Role of Spin-Orbit Coupling in High-Order Harmonic Generation Revealed by Supercycle Rydberg Trajectories.

High-harmonic generation is typically thought of as a sub-laser-cycle process, with the electron's excursion in the continuum lasting a fraction of the optical cycle. However, it was recently suggested that long-lived Rydberg states can play a particularly important role in high harmonic generation by atoms driven by the combination of the counterrotating circularly polarized fundamental light field and its second harmonic. Here we report direct experimental evidence of very long and stable Rydberg trajectories contributing to high-harmonic generation in such fields. We track their dynamics inside the laser pulse using the spin-orbit evolution in the ionic core, utilizing the spin-orbit Larmor clock. We confirm their effect on harmonic emission both via microscopic simulations and by showing how this radiation can lead to a well-collimated macroscopic far-field signal. Our observations contrast sharply with the general view that long-lived Rydberg orbits should generate negligible contribution to the macroscopic far-field high harmonic response of the medium.

Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC).

BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Precision Constraints for Three-Flavor Neutrino Oscillations from the Full MINOS+ and MINOS Dataset.

We report the final measurement of the neutrino oscillation parameters Δm_{32}^{2} and sin^{2}θ_{23} using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of 23.76×10^{20} protons on target producing ν_{µ} and ν[over ¯]_{µ} beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of ν_{µ} and the appearance of ν_{e} events between the Near and Far detectors yields |Δm_{32}^{2}|=2.40_{-0.09}^{+0.08}(2.45_{-0.08}^{+0.07})×10^{-3} eV^{2} and sin^{2}θ_{23}=0.43_{-0.04}^{+0.20}(0.42_{-0.03}^{+0.07}) at 68% C.L. for normal (inverted) hierarchy.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc.

Sleep disturbance in men receiving androgen deprivation therapy for prostate cancer: The role of hot flashes and nocturia.

BACKGROUND: Patients with prostate cancer receiving androgen deprivation therapy (ADT) are at risk of sleep disturbance; however, to the authors' knowledge, the mechanisms by which ADT may affect sleep are not well understood. The current study compared objective and subjective sleep disturbance in ADT recipients and controls and examined whether sleep disturbance in ADT recipients is attributable to the influence of ADT on hot flashes and nocturia. METHODS: Patients with prostate cancer were assessed before or within 1 month after the initiation of ADT as well as 6 months and 12 months later (78 patients). Patients with prostate cancer were treated with prostatectomy only (99 patients) and men with no history of cancer (108 men) were assessed at similar intervals. Participants self-reported their sleep disturbance (Insomnia Severity Index) and interference from hot flashes (Hot Flash Related Daily Interference Scale). One hundred participants also wore actigraphs for 3 days at the 6-month assessment to measure objective sleep disturbance and reported their nocturia frequency. RESULTS: ADT recipients reported worse sleep disturbance, higher rates of clinically significant sleep disturbance, and greater hot flash interference than controls (Ps≤.03). In cross-sectional analyses among those with actigraphy data, ADT recipients had greater objective sleep disturbance and more episodes of nocturia (Ps<.01). Cross-sectional mediation analyses demonstrated that the association between ADT and objectively and subjectively measured sleep disturbance was partly attributable to nocturia and hot flashes (Ps<.05). CONCLUSIONS: The results of the current study suggest that the association between ADT and sleep may be partly explained by nocturia and hot flash interference. Future studies should examine behavioral and pharmacologic interventions to address these symptoms among ADT recipients. Cancer 2018;124:499-506. © 2017 American Cancer Society.

Effect of androgen deprivation therapy on sexual function and bother in men with prostate cancer: A controlled comparison.

