TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.

French AFU Cancer Committee Guidelines - Update 2022-2024: management of kidney cancer.

AIM: To update the recommendations for the management of kidney cancers. METHODS: A systematic review of the literature was conducted from 2015 to 2022. The most relevant articles on the diagnosis, classification, surgical treatment, medical treatment and follow-up of kidney cancer were selected and incorporated into the recommendations. Therefore, the recommendations were updated while specifying the level of evidence (high or low). RESULTS: The gold standard for the diagnosis and evaluation of kidney cancer is contrast-enhanced chest and abdominal CT. MRI and contrast-enhanced ultrasound are indicated in special cases. Percutaneous biopsy is recommended in situations where the results will influence the therapeutic decision. Renal tumours should be classified according to the pTNM 2017 classification, the WHO 2022 classification and the ISUP nucleolar grade. Metastatic kidney cancer should be classified according to the IMDC criteria. Partial nephrectomy is the gold standard treatment for T1a tumours and can be performed by an open approach, by laparoscopy or by robot-guidance. Active surveillance of tumours less than 2cm in size can be considered regardless of the patient's age. Ablative therapies and active surveillance are options in elderly patients with comorbidity. T1b tumours should be treated by partial or radical nephrectomy depending on the complexity of the tumour. Radical nephrectomy is the first-line treatment for locally advanced cancers. Adjuvant treatment with pembrolizumab should be considered in patients at intermediate and high risk for recurrence after nephrectomy. In metastatic patients: Immediate cytoreductive nephrectomy may be offered to oligometastatic patients in combination with local treatment of metastases if this can be complete and delayed cytoreductive nephrectomy can be proposed for patients with a complete response or a significant partial response. Medical treatment should be proposed as first-line therapy for patients with a poor or intermediate prognosis. Surgical or local treatment of metastases can be proposed in case of single or oligo-metastases. The recommended first-line drugs for metastatic patients with clear cell renal carcinoma are the combinations axitinib/pembrolizumab, nivolumab/ipililumab, nivolumab/cabozantinib and lenvatinib/pembrolizumab. Cabozantinib is the recommended first-line treatment for patients with metastatic papillary carcinoma. Cystic tumours should be classified according to the Bosniak classification. Surgical removal should be proposed as a priority for Bosniak III and IV lesions. It is recommended that patient monitoring be adapted to the aggressiveness of the tumour. CONCLUSION: These updated recommendations are a reference that will allow French and French-speaking practitioners to improve kidney cancer management.

TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: Treatment with tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (RCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile. We report final results from TiNivo, a phase Ib/II study of tivozanib combined with nivolumab. PATIENTS AND METHODS: In phase Ib, patients with metastatic RCC received tivozanib 1.0 mg once daily (QD) for 21 days followed by 7 days off treatment (n = 3) or tivozanib 1.5 mg QD (n = 3) plus nivolumab 240 mg every 2 weeks. The maximum tolerated dose was determined to be tivozanib 1.5 mg, and 22 additional patients were enrolled at the maximum tolerated dose for phase II. Primary end points included safety and tolerability, with secondary end points of objective response rate, disease control rate, and progression-free survival. RESULTS: In total, 25 patients were treated with tivozanib 1.5 mg QD [12 (48%) treatment-naïve; 13 (52%) previously treated]. Treatment-related grade 3/4 AEs were reported in 20 patients (80%); 4 patients (17%) experienced AEs that led to dose reduction, and 8 (32%) discontinued due to AEs. The objective response rate was 56% (including one complete response) and disease control rate was 96%, with a median time to best response of 7.9 weeks. Twenty patients (80%) had tumor shrinkage. With a median follow-up of 19.0 months (range, 12.6-22.8), median progression-free survival was 18.9 months (95% confidence interval 16.4-not reached) in all patients and was similar in treatment-naïve and previously treated patients. CONCLUSIONS: Tivozanib plus nivolumab combination therapy showed a generally tolerable AE profile and promising antitumor efficacy. These results support further development of tivozanib combined with nivolumab as a treatment option in patients with treatment-naïve or previously treated metastatic RCC. CLINICAL TRIAL NUMBER: NCT03136627.

Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab.

