PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. METHODS: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. RESULTS: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). CONCLUSION: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Everolimus or sunitinib as first-line treatment of metastatic papillary renal cell carcinoma: A retrospective study of the GETUG group (Groupe d'Etude des Tumeurs Uro-Génitales).

BACKGROUND: Two phase II trials (NCT00688753 and NCT00541008) reported efficacy data of sunitinib and everolimus in first-line treatment of metastatic papillary renal cell carcinoma (mpRCC). Although most patients receive sunitinib or a mammalian target of rapamycin (mTOR) inhibitor in first- and second-line treatment, the optimal strategy remained unknown. MATERIAL AND METHODS: In 23 centres of the Groupe d'Etude des Tumeurs Urogénitales group, after centralised pathological review, we analysed retrospectively progression-free survival (PFS) of patients with mpRCC treated in first-line treatment (PFS-1) with sunitinib or everolimus (primary end-point), PFS in second-line treatment (PFS-2), overall survival (OS), objective response rate, disease control rate (DCR), overall sequence and prognostic factors for OS (secondary end-points). RESULTS: One hundred thirty-eight patients (119 men and 19 women), median age 62.5 years, with mpRCC type 1 (n = 24) or non-type 1 (n = 114), received first-line sunitinib (n = 107) or everolimus (n = 31). With a median follow-up of 92 months, we found no significant difference between the treatment groups in terms of PFS-1 (5.5 versus 6.2 months) and DCR (69% versus 83%). Ninety-eight patients received a second-line treatment, 69% with mTOR inhibitors after sunitinib and 100% with tyrosine kinase inhibitors after everolimus, with similar DCR (64% versus 58%), median PFS-2 (3.4 versus 4.8 months) and OS (16.0 versus 20.3 months). No factor was prognostic for PFS-1, whereas leukocytosis, anaemia and the time from diagnosis to first systemic therapy < 1 year were prognostic for OS. We found no prognostic difference between both pRCC subtypes. The International Metastatic Renal Cell Database Consortium risk factors were prognostic for OS. CONCLUSION: Sunitinib and everolimus had similar efficacy in first-line treatment of patients with mpRCC.

Long survival of patients with metastatic clear cell renal cell carcinoma. Results of real life study of 344 patients.

The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real-life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty-four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.

Simple and dual cross-linked chitosan millicapsules as a particulate support for cell culture.

The chitosan hydrochloride (Cs·HCl) was obtained as a polymer soluble in physiological solutions to be used as potential support for safely cell culture or cell encapsulation. Viability tests showed that concentrations between 0.16 and 5 mg/mL of Cs·HCl were not toxic for the HEK293 cells. In parallel, aldehyde-functionalized pullulan (Pul-CHO) was synthesized as the macromolecular cross-linker. Cs·HCl was dissolved in 0.9% NaCl and injected (INJECTOMAT SEP 21S PLUS) through a needle to obtain small droplets in a sodium tripolyphosphate solution in the absence and presence of 0.1% (w/v) Pul-CHO. Simple and dual cross-linked millicapsules were obtained with pore size ranging from 50 µm to 5 µm, respectively. FITC-Dextran with molecular weights of 4000 and 70,000 g/mol was encapsulated during microcapsule synthesis as macromolecular models to check the permeability of Cs millicapsules. The results show that FITC-Dextran 4000 and 70,000 diffuses quickly from simple cross-linked millicapsules while dual cross-linked millicapsules release slowly both FITC-dextrans. Microscopy experiments show that HEK 293 cells adhere to the surface of millicapsules. Taken together the data reveal that Cs millicapsules allow the cell growth on their surface, and thus, they offer new perspectives for cell encapsulation strategy.

Predictive factors of 18F-choline PET/CT positivity in patients with prostate cancer recurrence after radiation therapy: is the impact of PSA nadir underestimated?