OBJECTIVES: The adverse sexual effects of androgen deprivation therapy (ADT) on men with prostate cancer have been well described. Less well known is the relative degree of sexual dysfunction and bother associated with ADT compared to other primary treatment modalities such as radical prostatectomy. We sought to describe the trajectory and relative magnitude of changes in sexual function and bother in men on ADT and to examine demographic and clinical predictors of ADT's adverse sexual effects. METHODS: Prostate cancer patients treated with ADT (n = 60) completed assessments of sexual function and sexual bother 3 times during a 1-year period after the initiation of ADT. Prostate cancer patients treated with radical prostatectomy only and not receiving ADT (n = 85) and men with no history of cancer (n = 86) matched on age and education completed assessments at similar intervals. RESULTS: Androgen deprivation therapy recipients reported worsening sexual function and increasing bother over time compared to controls. Effect sizes for the differences in sexual function were large to very large, and for bother were small to very large. Age younger than 83 years predicted relatively poorer sexual function, and age younger than 78 years predicted greater sexual bother at 12 months in men on ADT compared to men not on ADT. CONCLUSIONS: Most men on ADT for prostate cancer will never return to baseline levels of sexual function. Interventions focused on sexual bother over function and designed to help couples build and maintain satisfying relationship intimacy are likely to more positively affect men's psychological well-being while on ADT than medical or sexual aids targeting sexual dysfunction.

Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer.

BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab. METHODS: Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10 mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10 mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor ß (TGFß) and CD105 levels as well as tissue immunostaining for TGFß receptors. RESULTS: Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P = .09). Grade ≥ 3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P = .9). Baseline serum TGFß levels below the median (<10.6 ng/mL) were associated with longer median PFS (5.6 vs 2.1 months; P = .014). CONCLUSIONS: TRC105 failed to improve PFS when added to bevacizumab. TGFß warrants further study as a biomarker in RCC. Cancer 2017;123:4566-4573. © 2017 American Cancer Society.

Transarterial Yttrium-90 Radioembolization Treatment of Patients with Liver-Dominant Metastatic Renal Cell Carcinoma.

PURPOSE: To evaluate safety and efficacy of transarterial hepatic radioembolization treatment of patients with liver-dominant metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: From July 2010 to December 2014, 18 patients with liver-dominant metastatic RCC were treated with yttrium-90 glass microsphere radioembolization. Retrospective review of medical records and imaging studies was performed to evaluate toxicities, treatment response, and overall survival. The median follow-up period from radioembolization treatment was 17.8 months (range, 3-54.4 months). RESULTS: Median overall survival from RCC diagnosis was 64 months (95% confidence interval [CI], 0-144.1 months), from diagnosis of liver metastasis was 29 months (95% CI, 7.2-50.8 months), and from radioembolization treatment was 22.8 months (95% CI, 13.2-32.3 months). After treatment, 10 patients reported grade 1 clinical toxicities, and 8 patients had grade 1 or 2 biochemical toxicities. The best radiographic responses of 17 patients who underwent contrast-enhanced cross-sectional imaging showed complete response in 16 patients and partial response in 1 patient evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The last available imaging of these 17 patients demonstrated complete response in 14 patients, partial response in 1 patient, and progression of disease in 2 patients. Images of a patient who underwent noncontrast CT showed stable disease as best response and stable disease on the last available imaging evaluated by RECIST. CONCLUSIONS: Radioembolization is safe and effective and led to improved hepatic disease control and overall survival in patients with liver-dominant metastatic RCC.

Clinical role of additional adjuvant chemotherapy in patients with locally advanced urothelial carcinoma following neoadjuvant chemotherapy and cystectomy.

PURPOSE: Neoadjuvant chemotherapy (NAC) can downstage invasive bladder cancers prior to radical cystectomy (RC) and improve overall survival. However, the optimal management in patients with persistent non-organ confined disease (pT3-T4 and/or pN+) following RC has not been completely defined. The aim of this study was to describe outcomes associated with the use of adjuvant chemotherapy (AC) in patients with residual non-organ confined cancer at RC following NAC. MATERIALS AND METHODS: Using data from a high-volume referral institution, pT3-T4 and/or pN+ patients who received NAC and then also RC were identified. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with Kaplan-Meier analysis. RESULTS: From 2001 to 2013, 161 patients received NAC and then RC. Eighty-eight pT3-T4 and/or pN+ patients were identified. Twenty-nine (33 %) received AC. Adjuvant chemotherapy in the majority of patients was carboplatin-based (16), followed by cisplatin (8) and other, mainly taxane-containing regimens (5). The median RFS was 17.5 months in the AC and 13.7 months in the non-AC group (p = 0.78). AC remained an insignificant predictor for RFS after adjusting for pT, pN and margin status (HR 0.89, 95 % CI 0.48-1.68]). CSS was 23 and 22 months (p = 0.65) and remained insignificant after adjusting for pathologic confounders. CONCLUSIONS: In our current study population, adjuvant conventional cytotoxic chemotherapy was not associated with significant improvements in RFS or CSS. The choice of AC regimens, and incorporation of newer treatments, may be the key for improving outcomes in this high-risk patient group.