BACKGROUND: An elevated pre-treatment neutrophil to lymphocytes ratio (NLR) is associated with poor prognosis in various malignancies. Optimal cut-off is highly variable across studies and could not be determined individually for a patient to inform his prognosis. We hypothesize that NLR variations could be more useful than baseline NLR to predict progression-free survival (PFS) and overall survival (OS) in patients (pts) receiving anti-PD1 treatment. PATIENTS AND METHODS: All pts with metastatic renal cell carcinoma (mRCC) and metastatic non-small cell lung cancer (mNSCLC) who received anti-PD1 nivolumab monotherapy in second-line setting or later were included in this French multicentric retrospective study. NLR values were prospectively collected prior to each nivolumab administration. Clinical characteristics were recorded. Associations between baseline NLR, NLR variations and survival outcomes were determined using Kaplan-Meier's method and multivariable Cox regression models. RESULTS: 161 pts (86 mRCC and 75 mNSCLC) were included with a median follow-up of 18 months. On the whole cohort, any NLR increase at week 6 was significantly associated with worse outcomes compared to NLR decrease, with a median PFS of 11 months vs 3.7 months (p < 0.0001), and a median OS of 28.5 months vs. 18 months (p = 0.013), respectively. In multivariate analysis, NLR increase was significantly associated with worse PFS (HR 2.2; p = 6.10-5) and OS (HR 2.1; p = 0.005). Consistent results were observed in each cohort when analyzed separately. CONCLUSION: Any NLR increase at week 6 was associated with worse PFS and OS outcomes. NLR variation is an inexpensive and dynamic marker easily obtained to monitor anti-PD1 efficacy.

Nivolumab in patients with advanced renal cell carcinoma in France: interim results of the observational, real-world WITNESS study.

BACKGROUND: Nivolumab is the first immune checkpoint inhibitor approved in Europe for the treatment of advanced renal cell carcinoma (aRCC) in patients resistant to prior antiangiogenic therapy. WITNESS is an ongoing, prospective, observational study designed to evaluate the effectiveness and safety of nivolumab in patients with aRCC treated in real life (or routine practice) in France (ClinicalTrials.gov identifier: NCT03455452). PATIENTS AND METHODS: This study includes adult patients with a confirmed diagnosis of aRCC who have initiated nivolumab after 1-2 prior lines of antiangiogenic therapy. Endpoints include overall survival (OS), progression-free survival (PFS), duration of treatment (DOT), duration of response (DOR), overall response rate (ORR), subgroup analyses, and treatment-related adverse events (TRAEs). Results after a median follow-up of 12.3 months are presented here. RESULTS: A total of 325 patients with aRCC were included, of whom 38.2% had a Karnofsky score <80, 77.8% received nivolumab as second-line therapy, and 69.5% had undergone a previous nephrectomy. In the overall population, median OS was 20.5 [95% confidence interval (CI) 17.6-25.0] months and median PFS was 5.2 (95% CI 4.5-5.9) months. ORR was 34.5%, median DOT was 3.8 months, and median DOR was 16.5 months. Nivolumab was effective in different subgroups including patients with bone or glandular metastases and those receiving baseline corticosteroids. Moreover, effectiveness was observed irrespective of prior nephrectomy and line of treatment. No new safety signals were identified; TRAEs of any grade were reported in 32.0% of patients, grade ≥3 and serious TRAEs in 11.1% each, and TRAEs leading to discontinuation in 8.9%. CONCLUSIONS: Preliminary results of the ongoing WITNESS study confirm the real-world effectiveness and safety of nivolumab monotherapy in previously treated patients with aRCC. Treatment benefits were similar to those observed in the pivotal phase III CheckMate 025 randomized clinical trial, despite a broader, real-life study population.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Avelumab first-line maintenance treatment for advanced urothelial carcinoma: review of evidence to guide clinical practice.

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a 'watch-and-wait' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and 'real-world' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC.

Anderson localization of near-visible light in two dimensions.

We report on the observation of Anderson localization of near-visible light in two-dimensional systems. Our structures consist of planar waveguides in which disorder is introduced by randomly placing pores with controlled diameter and density. We show how to design structures in which localization can be observed and describe both the realization of the materials and the actual observation of Anderson localized modes by near-field scanning microscopy.

