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.

Characterization of the semen microbiota of healthy stud dogs using 16S RNA sequencing.

The reproductive microbiota of male dogs has never been investigated using culture-independent sequencing techniques. The purpose of the present study was to get seminal knowledge on the microbiota of the ejaculate. Specifically, factors as the fraction of the ejaculate, the sperm quality (normospermia, teratozoospermia), and the living environment were evaluated. The sperm-rich and the prostatic fractions of the ejaculate were collected from healthy stud dogs. Following the sperm analysis, samples from twenty animals (normospermic n = 10 and teratozoospermic n = 10) were stored at - 80 °C until further processing including DNA extraction and 16S rRNA sequencing. Alpha- (Shannon index) and beta- (Bray-Curtis, Unweighted UniFrac) diversities were assessed and compared (PERMANOVA) based on the group of samples (biological samples from the ejaculate and controls), the fraction of the ejaculate (sperm-rich and prostatic fractions), the animal group (normospermia and teratozoospermia), and the living environment of the animal (kennel or pet living in-house). The most abundant bacterial phyla in canine semen samples were Proteobacteria, Firmicutes, and Actinobacteria. Overall, the dominant bacterial family was that of Pasteurellaceae The genus Mycoplasma was never detected. No differences in terms of bacterial composition were found based on the fraction of the ejaculate and based on the animal group (P > 0.05). On the other hand, differences in alpha and beta diversities were highlighted based on the living environment (P = 0.001). Overall, the results of the present study provide preliminary insights on dog semen microbiota, opening a new chapter in the field of canine andrology. Our results suggest that the environment may play a role in influencing the reproductive microbiota of male dogs and that the prostatic fraction of the ejaculate can be used for further research as a representative of the semen microbiota.

[Artificial urinary sphincter in patients with urinary incontinence after High Intensity Focused ultrasound]. / Sphincter urinaire artificiel chez les patients présentant une incontinence urinaire après High Intensivity Focused Ultrasound Therapy.

INTRODUCTION: Urinary incontinence after High Intensity Focused ultrasound (HIFU) is a poorly documented issue. To our knowledge, no study has evaluated the outcomes of artificial urinary sphincter (AUS) after HIFU. The aim of this study was to evaluate the functional outcomes of AUS for post-HIFU urinary incontinence. METHODS: The charts of all male patients who underwent an AUS implantation between 2004 and 2020 in 13 centers were reviewed retrospectively. Only men with a history of HIFU were included. The primary endpoint was social continence at 3 months defined as wearing 0 to 1 pad per day. RESULTS: Out of 1318 procedures, nine men were implanted with an AUS after HIFU including four men with an history of pelvic irradiation: 3 pelvic radiation therapy and 1 prostatic brachytherapy. The patients were divided into two groups, 5 in the HIFU group without a history of pelvic irradiation, 4 patients in the HIRX group with a history of pelvic irradiation. The median age was 74 years (IQR 71-76). There was no perioperative complication. The median follow-up was 47.5 (IQR 25-85.5) months. Social continence at 3 months was 75% in the total cohort: 80% in the HIFU group and 67% in the HIRX group. CONCLUSION: AUS implantation may provide satisfactory long-term functional outcomes in the treatment of stress urinary incontinence resulting from HIFU. Larger series are needed to confirm these findings. LEVEL OF EVIDENCE: 4.

Erlotinib in routine clinical practice for first-line maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC).

PURPOSE: The controlled phase III trial SATURN demonstrated that maintenance therapy with erlotinib after the first-line platinum-based chemotherapy prolonged progression-free survival (PFS) and overall survival (OS) of non-small cell lung cancer (NSCLC) patients with advanced, non-progressive disease. We conducted the non-interventional study SATURN NIS to investigate the effectiveness and tolerability of erlotinib maintenance in daily clinical practice. METHODS: This single-arm NIS screened 290 patients with locally advanced or metastatic NSCLC (stage IIIB or IV) and stable disease after standard platinum-based first-line chemotherapy in 95 institutions across Germany. Erlotinib was dosed and administered corresponding to the terms of the marketing authorization at the time of recruitment. The main effectiveness endpoint was subjects' OS at 1 year. Subgroup analyses of survival estimates of OS and PFS were performed. RESULTS: 272 patients were eligible for analysis (median age 66 years, 37.1% females, 99.6% Caucasian, median ECOG performance status 1, 61.8% adenocarcinoma, 96.3% of patients with stable disease). Maintenance therapy with erlotinib resulted in median OS comparable to that of the SATURN phase III trial 10.4 months [95% CI: (8.8; 12.5) vs. 11.9 months]. The 1-year survival rate was 45.6% [95% CI: (37.5%; 53.6%)]. No new safety signals were observed. As expected, patients with epidermal growth factor receptor (EGFR) mutations derived a greater benefit concerning OS and PFS than EGFR-wild-type patients. Moreover, a significant association of OS and PFS and the smoking status was observed. CONCLUSIONS: The results of this non-interventional study support the current clinical practice of erlotinib switch maintenance in EGFR-mutation-positive patients.

Tumor necrosis after preventive embolization of large renal angiomyolipomas.

