovigilance program, none of these multitransfused patients was screened for iron overload despite a median survival of 4.6 years. In 2015 at disclosure of transfusion burden, 26 multitransfused patients were alive. Six (23.1%) had hepatic iron overload: 3.9-11.2 mg Fe/g dry weight. No cardiac iron depositions were found. CONCLUSION: Patients with solid malignancies are at risk for multitransfusion and iron overload even when adhering to restrictive RBC transfusion policies. With improved long-term cancer survivorship, increased awareness of iatrogenic side effects of supportive therapy and development of evidence-based guidelines are essential. IMPLICATIONS FOR PRACTICE: In the presence of a restrictive transfusion policy, ∼30% of transfused adult patients with solid cancer are multitransfused and ∼50% become long-term survivors, underscoring the need for evidence-based guidelines for the detection and management of transfusion-related iron overload in this group of patients. In each institution, a hemovigilance program should be implemented that captures the lifetime cumulative transfusion burden in all patients with cancer, irrespective of tumor type. This instrument will allow timely assessment and treatment of iron overload in cancer survivors, thus preventing organ dysfunction and decreased quality of life.

Oligometastatic Prostate Cancer: Results of a Dutch Multidisciplinary Consensus Meeting.

BACKGROUND: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear. OBJECTIVE: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice. DESIGN, SETTING, AND PARTICIPANTS: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement was determined with statements (five-point scale). Consensus was defined as ≥75% panel agreement with a statement. RESULTS AND LIMITATIONS: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC. CONCLUSIONS: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC. PATIENT SUMMARY: A group of Dutch medical specialists agreed that prostate cancer patients having few metastases may benefit from a new therapeutic approach. Clinical studies need to determine which treatment is best for each specific situation.

Cabozantinib in the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor targeted therapy: clinical trial evidence and experience.

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits MET and AXL, both associated with poor prognosis in renal cell carcinoma (RCC), next to vascular endothelial growth factor receptor 2, KIT, FLT3 and RET. Chronic treatment with vascular endothelial growth factor receptor (VEGFR)-targeting sunitinib upregulates MET and AXL in RCC, indicating that cabozantinib may be particularly effective in patients with advanced RCC whose disease progressed on prior VEGFR-targeted treatment. Cabozantinib (60 mg once daily) has been investigated in comparison to everolimus (10 mg once daily) in a phase III randomized controlled trial (RCT) in 658 patients with advanced RCC of whom 71% had received one prior and 29% had received at least two prior lines of VEGR-targeted therapy. This study demonstrated highly significant improved progression-free survival of 7.4 months versus 3.9 months with a hazard ratio (HR) of 0.51 [95% confidence interval (CI) 0.41-0.62] in favour of cabozantinib. Cabozantinib also showed a superior overall survival of 21.4 months versus 16.5 months (HR 0.66; 95% CI 0.53-0.83). Objective response rate was higher in cabozantinib-treated patients, 17% versus 3%. Clinical benefit was shown in all subgroups of patients, including in patients with bone or visceral metastases. The safety profile was acceptable with manageable side effects. Based on this study, cabozantinib is a highly effective approved second-line treatment option for patients with advanced RCC with a manageable toxicity profile. Other recently approved second-line agents include checkpoint inhibitor nivolumab and VEGF-targeting agent lenvatinib combined with everolimus. In the absence of predictive markers as well as head-to-head comparisons of these three recently approved treatments, the choice between these drugs in second-line treatment will probably be made based on comorbidities, tolerability of previous treatment and presence of high tumour burden with rapidly progressive disease. Future pretreatment assessment of MET and AXL tumour aberration may aid clinicians to make a rational choice between currently approved second-line treatment options.

International evaluation of the psychometrics of health-related quality of life questionnaires for use among long-term survivors of testicular and prostate cancer.

