The CHASIT study: sequential chemo-immunotherapy in patients with locally advanced urothelial cancer - a non-randomized phase II clinical trial.

BACKGROUND: Patients with locally advanced irresectable or clinically node positive urothelial cancer (UC) have a poor outcome. Currently, these patients can only be cured by receiving induction chemotherapy and, if an adequate radiological response is obtained, radical surgical resection. Long-term survival, however, strongly depends on the absence of residual tumor in the surgical resection specimen, i.e. a pathological complete response (pCR). The reported pCR rate following induction chemotherapy in locally advanced or clinically node-positive UC is 15%. The 5-year overall survival rate for patients achieving a pCR is 70-80% versus 20% for patients who have residual disease or nodal metastases. This clearly demonstrates the unmet need to improve clinical outcome of these patients. Recently, the JAVELIN Bladder 100 study demonstrated an overall survival benefit of sequential chemo-immunotherapy in patients with metastatic UC. The CHASIT study aims to translate these findings to the induction setting by assessing the efficacy and safety of sequential chemo-immunotherapy in patients with locally advanced or clinically node-positive UC. In addition, patient biomaterials are collected to investigate biological mechanisms of response and resistance to chemo-immunotherapy. METHODS: This multicenter, prospective phase II clinical trial includes patients with stage cT4NxM0 or cTxN1-N3M0 UC of the bladder, upper urinary tract or urethra. Patients who do not experience disease progression after 3 or 4 cycles of platinum-based chemotherapy are eligible for inclusion. Included patients receive 3 cycles of anti-PD-1 immunotherapy with avelumab followed by radical surgery. Primary endpoint is the pCR rate. It is hypothesized that sequential chemo-immunotherapy results in a pCR rate of ≥ 30%. To obtain a power of 80%, 64 patients are screened and 58 patients are included in the efficacy analysis. Secondary endpoints are toxicity, postoperative surgical complications, progression-free, cancer-specific and overall survival at 24 months. DISCUSSION: This is the first study to assess the potential benefit of sequential chemo-immunotherapy in patients with locally advanced or node positive UC. If the primary endpoint of the CHASIT study is met, i.e. a pCR rate of ≥ 30%, a randomized controlled trial is foreseen to compare this new treatment regimen to standard care. TRIAL REGISTRATION: NCT05600127 at Clinicaltrials gov, registered on 31/10/2022.

Scaffold-based tissue engineering: Supercritical carbon dioxide as an alternative method for decellularization and sterilization of dense materials.

Development of ready-to-use biomaterials and scaffolds is vital for further advancement of scaffold-based tissue engineering in clinical practice. Scaffolds need to mimic 3D ultrastructure, have adequate mechanical strength, are biocompatible, non-immunogenic and need to promote tissue regeneration in vivo. Although decellularization of native tissues seems promising to deliver scaffolds that meet these criteria, adequate decellularization of hard, poorly penetrable and poorly diffusible tissues remains challenging whilst being a very time-consuming process. In this study, a method to decellularize hard, dense tissues using supercritical carbon-dioxide preceded by a freeze/thaw cycle and followed by several washing steps is presented, demonstrating decellularisation efficiency and substantially reduced production/handling time. Additionally, supercritical carbon-dioxide treatment was used as sterilization method, further reducing the time required to produce the final scaffold. Histological evaluation showed that, after fine-tuning of the process, a partially acellular scaffold was obtained, with preservation of glycosaminoglycans and collagen fibers, albeit that the amount of residual dsDNA was still higher then chemically decellularized tissue. Biomechanical properties of the scaffold were similar to the native, non-decellularized tissue. After sterilization with supercritical carbon-dioxide the simulated functional outcome was more similar to native trachea, when compared to sterilization using gamma irradiation. Thus, decellularization and sterilization using supercritical carbon-dioxide with washing steps is an effective method for dense cartilaginous materials, and tuneable to meet different demands in other applications, but further optimization may be required. STATEMENT OF SIGNIFICANCE: Further advancement of the use of tissue engineered tracheal constructs is restricted by the lack of the ideal scaffold. Decellularized trachea is considered a promising scaffold, but the hard, poorly diffusible tissue remains challenging while forming a very time consumable process. Decellularization using supercritical carbon dioxide (scCO2) seems promising, resulting in efficient removal of cellular material while reducing production and handling time. Addition of scCO2 as a sterilization method resulted in further time reduction while improving functional outcome in comparison with traditional sterilization methods. This study presents an promising alternative method for decellularization and sterilization of dense materials, which can be tuned to meet different demands in other applications.

Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up.

