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.

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.

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.

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.

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.

Alternatively spliced tissue factor promotes breast cancer growth in a ß1 integrin-dependent manner.

Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to ß1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.

The relationship between tissue factor and cancer progression: insights from bench and bedside.

It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.

Evaluation of lecithinized human recombinant super oxide dismutase as cardioprotectant in anthracycline-treated breast cancer patients.

AIM: Anthracycline-induced cardiotoxicity is (partly) mediated by free radical overload. A randomized study was performed in breast cancer patients to investigate whether free radical scavenger super oxide dismutase (SOD) protects against anthracycline-induced cardiotoxicity as measured by changes in echo, electrocardiography and an array of biomarkers. METHOD AND RESULTS: Eighty female, chemotherapy-naïve breast cancer patients (median age 49, range 24-67 years) scheduled for four or five courses of adjuvant 3 weekly doxorubicin plus cyclophosphamide (AC) chemotherapy, were randomly assigned to receive 80 mg PC-SOD (human recombinant SOD bound to lecithin) or placebo, administered intravenously (i.v.) immediately prior to each AC course. The primary end point was protection against cardiac damage evaluated using echocardiography, QT assessments and a set of biochemical markers for myocardial function, oxidative stress and inflammation. Assessments were performed before and during each course of chemotherapy, and at 1, 4 and 9 months after completion of the chemotherapy regimen. In all patients cardiac effects such as increases in NT-proBNP concentration and prolongation of the QTc interval were noticed. There were no differences between the PC-SOD and placebo-treated patients in systolic or diastolic cardiac function or for any other of the biomarkers used to assess the cardiac effects of anthracyclines. CONCLUSION: PC-SOD at a dose of 80 mg i.v. is not cardioprotective in patients with breast carcinoma treated with anthracyclines.

Abdominal visceral and subcutaneous fat increase, insulin resistance and hyperlipidemia in testicular cancer patients treated with cisplatin-based chemotherapy.

BACKGROUND: Testicular cancer survivors treated with chemotherapy are at increased risk for metabolic syndrome (MetS) and cardiovascular disease (CVD). We explored acute effects of chemotherapy by assessing metabolic factors, abdominal fat volume, hepatic triglyceride content (HTC) and aortic wall stiffness. MATERIAL AND METHODS: We studied 19 testicular cancer patients (age 20-54 years) before, at three and nine months after the start of chemotherapy. Blood serum was analyzed for lipids, glucose and insulin. Abdominal visceral and subcutaneous fat volume and aortic pulse wave velocity were assessed by magnetic resonance imaging (MRI) techniques; HTC was measured by proton MR spectroscopy. RESULTS: Three months after start of chemotherapy visceral abdominal fat volume had significantly increased from 202 ± 141 to 237 ± 153 ml (p = 0.009) whereas body mass index and subcutaneous fat volume significantly increased nine months after treatment from 24.4 ± 4.0 to 26.4 ± 4.1 kg/m(2) (p = 0.01) and from 556 ± 394 to 668 ± 460 ml (p = 0.002) respectively. Serum total cholesterol, low-density lipoprotein cholesterol and insulin also significantly increased three months after start of treatment from 4.88 ± 1.1 to 5.61 ± 1.50 mmol/l (p = 0.002), 3.31 ± 1.16 to 3.73 ± 1.41 mmol/l (p = 0.02) and 5.7 ± 4.4 to 9.6 ± 6.3 mU/ml (p = 0.03), respectively. Nine months after start of chemotherapy serum lipid and insulin concentrations had returned to baseline. HTC increased in seven of the 19 patients (36.8%) during follow-up. Aortic pulse wave velocity remained unchanged at the three time points measured. CONCLUSION: Cisplatin-based chemotherapy was associated with acute insulin resistance, dyslipidemia and an immediate increase in abdominal visceral adipose tissue and abdominal subcutaneous adipose tissue in testicular cancer patients. A large prospective cohort study with long follow-up is warranted to characterize the time course and relationship between acutely induced obesity and hypercholesterolemia and the development of metabolic syndrome and CVD years later in individual testicular cancer survivors.

Murine tissue factor coagulant activity is critically dependent on the presence of an intact allosteric disulfide.