OBJECTIVES: The purpose of this study was to retrospectively evaluate tumor necrosis following preventive embolization in patients with renal angiomyolipoma (RAML) at high risk of bleeding. PATIENTS AND METHODS: Arterial embolization was performed in 24 patients (22 women, 2 men; mean age, 43±13 years) with a total of 30 RAMLs (mean volume, 137 cm(3)±163) between 1996 and 2012. Two sub-groups of patients were identified and further compared based on the presence or not of necrosis following arterial embolization. RESULTS: The technical and clinical success rates of arterial embolization of RAMLs were 97% and 87%, respectively. The mean initial volume of RAMLs differed between the two sub-groups with 331 cm(3) in the group with tumor necrosis and 88 cm(3) in the group without tumor necrosis (P=0.0047). High-fat content RAMLs were predominantly observed in the necrosis group and the mean volume reduction observed for high-fat RAMLs was 65% whereas it was 36% for low-fat content RAMLs. The six patients who developed RAML necrosis had arterial embolization using microspheres (one patient with microspheres alone and five with a combination of microspheres and metallic coils). All necrotic RAMLs displayed arterial dysplasia. CONCLUSION: The risk of tumor necrosis is higher for larger RAMLs. The role of distal arterial embolization with microspheres in tumor necrosis in RAML is suggested by the results of our study but could not be definitely demonstrated statistically due to the limited sample size.

[Pioglitazone protects against elastocalcinosis and improves aortic wall elasticity]. / Importance de l'activation des PPARgamma dans la pharmacologie de la rigidité artérielle.

Specific treatment of age-related aortic wall arteriosclerosis and stiffening is lacking. As anti-inflammatory ligands for peroxisome proliferator-activated receptor-gamma have beneficial effects on the arterial wall in atherosclerosis, we investigated whether chronic pioglitazone treatment protects against another form of vascular wall disease, arteriosclerosis. In a rat model of elastocalcinotic arteriosclerosis (hypervitaminosis D and nicotine, VDN), we evaluated whether pioglitazone attenuated arteriosclerosis and its consequences, aortic wall rigidity, increased aortic pulse pressure and left ventricular hypertrophy. In VDN rats, medial calcification was associated with monocyte/macrophage infiltration and induction of TNF-alpha and IL-1B. Pioglitazone decreased TNF-alpha and IL-1B mRNA expression, blunted aortic wall calcification and prevented fragmentation of elastic fibers. Pioglitazone reduced aortic wall stiffness, aortic pulse pressure and left ventricular hypertrophy. Our results may be clinically relevant in elderly patients suffering from aortic wall stiffening and isolated systolic hypertension.

Image analysis of dendritic cells in the human fetal thymus.

The distribution and evolution of thymic dendritic cells (DC) were studied during human ontogeny. Immunochemical techniques were used to detect S100 protein-positive cells on fetal thymus sections, at different post-fecundation (PF) ages; an image analysis of these positive cells was then carried out. Variations in the percentage of these cells in the medulla were determined according to age: the higher percentages were seen at 12 and 16 weeks PF. Dendritic cells were present at an early stage in the thymic rudiment (7 weeks PF), a finding consistent with an origin of these cells in the fetal liver, and with the possible existence of local attraction and/or maturation factors. The expression of the CD54 adhesion molecule revealed the existence of particular interactions between DC and lymphocytes in the medullary area, and at the cortico-medullar junction. Diffuse CD11a (LFA-1) expression on lymphocytes was consistent throughout gestation. The monocyte/macrophage markers (CD11b, CD14) and the reaction of non-specific esterases showed that the distribution pattern of these cells differed from the DC pattern. These ontogenic data are related to the significant role played by DC throughout the different stages of thymopoiesis.

Instillation of steroids in the eye: its effect on lymphocytes in regional lymph nodes and in peripheral blood.

The blastogenic response to mitogens by lymphocytes after topical instillation of steroids was studied in rabbits. The effect on lymphocytes from the local draining lymph nodes and peripheral blood was assessed. There was no effect on the lymphocytes of local draining lymph nodes; however, a decrease in phytohaemagglutinin response occurred in peripheral blood lymphocytes.

Active enhancement in the primate by bone marrow I. Ia-like determinants on nucleated bone marrow cells.

This study investigates the possibility that the active enhancing properties of bone marrow (BM) cells may be related to Ia-like determinants on their surface membranes. Less chromium was released on a cell per cell basis from nucleated baboon BM cells used as targets in complement-dependent cytotoxicity than from labelled lymph node lymphocytes. On the other hand, BM cells stimulated allogeneic lymphocytes in culture more vigorously than lymph node lymphocytes. BM cells with lymphocyte-activating properties could be enriched by fractionation on a discontinous bovine serum albumin gradietnt. BM cells responded poorly to allogeneic cell stimulation in mixed culture. Platelet absorption studies of an alloantiserum supported the conclusion that nucleated BM cells, and particularly BM fractions collected from the less dense interfaces of a bovine serum albumin gradient, express relatively more lymphocyte-activating or Ia-like determinants than "serologically defined" determinants.