BACKGROUND: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns. PATIENTS AND METHODS: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary endpoints were progression-free survival per RECIST version 1.1 by blinded independent central review (BICR) and overall survival. In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary endpoint was objective response rate per RECIST version 1.1 by BICR. RESULTS: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. The median follow-up was 62.9 months (range 58.6-70.9 months; data cut-off 1 October 2020). At 48 months, overall survival rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; progression-free survival rates were 9.5% and 2.7%, respectively. The median duration of response (DOR) was 29.7 months (range 1.6+ to 60.5+ months) for pembrolizumab and 4.4 months (range 1.4+ to 63.1+ months) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. The median follow-up was 56.3 months (range 51.2-65.3 months; data cut-off 26 September 2020). The confirmed objective response rate was 28.9% (95% confidence interval 24.3-33.8), and the median DOR was 33.4 months (range 1.4+ to 60.7+ months); the 36-month DOR rate was 44.8%. Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports. CONCLUSION: With ∼5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients. CLINICAL TRIAL REGISTRY AND ID: With ClinicalTrials.gov NCT02256436 (KEYNOTE-045); https://clinicaltrials.gov/ct2/show/NCT02256436 and NCT02335424 (KEYNOTE-052); https://clinicaltrials.gov/ct2/show/NCT02335424.

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

BACKGROUND: Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld. PATIENTS AND METHODS: The CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%). RESULTS: A total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48). CONCLUSION: The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC. TRIAL REGISTRATION: Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954.

Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study.

BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

The Dutch nationwide trauma registry: The value of capturing all acute trauma admissions.

INTRODUCTION: Twenty years ago the Dutch trauma care system was reformed by the designating 11 level one Regional trauma centres (RTCs) to organise trauma care. The RTCs set up the Dutch National Trauma Registry (DNTR) to evaluate epidemiology, patient distribution, resource use and quality of care. In this study we describe the DNTR, the incidence and main characteristics of Dutch acutely admitted trauma patients, and evaluate the value of including all acute trauma admissions compared to more stringent criteria applied by the national trauma registries of the United Kingdom and Germany. METHODS: The DNTR includes all injured patients treated at the ED within 48 hours after trauma and consecutively followed by direct admission, transfers to another hospital or death at the ED. DNTR data on admission years 2007-2018 were extracted to describe the maturation of the registry. Data from 2018 was used to describe the incidence rate and patient characteristics. Inclusion criteria of the Trauma Audit and Research (TARN) and the Deutsche Gesellschaft für Unfallchirurgie (DGU) were applied on 2018 DNTR data. RESULTS: Since its start in 2007 a total of 865,460 trauma cases have been registered in the DNTR. Hospital participation increased from 64% to 98%. In 2018, a total of 77,529 patients were included, the median age was 64 years, 50% males. Severely injured patients with an ISS≥16, accounted for 6% of all admissions, of which 70% was treated at designated RTCs. Patients with an ISS≤ 15were treated at non-RTCs in 80% of cases. Application of DGU or TARN inclusion criteria, resulted in inclusion of respectively 5% and 32% of the DNTR patients. Particularly children, elderly and patients admitted at non-RTCs are left out. Moreover, 50% of ISS≥16 and 68% of the fatal cases did not meet DGU inclusion criteria CONCLUSION: The DNTR has evolved into a comprehensive well-structured nationwide population-based trauma register. With 80,000 inclusions annually, the DNTR has become one of the largest trauma databases in Europe The registries strength lies in the broad inclusion criteria which enables studies on the burden of injury and the quality and efficiency of the entire trauma care system, encompassing all trauma-receiving hospitals.

Novel treatment options in the management of metastatic castration-naïve prostate cancer; which treatment modality to choose?

Androgen-deprivation therapy (ADT) has been the mainstay of treatment of metastatic prostate cancer since the first report of its hormonal dependence in the 1940s. Since 2015, the addition of docetaxel and the addition of abiraterone to ADT have conferred substantial overall survival benefit in men with metastatic castration-naïve prostate cancer (mCNPC). The shift of these treatment options for metastatic prostate cancer from the castration-resistant setting to the castration-naïve setting has led to new challenges in the management of this disease. It remains to be determined which patients may benefit most from either early concomitant docetaxel or from abiraterone with ADT, since biomarkers for early therapy response and risk stratification are currently lacking. Therefore, the ability to personalize medicine is hampered. Furthermore, the earlier detection of metastatic prostate cancer by using new imaging modalities makes the application of clinical trial results in daily practice increasingly challenging. Recently, both local radiotherapy to the primary tumor combined with ADT and abiraterone combined with ADT showed a survival benefit in low-volume disease patients. The latest data also demonstrated a survival benefit with the addition of apalutamide or enzalutamide to ADT. The extent of metastatic disease may become one of the most important factors to determine treatment choice. In this review article, we summarize trial data to provide guidance for treatment selection in metastatic castration-naïve prostate cancer.

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BACKGROUND: Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. PATIENTS AND METHODS: Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. CONCLUSIONS: Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02256436.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer.

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3-4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo- (NAC) or radiotherapy (NAR). A population-based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2-4aN0M0 UC between 1995-2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD-rates were compared using Chi-square tests and OS was estimated by Kaplan-Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD-status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3-4a UC. Median follow-up was 9.2 years. In cT2 UC, pCD-rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3-4a UC, pCD-rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5-year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3-4a UC, 5-year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3-4a UC (HR: 0.67, 95%CI 0.51-0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72-1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3-4a disease.