New injectable self-assembled hydrogels that promote angiogenesis through a bioactive degradation product.

Hydrogels used in regenerative medicine are often designed to allow cellular infiltration, degradation, and neovascularization. Low molecular weight hydrogels (LMWHs), formed by self-assembly via non-covalent interactions, are gaining significant interest because they are soft, easy to use and injectable. We propose LMWHs as suitable body implant materials that can stimulate tissue regeneration. We produced four new LMWHs with molecular entities containing nucleic acid and lipid building blocks and analyzed the foreign body response upon subcutaneous implantation into mice. Despite being infiltrated with macrophages, none of the hydrogels triggered detrimental inflammatory responses. Most macrophages present in the hydrogel-surrounding tissue acquired an immuno-modulatory rather than inflammatory phenotype. Concomitantly, no fibrotic capsule was formed after three weeks. Our glyconucleolipid LMWHs exhibited different degradation kinetics in vivo and in vitro. LMWHs with high angiogenic properties in vivo, were found to release glyconucleoside (glucose covalently linked to thymidine via a triazole moiety) as a common by-product of in vitro LMWH degradation. Chemically synthesized glyconucleoside exhibited angiogenic properties in vitro in scratch assays with monolayers of human endothelial cells and in vivo using the chick chorioallantoic membrane assay. Collectively, LMWHs hold promise as efficient scaffolds for various regenerative applications by displaying good biointegration without causing fibrosis, and by promoting angiogenesis through the release of a pro-angiogenic degradation product. STATEMENT OF SIGNIFICANCE: The main limitations of biomaterials developed in the field of tissue engineering remains their biocompatibility and vascularisation properties. In this context, we developed injectable Low Molecular Weight Hydrogels (LMWH) exhibiting thixotropic (reversible gelation) and thermal reversible properties. LMWH having injectability is of great advantage since it allows for their delivery without wounding the surrounding tissues. The resulting gels aim at forming scaffolds that the host cells colonize without major inflammation, and that won't be insulated by a strong fibrosis reaction. Importantly, their molecular degradation releases a product (a glycosyl-nucleoside conjugate) promoting angiogenesis. In this sense, these LMWH represent an important advance in the development of biomaterials promoting tissue regeneration.

Endovascular management of chronic disabling ilio-caval obstructive lesions: long-term results.

OBJECTIVE: To report the long-term results of stenting for chronic ilio-caval obstructive lesions. MATERIAL AND METHODS: From January 1996 to January 2008, 89 patients (72 women, 17 men; median age 43 years) were admitted for endovascular treatment of chronic disabling non-malignant obstructive ilio-caval lesions. Patients were classified as C2 in 15 cases, C3 in 59, C4 in seven, C5 in two and C6 in six. Median preoperative venous disability score (VDS) and venous clinical severity score (VCSS) were 2 and 9, respectively. Aetiology was primary in 52 patients, secondary in 35 and congenital in two. Lesions were bilateral in seven cases, eight patients had inferior vena cava (IVC) involvement and 18 had common femoral vein (CFV) obstructive lesions. Complete occlusion was found in 30 cases. RESULTS: Technical success was achieved in 98%. The median hospital stay was 2 days. During a median follow-up of 38 months (range: 1-144 months), one patient died and five cases of thromboses occurred. Iterative stenting was performed for restenosis in six cases. Primary, assisted-primary and secondary patency rates, in terms of intention to treat, were 83%, 89% and 93%, respectively, at 3 and 10 years, with a median VDS of 1. Univariate analysis found that significant factors affecting patency were CFV involvement for primary patency and history of deep venous thrombosis (DVT) and CFV involvement for secondary patency. The last 46 patients had statistically more severe lesions than the first 43 (higher VDS, more secondary lesions, more occlusions, more stented segments, higher length of stented vein), and in spite of which patency rates are not different. CONCLUSION: Endovenous angioplasty, combined with stenting, is a sure, safe, effective and very minimally invasive technique which provides good long-term patency rates. Currently, it is recognised as the technique of choice for the treatment of ilio-caval obstructive lesions. Surgery should be proposed only in case of failure.