BACKGROUND: The objective of this study is to explore the impact of PSA nadirs on detection rates of prostate cancer (PCa) recurrence with 18F-choline (CH) PET/CT after external beam radiation therapy (EBRT). METHODS: In this retrospective study, data were collected from 54 patients with suspicion of PCa biochemical recurrence after EBRT (28 patients treated initially with EBRT and 26 as salvage therapy in the absence of PSA decrease after initial treatment), who underwent 18F-CH PET/CT between 2010 and 2015. PSA nadir and trigger PSA were collected from patient files. Relative PSA was calculated by subtracting the nadir from the trigger PSA. RESULTS: Median PSA nadir was 0.31 (0.01-13.31) ng/mL, trigger PSA was 7.85 (0.47-111.60) ng/mL, and relative PSA was 6.05 (0.24-104.59) ng/mL. Overall, 40 (74%) PET/CT scans were positive: recurrence was local and/or regional in 29 patients, distant in 15 and combined both in four, with no association between PSA values and sites of recurrence. In univariate analysis, trigger (p = 0.015) and relative (p = 0.0005) PSA values and PSA velocity (p = 0.01) were significantly linked to positive PET/CT, but PSA nadir was not. In subgroup analysis, these significant differences were only found in the salvage EBRT group. Akaike Information Criterion multivariate model comparison found that relative PSA was a better predictor of positive PET/CT than trigger PSA (PSAt). 18F-CH PET/CT detection rates increased with trigger and relative PSA: 0% (0/4 patients), 71% (5/7 patients), and 81% (35/43 patients) for PSAt <2 ng/mL, 2≤ PSAt ≤4 ng/mL, and PSAt >4 ng/mL, respectively, and 14% (1/7 patients), 50% (5/10 patients), and 92% (34/37 patients) when relative PSA was taken into account instead of trigger PSA, with seven (13%) patients changing subgroups. CONCLUSIONS: We found a high overall detection rate and an increase in detection rates proportional to trigger and relative PSAs. Although relative PSA, taking into account PSA nadir, was a better predictive factor of PET/CT positivity in univariate analysis, this was most noticeable for high PSAs. For low PSAs, trigger PSA remains most relevant. Larger series with intermediate PSA values need to be studied to fully apprehend nadir impact.

Relationship between obstructive sleep apnea syndrome and metabolic syndrome in a patient with chronic extrinsic allergic alveolitis.

Obstructive sleep apnea syndrome (OSAS) is a health issue of major importance globally. Although OSAS has a prevalence of 4-10% in the general population, it is less diagnosed, with redoubtable consequences on the quality of life and the professional performance. Observational studies showed that lack of sleep is correlated with weight gain and an increased risk of obesity; this relationship was confirmed by mutually reinforcing pathophysiological mechanisms. We report a case that is relevant for the consequences of the pharmaceutical treatment which proved effective in extrinsic allergic alveolitis, but was not supported by an effective intervention on lifestyle (by proper dietary adjustment and increased physical activity) thus exacerbating the obesity, the OSAS and the metabolic syndrome. We believe that this case exemplifies the relevant pathophysiological interdependence between obesity, metabolic syndrome and OSAS.

Obstructive Sleep Apnea Syndrome in a Railroad Controller Worker.

Sleep Apnea Syndrome (SAS) constitutes a healthcare issue of major importance at international level with a prevalence of 5% in the active population. Consequentially to the induced co-morbidities, the mortality reaches as high as 39% at eight years time lapse from the initial diagnostic. Seldom undiagnosed, the severity spectrum of SAS, in the absence of therapy, only continues to amplify. Here below, we are presenting the case of a 49 years old patient, railroad controller worker, non-smoker and occasionally alcohol user, who was hospitalized in our Clinic for Occupational Medicine. During last year, the patient was accusing excessive daytime somnolence, breath arrests during sleep, intense snoring, morning headaches, morning oral dryness, pin point chest pain, nocturia (4-5 nocturnal urination), concentration difficulties and an overall reduced work capacity. The presumptive diagnostic of Obstructive Sleep Apnea is being considered based on the correlation between the clinical presentation and the Epworth, Stanford and Berlin questionnaire results. The key diagnostic element was the polygraph recording over an 8 hours sleep period. Positive Diagnosis: Obstructive Sleep Apnea severe form. Management and recommendations: (1) Behavioral therapy (weight loss) and (2) CPAP (Continuous Positive Airway Pressure) therapy which was instituted immediately after the positive diagnosis was made. As a consequence, the respiratory symptoms, the frequent episodes of daytime snoozing and the concentration difficulties at work place diminished considerably.

Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: long term outcome of the Temporary Authorization for Use programme in France.

BACKGROUND: COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a Temporary Authorization for Use (TAU) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TAU. METHODS: Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TAU for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors. RESULTS: Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years. CONCLUSIONS: Biochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders' patients could beneficiate from AA for more than 3 years.