Changes in physical functioning and muscle strength in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison.

PURPOSE: The purpose of the study is to examine changes in muscle strength and self-reported physical functioning in men receiving androgen deprivation therapy (ADT) for prostate cancer compared to matched controls. METHODS: Prostate cancer patients scheduled to begin ADT (n = 62) were assessed within 20 days of starting ADT and 6 and 12 months later. Age and geographically matched prostate cancer controls treated with prostatectomy only (n = 86) were assessed at similar time intervals. Grip strength measured upper body strength, the Chair Rise Test measured lower body strength, and the SF-12 Physical Functioning scale measured self-reported physical functioning. RESULTS: As expected, self-reported physical functioning and upper body muscle strength declined in ADT recipients but remained stable in prostate cancer controls. Contrary to expectations, lower body muscle strength remained stable in ADT recipients but improved in prostate cancer controls. Higher Gleason scores, more medical comorbidities, and less exercise at baseline predicted greater declines in physical functioning in ADT recipients. CONCLUSIONS: ADT is associated with declines in self-reported physical functioning and upper body muscle strength as well as worse lower body muscle strength relative to prostate cancer controls. These findings should be included in patient education regarding the risks and benefits of ADT. Findings also underscore the importance of conducting research on ways to prevent or reverse declines in physical functioning in this patient population.

Characteristics and predictors of fatigue among men receiving androgen deprivation therapy for prostate cancer: a controlled comparison.

PURPOSE: Although fatigue is a common problem for men with prostate cancer undergoing androgen deprivation therapy (ADT), there has been little systematic research on this issue. The present study examined changes in fatigue among prostate cancer patients receiving ADT compared to controls and predictors of heightened fatigue in ADT patients. METHODS: Prostate cancer patients treated with ADT (ADT+ group, n = 60) completed assessments of fatigue prior to or just after ADT initiation (baseline) and 6 and 12 months later. Prostate cancer patients treated with prostatectomy only (ADT- group, n = 85) and men without cancer (CA- group, n = 86) matched on age and education completed assessments at similar intervals. RESULTS: Group-by-time interactions for fatigue severity, interference, and duration were observed when comparing the ADT+ group to the controls. Groups did not differ at baseline; however, the ADT+ group reported worse fatigue at 6 and 12 months. The same pattern was observed for changes in the prevalence of clinically meaningful fatigue and the extent of clinically meaningful change in fatigue. Within the ADT+ group, higher baseline comorbidity scores were associated with greater increases in fatigue interference, and higher baseline Gleason scores were associated with greater increases in fatigue duration. CONCLUSIONS: Prostate cancer patients receiving ADT demonstrate a trajectory of worsened fatigue during the first 12 months following treatment initiation relative to the controls. Greater comorbidities and higher Gleason scores at baseline appear to be risk factors for heightened fatigue during the first year following ADT initiation. Results highlight important time points for implementation of interventions aimed at fatigue reduction.

Course and Moderators of Hot Flash Interference during Androgen Deprivation Therapy for Prostate Cancer: A Matched Comparison.