Efficacy of Viabahn in the treatment of severe superficial femoral artery lesions: which factors influence long-term patency?

PURPOSE: To evaluate superficial femoral artery (SFA) occlusive disease treatment by means of covered stents. STUDY DESIGN: retrospective. METHOD: From 2000 to 2005, a Hemobahn/Viabahn endoprosthesis was implanted in 102 limbs (95 patients; mean age: 72.1 years, 52-94) for intermittent claudication (group I, n=50 limbs), critical (group II, n=32) or acute ischemia (group III, n=20). Lesions treated were Trans-Atlantic Inter-Society Consensus (TASC) A (n=9) B (n=42), C (n=28) or D (n=23), associated with a good (2 or 3 leg arteries, n=60) or a poor (1 or 0 artery, n=42) runoff. RESULTS: The endograft was placed successfully in all cases, but 3 early deaths (3.2%) (1 in group II and 2 in group III), and 4 acute thromboses (4%) occurred. Primary and secondary actuarial patency rates were 97+/-1.7%, and 99+/-1% at 1 month, 74+/-4.8% & 84+/-4.1% at 1 year,and 71+/-9.5% & 79+/-8.5% at 3 years, after a mean follow-up of 30.2 months (1-60). Long-term primary and secondary patencies were significantly different between TASC Cand TASC D lesions (P<.004 & .001). CONCLUSION: Severity of lesions, rather than preoperative symptoms or runoff, is mainly to be considered before using Hemobahn/Viabahn endoprosthesis in severe SFA occlusive lesions.

Management of gastroesophageal reflux disease by primary care physicians and gastroenterologists: a prospective study of patients' records.

BACKGROUND: We previously compared the perceptions and practices of primary care physicians (PCP) and gastroenterologists (GE) in the management of gastroesophageal reflux disease (GORD), but the data were only declarative statements. OBJECTIVE: The aim of the present study was to analyze the respective management of GORD by PCP and GE on the basis of patients' records, and to look for any discrepancies between the declared and actual practices in both groups of physicians in the management of GORD. METHODS: A representative sample of French physicians was asked to enroll two consecutive patients with frequent and typical symptoms of GORD into a prospective observational survey. RESULTS: A total of 136 PCP and 91 GE participated in the survey and enrolled 271 and 182 patients, respectively, with frequent GORD symptoms (453 patients in total). Patients consulting GE were slightly younger, and had waited longer before arranging a consultation despite having symptom severity and impact on daily life similar to those visiting PCP. Most patients enrolled by GE had undergone upper GI endoscopy (95% versus 64% from PCP, P<0.01). In both groups of physicians, recourse to endoscopy for their patients was more frequent than they estimated. Prescription therapies for GORD were usually Proton Pump Inhibitors (PPI) in both groups of physicians and were in keeping with the declared findings. CONCLUSIONS: Despite differences between patients' characteristics, the management of frequent GORD was similar by both groups of physicians. The reasons why both groups of physicians underrated their actual recourse to endoscopy for their patients warrant further investigation.

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders.

BACKGROUND: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. PATIENTS AND METHODS: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. RESULTS: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10- 6). CONCLUSIONS: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

Perceptions and practices on the management of gastro-oesophageal reflux disease: results of a national survey comparing primary care physicians and gastroenterologists.

BACKGROUND: Literature comparing generalist and specialist care is accumulating in many disease areas, but very few studies focussed on gastrointestinal diseases and little is known about gastro-oesophageal reflux disease. AIM: To compare the management of gastro-oesophageal reflux disease (GERD) by French primary care physicians and gastroenterologists. METHODS: A postal survey was conducted in a representative sample of French physicians who were asked to complete a questionnaire that consisted of 44 questions relating to their usual medical practice for the diagnostic and therapeutic management of frequent GERD. RESULTS: 136 primary care physicians and 91 gastroenterologists participated in the survey (54%). Alarm symptoms were identified more frequently by primary care physicians than gastroenterologists, but the appraisal of their seriousness was less acute by primary care physicians than gastroenterologists. Upper endoscopy was prescribed more frequently by gastroenterologists (64% vs. 38%, P < 0.01). Physicians in both groups mainly recommended lifestyle modification. For GERD treatment, most respondents declared using a 'step-down' strategy with proton pump inhibitors, and only slight differences in drug prescription were identified between primary care physicians and gastroenterologists. Both groups of physicians also have similar perception of symptom persistence after treatment, but satisfaction with treatments was slightly higher for gastroenterologists than primary care physicians (7.6 vs. 7.1 on a scale from 0 to 10, P < 0.01). CONCLUSIONS: Overall patterns of GERD diagnosis and management are comparable between primary care physicians and gastroenterologists. Both groups perceive that GERD therapy can still be improved.