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).

BACKGROUND: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. PATIENTS AND METHODS: This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. RESULTS: Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. CONCLUSION: This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. TRIAL NUMBER: NCT01830231.

Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics.

Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.

The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer.

INTRODUCTION: The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC. PATIENTS AND METHODS: Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel. RESULTS: From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase. CONCLUSION: Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.

Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is ∼99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a marker of host inflammation, has been associated with poor outcome in several solid tumors. Here, we investigated associations of the derived NLR (dNLR) and duration of initial androgen deprivation therapy (ADT) with survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy. PATIENTS AND METHODS: Data from the multinational randomized phase III studies VENICE and TAX327 included a total of 2230 men with mCRPC randomized to receive first-line chemotherapy, and were used as training and validation sets, respectively. Associations of dNLR and duration of initial ADT with overall survival (OS) were evaluated by multivariable Cox regression analysis in the training set stratified for performance status and treatment arm. The model was then tested in the validation set. Subsequently, we investigated the treatment effect of docetaxel on OS in subgroups according to dNLR and duration of initial ADT. RESULTS: In the training set, both dNLR ≥median (2) and duration of initial ADT

Ultrafast spin-transfer torque driven by femtosecond pulsed-laser excitation.

Spin currents have an important role in many proposed spintronic devices, as they govern the switching process of magnetic bits in random access memories or drive domain wall motion in magnetic shift registers. The generation of these spin currents has to be fast and energy efficient for realization of these envisioned devices. Recently it has been shown that femtosecond pulsed-laser excitation of thin magnetic films creates intense and ultrafast spin currents. Here we utilize this method to change the orientation of the magnetization in a magnetic bilayer by spin-transfer torque on sub-picosecond timescales. By analysing the dynamics of the magnetic bilayer after laser excitation, the rich physics governing ultrafast spin-transfer torque are elucidated opening up new pathways to ultrafast magnetization reversal, but also providing a new method to quantify optically induced spin currents generated on femtosecond timescales.

Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer.

INTRODUCTION: Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds. METHODS: To identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation. RESULTS: We observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide. CONCLUSIONS: In conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.

Analysis of docetaxel therapy in elderly (≥70 years) castration resistant prostate cancer patients enrolled in the Netherlands Prostate Study.

BACKGROUND: Prostate cancer truly is an age-associated disease. Due to the increased life expectancy and more sensitive diagnostic techniques in the Western world, prostate cancer is diagnosed more frequently and with rapidly increasing incidence and prevalence rates. However, age above 65 or 70 years has been an exclusion criterion in clinical trials for decades and the knowledge about chemotherapy tolerance in elderly is limited. METHODS: We performed a retrospective analysis of data acquired from the recently published Netherlands Prostate Study (NePro) to evaluate the influence of advanced age on docetaxel therapy in elderly men (>70 years) with castration resistant prostate cancer (CRPC) and bone metastases. Statistical analyses were performed stratified for age into four categories: <70 (n=315), 70-74 (n=150), 75-79 (n=85), and ≥80 years old (n=18). RESULTS: We analysed 568 patients (median age 68.1 years, range 46-89 years, 44.5% aged ≥70 years). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, time to progression (TTP), overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity and were five times less likely to complete the first three treatment cycles at the intended dose (Odds ratio (OR) 5.34, p=0.0052) and showed decreased overall survival (15.3 months versus 24.5 months in <80 years group, p=0.020). CONCLUSION: In CRPC patients up to the age of 80 years, docetaxel chemotherapy is well tolerated, with toxicity levels and TTP comparable to those of younger patients. For chemotherapeutic treatment of patients above the age of 80 years an individual assessment should be made.

Linking the lytic and lysogenic bacteriophage cycles to environmental conditions, host physiology and their variability in coastal lagoons.

Changes in environmental conditions and prokaryote physiology can strongly affect the dynamics of both the lysogenic and lytic bacteriophage replication cycles in aquatic systems. However, it remains unclear whether it is the nature, amplitude or frequency of these changes that alter the phage replication cycles. We performed an annual survey of three Mediterranean lagoons with contrasting levels of chlorophyll a concentration and salinity to explore how these cues and their variability influence either replication cycle. The lytic cycle was always detected and showed seasonal patterns, whereas the lysogenic cycle was often undetected and highly variable. The lytic cycle was influenced by environmental and prokaryotic physiological cues, increasing with concentrations of dissolved organic carbon, chlorophyll a, and the proportion of respiring cells, and decreasing with the proportion of damaged cells. In contrast, lysogeny was not explained by the magnitude of any environmental or physiological parameter, but increased with the amplitude of change in prokaryote physiology. Our study suggests that both cycles are regulated by distinct factors: the lytic cycle is dependent on environmental parameters and host physiology, while lysogeny is dependent on the variability of prokaryote physiology. This could lead to the contrasting patterns observed between both cycles in aquatic systems.