PURPOSE: Many men receiving androgen deprivation therapy for prostate cancer experience hot flashes. This study aimed to describe the course of hot flash interference with time in androgen deprivation therapy recipients relative to matched prostate cancer and cancer-free controls from before the start of androgen deprivation therapy to 12 months later. We also examined demographic, clinical and genetic predictors of the impact of androgen deprivation therapy on hot flash interference. MATERIALS AND METHODS: Three groups were examined, including 60 patients with prostate cancer recruited before or within 21 days of starting androgen deprivation therapy, 83 age and education matched patients with prostate cancer treated with prostatectomy only, and 86 age and education matched men with no history of cancer. Participants provided blood samples and completed the Hot Flash Related Daily Interference Scale at baseline as well as 6 and 12 months later. RESULTS: Androgen deprivation therapy recipients reported increasing hot flash interference with time relative to controls (p <0.001). Group differences were evident at 6 and 12 months (all p <0.001) with androgen deprivation therapy recipients reporting greater hot flash interference than controls. Several genetic polymorphisms were found to predict greater increases in hot flash interference (all p <0.01), including polymorphisms on genes associated with vasoconstriction, immune function, neurotransmission and circadian rhythms. Androgen deprivation therapy recipients who were younger and had a lower body mass index at baseline also showed greater increases in hot flash interference with time (all p ≤0.01). CONCLUSIONS: This study, which is to our knowledge the first to prospectively examine hot flash interference in androgen deprivation therapy recipients, reveals that those with certain genetic polymorphisms, younger age and lower body mass index had greater increases in hot flash interference with time relative to controls.

Minimally invasive post-chemotherapy retroperitoneal lymph node dissection for nonseminoma.

INTRODUCTION: We present our experience with minimally-invasive retroperitoneal lymph node dissection (MI-RPLND) in the post-chemotherapy (PC) setting for residual masses in patients with nonseminoma. MATERIALS AND METHODS: Nineteen men who underwent PC MI-RPLND (14--laparoscopic, 5--robotic) for low-volume residual disease (no more than 5 clinically enlarged retroperitoneal masses, size < 5 cm, no adjacent organ or vascular invasion) between 2006 and 2011 were identified. Clinicodemographic information and pathological outcomes were reported. RESULTS: Median age of our study population was 32 (interquartile range [IQR]: 28-39). Most patients presented with clinical stage II disease (63%) and were categorized as good risk (90%) by the International Germ Cell Consensus Classification. Median size of residual masses on PC imaging was 2.1 cm (IQR: 1.7-3). Full-template bilateral RPLND was completed in 53% of cases, and modified left-sided RPLND in 47%. Median operative time was 370 minutes (IQR: 320-420), and median estimated blood loss was 300 cc (IQR: 150-450). Median length of stay was 3 days (IQR: 2-3). Five patients (26%) experienced a postoperative 30 day complication, but none were higher than Clavien grade II. On final pathology, median number of lymph nodes removed was 12 (IQR: 8-23), and 8 patients (42%) had residual teratoma. No patient experienced a recurrence at median follow up of 24 months (IQR: 5-76). CONCLUSIONS: PC MI-RPLND is a feasible option in a select group of patients with acceptable patient morbidity and short-term outcomes. Longer follow up is required to determine the oncologic efficacy of this approach.

Penile cancer--Guideline adherence produces optimum results.

OBJECTIVE: To audit the management and outcome of penile cancer in a tertiary university teaching hospital, comparing our results to international best practice and published guidelines. METHODS: The Hospital Inpatient Enquiry database of the Mercy University Hospital was interrogated for penile cancer patients treated between 2001 and 2012. Data relating to presentation, local treatment, histology, lymph-node management, outcome and survival was recorded. Data were analysed using the Log Rank test, with significance defined as P ≤ 0.05. RESULTS: Twenty-five patients were identified with a median age of 61 years. The majority of cases at presentation were ≥ T2 (54%) and intermediate to high grade (76%). The median follow-up of patients was 3.75 years (range 9 months-10 years). Overall survival was 76% (n = 19), these patients are all disease free to date. Disease-specific survival was 85% at 10 years. Penile cancer related mortality was 8% (n = 2), 4 patients (16%) died of non-penile cancer related causes. Twenty-two patients (88%) had surgery and 3 patients (12%) had radiotherapy. Based on EAU guidelines inguinal lymph node dissection (ILND) was performed in 64% (n = 16) of cases with 44% (n = 7) of these patients requiring concurrent bilateral pelvic lymph node dissection. Fifty percent (n = 8) of ILNDs showed metastatic disease. Ten year disease-specific survival for node negative versus node positive disease is 100% versus 57%. Thirty-two percent (n = 8) of patients received chemotherapy. CONCLUSIONS: Penile cancer is a rare oncological condition that often requires bilateral inguinal ± pelvic lymph node dissection and should be managed according to published guidelines, in specialist centres in order to maximize outcomes.