Comparative study of characteristics and disease management between subjects with frequent and occasional gastro-oesophageal reflux symptoms.

BACKGROUND: Little is known about the distinctive characteristics of subjects with frequent (at least weekly) and occasional gastro-oesophageal reflux symptoms. AIM: To compare the characteristics and disease management of subjects complaining of at least weekly and less frequent gastro-oesophageal reflux symptoms. METHODS: Population-based postal survey carried out in France in 2003 among a representative sample of 8000 subjects. RESULTS: The prevalence of frequent and occasional gastro-oesophageal reflux symptoms was 7.8% and 23.4%, respectively. Compared to subjects with occasional gastro-oesophageal reflux symptoms, those with frequent symptoms were older, suffered from more severe symptoms and felt greater impact on daily living, despite a slightly shorter duration of symptoms. These subjects more often sought medical advice. Most of them had treated the last episode of symptoms primarily with a proton-pump inhibitor and less often with antacids/alginates. The degree of treatment satisfaction was lower in subjects with frequent gastro-oesophageal reflux symptoms, in relation to a more frequently observed persistence of symptoms irrespective of the medication used except for proton-pump inhibitors. CONCLUSIONS: This survey suggests that subjects complaining of frequent or occasional gastro-oesophageal reflux symptoms constitute two distinctive groups. Despite greater healthcare use, the former group shows a lower level of satisfaction with disease management. Nevertheless, a substantial subset of subjects with occasional symptoms also complained of impaired health-related quality of life and sought health care.

Intramuscular pressure and surface EMG in voluntary ankle dorsal flexion: Influence of elastic compressive stockings.

Intramuscular pressure (IMP) is of major importance in blood flow and is often taken as a good estimate of muscular tension. However, its measurement remains invasive. The aims of the present work were: (1) to re-examine the possibility of evaluating IMP and muscular tension changes by means of surface electromyographic recordings, and (2) to clarify the influence of elastic compressive stockings (ECS). Surface EMG of muscles tibialis anterior (TA), soleus, gastrocnemius, and IMP from the anterior tibial compartment (ATC), deep posterior compartment (DPC), superficial posterior compartment (SPC) of the right leg, were simultaneously recorded in nine healthy subjects. Subjects performed series of voluntary concentric TA contractions (right ankle dorsal flexions) and TA isometric contractions, with or without elastic ECS, in a decubitus posture. Rest IMP mean values, measured over 60 s, ranged between 12.3 and 26.6 mmHg, i.e. in the range or slightly higher than those reported in the literature. When ECS were applied, mean IMP increase was 6.4 mmHg in ATC, 8.7 mmHg in DPC and 21.0 mmHg in SPC, while the corresponding EMG amplitude decreased. In ankle dorsal flexion movements, instantaneous values of TA-EMG amplitudes were linearly correlated to ATC-IMP instantaneous values, over the whole of the EMG rising part of every movement. When ECS were applied, the relationships between TA-EMG amplitude and ATC-IMP amplitude remained linear but where shifted towards higher IMP, in agreement with the increase in rest IMP. Because of antagonist co-contractions, IMP from DPC and SPC were also linearly correlated with ATC-IMP but with low coefficients of proportionality. As in TA concentric contractions, TA-EMG amplitudes were linearly correlated to ATC-IMP instantaneous values in isometric contractions, but the slopes of the latter were always greater. This result is explained by the relationship between muscle tension and shortening velocity. Al the results showed that: (1) instantaneous changes in surface EMG amplitude may provide a good estimate of IMP changes during the rising part of isometric, but also of concentric voluntary contractions; (2) elastic compressive stockings do not impair subjects relaxation capacity but actually increase the ratio IMP/muscle activation. As a consequence, ECS may actually increase the venous return during voluntary contractions.