BACKGROUND: Understanding of the physical, functional and psychosocial health problems and needs of cancer survivors requires cross-national and cross-cultural standardization of health-related quality of life (HRQoL) questionnaires that capture the full range of issues relevant to cancer survivors. To our knowledge, only one study has investigated in a comprehensive way whether a questionnaire used to evaluate HRQoL in cancer patients under active treatment is also reliable and valid when used among (long-term) cancer survivors. In this study we evaluated, in an international context, the psychometrics of HRQoL questionnaires for use among long-term, disease-free, survivors of testicular and prostate cancer. METHODS: In this cross-sectional study, we recruited long-term survivors of testicular and prostate cancer from Northern and Southern Europe and from the United Kingdom who had participated in two phase III EORTC clinical trials. Participants completed the SF-36 Health Survey, the EORTC QLQ-C30 questionnaire, the QLQ-PR25 (for prostate cancer) or the QLQ-TC26 (for testicular cancer) questionnaires, and the Impact of Cancer questionnaire. Testicular cancer survivors also completed subscales from the Nordic Questionnaire for Monitoring the Age Diverse Workforce. RESULTS: Two hundred forty-two men (66% response rate) were recruited into the study. The average time since treatment was more than 10 years. Overall, there were few missing questionnaire data, although scales related to sexuality, satisfaction with care and relationship concerns of men without partners were missing in more than 10% of cases. Debriefing showed that in general the questionnaires were accepted well. Many of the survivors scored at the upper extremes of the questionnaires, resulting in floor and ceiling effects in 64% of the scales. All of the questionnaires investigated met the threshold of 0.70 for group level reliability, with the exception of the QLQ-TC26 (mean reliability .64) and the QLQ-PR25 (mean reliability .69). The questionnaires were able to discriminate clearly between patients with and without comorbid conditions. CONCLUSIONS: The currently available HRQoL questionnaires exhibit acceptable psychometric properties and were well received by patients, but additional efforts are needed to ensure that the full range of survivor-specific issues is assessed.

Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis?

BACKGROUND: Cancer-related venous thromboembolism (VTE) heralds a poor prognosis, especially in pancreatic adenocarcinoma (PAC). Tissue factor (TF) is implicated as one of the main culprits in PAC-associated VTE and disease progression. METHODS: In a prospective cohort study of 79 PAC patients, we measured plasma CA19-9 and microparticle-associated TF activity (MP-TF activity). In addition, we enumerated TF(+)MPs and MUC1(+)MPs in plasma (n=55), and studied the expression of TF, MUC1, CD31 and CD68 in tumour tissue (n=44). RESULTS: Plasma MP-TF activity was markedly elevated in PAC patients with VTE compared with those without (median: 1925 vs 113 fM Xa min(-1); P<0.001) and correlated with the extent of thromboembolic events, metastatic disease and short survival. Similar results were found for CA19-9. Patients with massively progressing thrombosis and cerebral embolisms despite anticoagulant therapy (n=3) had the highest MP-TF activities (12 118-40 188 fM Xa min(-1)) and CA19-9 (40 730-197 000 kU l(-1)). All tumours expressed MUC1 and TF. MP-TF activity did not correlate with intensity of TF expression in adenocarcinoma cells, but corresponded with numbers of TF(+) macrophages in the surrounding stroma. CONCLUSIONS: Circulating TF(+)MPs and mucins may concertedly aggravate coagulopathy in PAC. Understanding of underlying mechanisms may result in new treatment strategies for VTE prevention and improvement of survival.

Adherence to guideline recommendations for management of clinical T1 renal cancers in the Netherlands: a population-based study.

PURPOSE: For decades, small renal cancers are treated by radical nephrectomy (RN). Current guidelines recommend partial nephrectomy (PN) to preserve renal function and minimize cardiovascular comorbidity. As adherence to guidelines is largely unknown and international comparison to evaluate quality of health care is lacking, an pre-specified guideline evaluation of quality indicators concerning management of cT1 renal cancers was performed. METHODS: We performed a cohort study including patients with cT1 renal cancer between 2010 and 2014, identified through the Netherlands Cancer Registry. Time trends and variation in treatment were described. Factors associated with PN in cT1a and laparoscopic RN in cT1b were evaluated with logistic regression analyses. RESULTS: An increase in nephron-sparing treatment strategies (NSS) of cT1a patients (N total = 2436) was observed; in 2014, 67 % underwent NSS (62 % PN and 5 % thermal ablation). Age, a non-central tumor localization and being treated in a high-volume hospital were associated with PN. Although NSS were applied more frequently over time, the majority (70 %) of cT1b patients (N total = 2205) underwent RN in 2014, mainly performed laparoscopically. Increasing tumor size, tumor localization in the right kidney and being treated in a university hospital were associated with a lower probability of a laparoscopic RN versus open. Treatment in a high-volume hospital was associated with a higher probability of laparoscopic RN. CONCLUSIONS: Dutch patients with cT1 renal cancer are predominantly treated according to current guidelines. Data of this pre-specified quality indicator analysis of a urological national guideline may serve as a model for international comparison of treatment of cT1 renal cancers.