Characteristics of modern Gleason 9/10 prostate adenocarcinoma: a single tertiary centre experience within the Republic of Ireland.

INTRODUCTION: The 2005 international society of urological pathology consensus statement on Gleason grading in prostate cancer revised Gleason scoring in clinical practice. The potential for grade migration with this refinement poses difficulties in interpreting historical series. We report the characteristics of a recent cohort of consecutive Gleason score 9 or 10 prostate cancers in our institution. The purpose of this study was to define the clinicopathologic variables and staging information for this high-risk population, and to identify whether traditional prostate staging techniques are adequate for this subcohort of men. MATERIALS AND METHODS: A computational review of our pathology database was performed. Between May 2010 and September 2012, 1,295 consecutive biopsies were undertaken, 168 of which were high-grade tumours (12.97 %). This group were divided into two cohorts of which 84 (12.05 %) had a highest reported Gleason score of 9 (N = 79) or 10 (N = 5) and 84 were reported as Gleason 8. All biopsies were double-reported by pathologists with a special interest in uropathology. RESULTS: Men diagnosed with a Gleason pattern 5 tumour were statistically far more likely to have advanced disease on direct rectal examination of the prostate compared with Gleason sum 8 tumours (p < 0.001) and a positive first-degree family history of prostate cancer (p < 0.001). Overall, Gleason sum 9/10 prostate cancers were also found to be statistically more aggressive than Gleason sum 8 tumours on TRUS core biopsy analysis with significantly higher levels of perineural invasion (p < 0.0001) and extracapsular extension (p = 0.001) as well as a higher levels of tumour found within the core biopsy sample. Those men diagnosed with Gleason pattern 5 prostate cancer also had radiological indicators of increased tumour aggressiveness compared with Gleason sum 8 cancer with respect to bone (p = 0.0002) and visceral (p = 0.044) metastases at presentation. CONCLUSIONS: This series of Gleason score 9/10 prostate cancers serves to highlight the large disease burden, adverse pathologic features, and locally advanced nature of this aggressive subtype, which has previously been under-described in the literature, and differs from historical series in having a large high-grade cohort demonstrating high rates of metastatic disease. A history of prostate cancer amongst first-degree relatives was particularly prevalent in this population raising the issue of screening in a high-risk population. The high incidence of visceral metastatic disease at presentation supports upfront staging with CT thorax, abdomen, and pelvis in patients with Gleason 9 or 10 prostate cancers.

[Reconstruction of nasal cartilage defects using a tissue engineering technique based on combination of high-density polyethylene and hydrogel]. / Reconstruction du cartilage nasal par ingénierie tissulaire à base de polyéthylène de haute densité et d'un hydrogel.

AIM OF THE STUDY: Nasal reconstruction remains a challenge for any surgeon. The surgical indications for nasal reconstruction after oncologic resection, trauma or as part of cosmetic rhinoplasty, are steadily increasing. The current attitude for reconstruction is the use of autologous cartilage grafts of various origins (septal, ear or rib) trying to restore a physiological anatomy but their quantity is limited. Thus, in order to produce an implantable cartilaginous model, we developed a study protocol involving human nasal chondrocytes, growth factors and a composite biomaterial and studied at the molecular, cellular and tissue level the phenotype of the chondrocytes cultured in this model. MATERIALS AND METHODS: After extraction of chondrocytes and their amplification on plastic, the cells were cultured for 15 days either in monolayer or within an agarose hydrogel or a composite biomaterial (agarose/high density polyethylene: Medpor(®)) in the presence or not of a cocktail of soluble factors (BIT): bone morphogenetic protein-2 (BMP-2), insulin and triiodothyronine (T3). The quality of the chondrocyte phenotype was analyzed by PCR, western blotting and immunohistochemistry. RESULTS: During their amplification in monolayer, chondrocytes dedifferentiate. However, our results show that the BIT cocktail induces redifferentiation of chondrocytes cultured in agarose/Medpor with synthesis of mature chondrogenic markers. Thereby, chondrocytes associated with the agarose hydrogel will colonize Medpor and synthesize an extracellular matrix characteristic of nasal cartilage. CONCLUSION: This nasal cartilage tissue engineering protocol provides the first interesting results for nasal reconstruction.