Self-assembled nanofiber hydrogels for mechanoresponsive therapeutic anti-TNFα antibody delivery.

Low molecular weight hydrogels, prepared from glycosyl-nucleoside-lipid amphiphiles, exhibit shear-thinning behaviour and reversible thermally- and mechanically-triggered sol-gel transitions. Using mechanical shear stimulation, the release of entrapped anti-TNFα increases and the released anti-TNFα demonstrates efficacy in in vitro neutralization bioassays. Delivery of anti-TNFα is of general interest and broad medicinal utility for treating autoimmune diseases such as rheumatoid arthritis.

Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study.

PURPOSE: The aim of this open-label phase II study was to evaluate the activity of raltitrexed (Tomudex; AstraZeneca, Cergy, France) and oxaliplatin combination therapy in patients with diffuse malignant pleural mesothelioma. PATIENT AND METHODSs: Fifteen pretreated and 55 chemotherapy-naive patients (median age, 60 years; World Health Organization performance status of < or = 2) were enrolled. Most patients (66%) had advanced disease. Patients received raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 3 weeks. RESULTS: Twenty-four patients (34%) were classified as having a poor prognosis. In the overall study population, 14 patients (20%) had a partial response, and 32 patients (46%) had stable disease. The symptomatic response rates were as follows: shortness of breath, 36%; pain, 30%; activity, 23%; appetite, 21%; and asthenia, 20%. Median time to disease progression was 18 weeks (95% confidence interval [CI], 13 to 22 weeks). In chemotherapy-naive patients, median survival was 31 weeks (95% CI, 23 to 40 weeks) from the start of treatment and 49 weeks (95% CI, 40 to 52 weeks) from diagnosis of mesothelioma. In pretreated patients, median survival was 44 weeks (95% CI, 24 to 40 weeks) from the start of treatment and 226 weeks (95% CI, 63 to 292 weeks) from the diagnosis of mesothelioma. Overall 1-year survival was 26% (95% CI, 15.5% to 36.4%), survival was 22% (95% CI, 10.9% to 33.2%) in chemotherapy-naive patients and 40% (95% CI, 15.2% to 64.8%) in pretreated patients. Hematologic toxicity was mild, and there was no alopecia. The most common adverse events were asthenia, nausea/vomiting, and paraesthesia, and no treatment-related deaths were reported. CONCLUSION: The raltitrexed and oxaliplatin combination is an active outpatient regimen in malignant mesothelioma and has an acceptable tolerability profile.

Routine management of gastro-oesophageal reflux disease by gastroenterologists in France: a prospective observational study.

AIMS: To obtain data on routine care of gastro-oesophageal reflux disease by French gastroenterologists. PATIENTS: Five thousand and forty-five adults with gastro-oesophageal reflux disease. METHODS: Patients were recruited by a representative sample of 598 French gastroenterologists. A full disease history, with treatments given/investigations undertaken, was obtained from all patients. The patients' expectations with regard to the improvement of the symptoms' control and the corresponding assessments made by the gastroenterologists were recorded on a 4-point scale. RESULTS: The mean time since diagnosis was approximately 4 years. The most commonly presented symptom was heartburn (79% of patients). A total of 3735 patients (74%) underwent endoscopy because of gastro-oesophageal reflux disease. Erosive oesophagitis was present in 38% and Barrett's oesophagus in 8%. Medical therapy for gastro-oesophageal reflux disease was prescribed in 92% of patients, of whom 86% received proton pump inhibitors. Lifestyle advice was given to 73% of patients. Overall, 84% of patients and 72% of physicians expected 'highly' or 'moderately' improved control of gastro-oesophageal reflux disease. Gastroenterologists underrated the need for improvement of the symptoms' control as expressed by 'de novo' as well as 'previously diagnosed' patients. CONCLUSIONS: This study provides cross-sectional data on the management of gastro-oesophageal reflux disease by gastroenterologists in France. Most patients have high expectations of an improvement in their management, but gastroenterologists generally underrate these expectations.