Tissue factor activation (decryption) has been proposed to be dependent on the cysteine 186-cysteine 209 allosteric disulfide in the tissue factor extracellular domain. Tissue factor procoagulant activity is under the control of protein disulfide isomerase-dependent modulation and nitrosylation of this disulfide. Human tissue factor disulfide mutants have been proposed as a model for encrypted tissue factor, but poor expression of these mutants hampers research into tissue factor decryption. We, therefore, investigated whether mouse tissue factor cysteine 186-cysteine 209 disulfide bond mutants form a better suited model for tissue factor decryption. Stable mouse wild-type tissue factor, tissue factor(C190A), tissue factor(C213A) and tissue factor(C190/213A) disulfide mutant-expressing baby hamster kidney cells with equal levels of surface tissue factor were established. Tissue factor coagulant activity on these cells was determined using an active factor Xa-dependent chromogenic assay. The effect of nitrosylation on tissue factor function was also assessed. A tissue factor(C190/213A) mutant exerted marginal procoagulant activity, also after addition of supraphysiological concentration of factor VIIa. Tissue factor(C190A) and tissue factor(C213A) mutants showed reduced activity and the presence of tissue factor dimers. Nitrosylation of wild-type tissue factor cells decreased procoagulant function, an effect which was reversed by incubation with bacitracin, an inhibitor of protein disulfide isomerase, suggesting that this isomerase promotes de-nitrosylation of tissue factor. Mouse tissue factor procoagulant function is dependent on the Cys190-Cys213 disulfide bond and is modulated by nitrosylation. The murine model of disulfide-mutated tissue factor is more suitable for studying tissue factor decryption than are human tissue factor mutants.

Tasquinimod: a novel drug in advanced prostate cancer.

Tasquinimod, an oral quinolone-3-carboxamide with anti-tumor activity in preclinical models of prostate cancer, has been tested in patients with minimally symptomatic castration-resistant prostate cancer (CRPC), showing promising inhibitory effects on the occurrence of metastasis and delayed disease progression. Although its mode of action is not fully understood, tasquinimod presumably exerts its unique anti-tumor action through inhibition of angiogenesis and immunomodulation. In clinical studies, tasquinimod demonstrated anti-tumor activity in prostate cancer in combination with a mild-to-moderate side effect profile. With single-agent tasquinimod, dose-limiting toxicity was amylase elevation without signs of pancreatitis and sinus tachycardia. The maximum tolerated dose in Phase I studies in patients with CRPC was once daily administration of 0.5-1-mg tasquinimod orally. In a Phase II trial, significant clinical activity has been demonstrated in asymptomatic or minimally symptomatic, chemotherapy-naive, metastatic CRPC (mCRPC) patients. Men were randomized to tasquinimod or placebo in a 2:1 fashion; treatment with tasquinimod resulted in significant improvement of median progression-free survival (7.6 vs 3.3 months with placebo; p = 0.0042). Based on these encouraging effects, a randomized, double-blind, placebo-controlled trial in men with minimally symptomatic mCRPC has been designed. This large Phase III trial, powered for a primary end point of progression-free survival, has now enrolled the target number of 1200 men. If the Phase II data are validated in the Phase III trial a new compound with a unique mode of action might become approved as a future therapy for minimally symptomatic mCRPC patients.

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.

Patterns of care in the management of seminoma stage I: results from a European survey.

UNLABELLED: Study Type - Therapy (practise pattern survey). Level of Evidence 3b. What's known on the subject? and What does the study add? The uncertainties about differences in relapse and rates of other late events such as second malignancy and cardiovascular events for the three post-orchidectomy strategies in seminoma stage I patients has led to debates about whether the three strategies are equally effective and safe. The differences in interpretation of the data as well as the debates are likely to result in differences in treatment after orchidectomy in seminoma stage I patient management. Current care patterns after orchidectomy are, however, unknown. We assessed patterns of care for seminoma stage I patients after orchidectomy by distributing a survey among doctors treating such patients across Europe. The 969 respondents showed large differences in care strategies between specialties and countries that indicate the need for research into long-term relapse rates and long-term adverse effects to standardize and optimize care for seminoma stage I patients. OBJECTIVE: • To assess precise patterns of care after orchidectomy in Europe for stage I seminoma patients, we aimed to perform a survey among doctors in the various European countries. PATIENTS AND METHODS: • We distributed a survey in 2009 and 2010 among American Society of Clinical Oncology and European Association of Urology members. RESULTS: • In total, 969 questionnaires were included in the analysis. More than half of the 969 physicians (58%) currently offer only one post-surgical treatment: 18% only surveillance, 19% only radiotherapy and 21% only chemotherapy. Thirteen percent of the 969 physicians currently offer all three strategies, 25% offer surveillance and adjuvant radiotherapy or chemotherapy, and 5% offer either adjuvant radiotherapy or chemotherapy without surveillance. • We found large differences in care patterns between specialties and countries. Even within countries, care after orchidectomy was not standardized. • Before 2005, 73% of the physicians offered only one treatment and of those 51% gave adjuvant radiotherapy. CONCLUSIONS: • Large differences in pattern of care after orchidectomy for stage I seminoma patients exist between specialties and countries within Europe. • More information on long-term relapse rates and long-term adverse effects of the three strategies is needed to standardize and optimize care after orchidectomy.

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.

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.