Locomotor performance in highly-trained young soccer players: does body size always matter?

To examine the effects of body size on locomotor performance, 807 15-year-old French and 64 Qatari soccer players participated in the present study. They performed a 40-m sprint and an incremental running test to assess maximal sprinting (MSS) and aerobic speeds, respectively. French players were advanced in maturity, taller, heavier, faster and fitter than their Qatari counterparts (e.g., Cohen's d=+1.3 and + 0.5 for body mass and MSS). However, when adjusted for body mass (BM), Qatari players had possibly greater MSS than French players (d=+0.2). A relative age effect was observed within both countries, with the players born in the first quarter of the year being taller, heavier and faster that those born during the fourth quarter (e.g., d=+0.2 for MSS in French players). When directly adjusted for BM, these MSS differences remained (d=+0.2). Finally, in both countries, players selected in National teams were taller, heavier, faster and fitter than their non-selected counterparts (e.g., d=+0.6 for MSS in French players), even after adjustments for body size (d=+0.5). Differences in locomotor performances between players with different phenotypes are likely mediated by differences in body size. However, when considering more homogeneous player groups, body dimensions are unlikely to substantially explain the superior locomotor performances of older and/or international players.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.

BACKGROUND: Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. METHODS: In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. FINDINGS: Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). INTERPRETATION: The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease.

Targeted therapy of kidney cancer: keeping the art around the algorithms.

BACKGROUND: Therapy for metastatic kidney cancer is actively evolving, particularly in the results of registration drug trials that have led to the approval of vascular endothelial growth factor pathway drugs such as sorafenib, sunitinib, pazopanib, bevacizumab, and axitinib, with focus on patients with good- or intermediate-risk criteria and clear cell histology. Mammalian target of rapamycin (mTOR) drugs such as everolimus and temsirolimus pivotal trials emphasize experiences in the setting of prior treatment or high-risk features. Interferon and interleukin 2 also are part of the treatment algorithms. METHODS: The results of pivotal trials and the underlying context for the development of a cogent, cohesive treatment plan for an individual are reviewed, touching on decision points such as nephrectomy, metastasectomy, and medical initiation and discontinuation time points. RESULTS: To the extent that these drug therapies are essential for achieving best outcomes for patients, these pivotal trial results and associated guidelines exist within a multidimensional, multidisciplinary context of many other disease features, comorbid features, and non-drug treatment decisions. Other dimensions include investigational targeted therapies, patient selection strategies, surgical strategies, and immunotherapies, some of which are in active development. CONCLUSIONS: Clinicians should work toward the best use of drug sequencing and selection strategies based on core data derived from prospective randomized trials. To address individual patient needs, they should also recognize and emphasize individualized goals, to the extent that these are different from issues that were directly addressed in the trials.

Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer.

BACKGROUND: Sipuleucel-T is an autologous cellular immunotherapy approved by the US Food and Drug Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Its mechanism of action is based on stimulation of the patient's own immune system to target prostate cancer. Peripheral blood mononuclear cells, including antigen-presenting cells and T cells, are obtained from patients via leukapheresis and treated ex vivo with PA2024, a fusion protein consisting of prostatic acid phosphatase/granulocyte-macrophage colony-stimulating factor antigen. METHODS: Data relating to the potential pharmacodynamic biomarkers associated with sipuleucel-T activity are reviewed, as well as considerations for patient selection and for sequencing sipuleucel-T with other prostate cancer treatments. Possible directions for future development are also discussed, including treatment of less advanced prostate cancer populations, combination treatment, and immune modulation. RESULTS: Data from three randomized, double-blind, placebo-controlled phase III clinical trials of sipuleucel-T in patients with metastatic castration-rresistant prostate cancer have shown improvement in overall survival vs control. Here, we review its developing role in prostate cancer therapy and future directions for development. CONCLUSIONS: There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer.