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Tethered cord syndrome is a complication of spinal dysraphism. The tethering of the cord does not permit the normal cranial migration of the conus within the vertebral canal. The result is a neural dysfunction due to a traction neuropathy. Although this condition commonly presents in childhood, less severe degrees of tethering may remain asymptomatic until adult life. The authors report a new case of tethered cord syndrome in a 25-years-old young girl, cause of bladder dysfunction. Clear improvement of urinary repercussions is obtained after surgery. [Copyright &y& Elsevier]

Circulating senescent CD8 + T (T 8 sen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to immunotherapy in patients with advanced non-small cell lung cancer (aNSCLC). We aimed to better characterize T 8 sen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating T 8 sen cells were characterized by a higher expression of SA-βgal and the transcription factor T-bet, confirming their senescent status. Using whole virome profiling, cytomegalovirus (CMV) was the only virus associated with T 8 sen. CMV was necessary but not sufficient to explain high accumulation of T 8 sen (T 8 sen high status). In CMV + patients, the proportion of T 8 sen cells increased with cancer progression. Last, CMV-induced T 8 sen high phenotype but not CMV seropositivity itself was associated with worse progression-free and overall survival in patients treated with anti-PD-(L)1 therapy but not with chemotherapy. Overall, CMV is the unique viral driver of T 8 sen-driven resistance to anti-PD-(L)1 antibodies in patients with aNSCLC.

Background: Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy., Methods: We retrospectively included 623 patients with advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis., Results: In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p<0.001) for patients with low SFM (<3.95 kg/m 2 ), low FBM (<3.26 kg/m 2 ), low VFM (<0.91 kg/m 2 ), low MBM (<5.85 kg/m 2 ) and low BMI (<24.97 kg/m 2 ). The same parameters were significant in the Cox univariate analysis (p<0.001) and, in the multivariate stepwise Cox analysis, the significant parameters were MBM (p<0.0001), SFM (0.013) and WL (0.0003). In subanalyses according to the type of cancer, all body composition parameters were statistically significant for NSCLC in ROC, KM and Cox univariate analysis while, for melanoma, none of them, except MBM, was statistically significant. In multivariate Cox analysis, the significant parameters for NSCLC were MBM (HR=0.81, p=0.0002), SFM (HR=0.94, p=0.02) and WL (HR=1.06, p=0.004). For NSCLC, a KM analysis combining SFM and MBM was able to separate the population in three categories with the worse prognostic for the patients with both low SFM (<5.22 kg/m 2 ) and MBM (<6.86 kg/m 2 ) (p<0001). On the external validation cohort, combination of low SFM and low MBM was pejorative with 63% of mortality at 1 year versus 25% (p=0.0029)., Conclusions: 3D measured low SFM and MBM are significant prognosis factors of NSCLC treated by immune checkpoint inhibitors and can be combined to improve the prognostic value., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: This review presents the rationale for intratumoral immunotherapy, technical considerations and safety. Clinical results from the latest trials are provided and discussed., Recent Findings: Intratumoral immunotherapy is feasible and safe in a wide range of cancer histologies and locations, including lung and liver. Studies mainly focused on multi-metastatic patients, with some positive trials such as T-VEC in melanoma, but evidence of clinical benefit is still lacking. Recent results showed improved outcomes in patients with a low tumor burden. Intratumoral immunotherapy can lower systemic toxicities and boost local and systemic immune responses. Several studies have proven the feasibility, repeatability, and safety of this approach, with some promising results in clinical trials. The clinical benefit might be improved in patients with a low tumor burden. Future clinical trials should focus on adequate timing of treatment delivery during the course of the disease, particularly in the neoadjuvant setting., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The objective of the study is to propose the immunotherapy progression decision (iPD) score, a practical tool based on patient features that are available at the first evaluation of immunotherapy treatment, to help oncologists decide whether to continue the treatment or switch rapidly to another therapeutic line when facing a progressive disease patient at the first evaluation., Experimental Design: This retrospective study included 107 patients with progressive disease at first evaluation according to RECIST 1.1. Clinical, radiological, and biological data at baseline and first evaluation were analyzed. An external validation set consisting of 31 patients with similar baseline characteristics was used for the validation of the score., Results: Variables were analyzed in a univariate study. The iPD score was constructed using only independent variables, each considered as a worsening factor for the survival of patients. The patients were stratified in three groups: good prognosis (GP), poor prognosis (PP), and critical prognosis (CP). Each group showed significantly different survivals (GP: 11.4, PP: 4.4, CP: 2.3 months median overall survival, P < 0.001, log-rank test). Moreover, the iPD score was able to detect the pseudoprogressors better than other scores. On the validation set, CP patients had significantly worse survival than PP and GP patients (P < 0.05, log-rank test)., Conclusions: The iPD score provides oncologists with a new evaluation, computable at first progression, to decide whether treatment should be continued (for the GP group), or immediately changed for the PP and CP groups. Further validation on larger cohorts is needed to prove its efficacy in clinical practice., (©2023 American Association for Cancer Research.)

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology., Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Association of high body mass index (BMI) with longer survival has been reported in patients on immune checkpoint inhibitors (ICIs), but results are inconsistent. This 'obesity paradox' is potentially confounded by the effects of BMI change over time and of skeletal muscle depletion., Methods: We conducted a secondary analysis of a prospective cohort, including consecutive patients receiving ICI treatment for melanoma (n = 411) and non-small cell lung cancer (NSCLC) (n = 389) in routine care., Results: In the univariable analysis of the entire population, overweight/obesity (BMI ≥ 25 kg/m 2 ) was associated with longer survival (p < 0.01); however, this effect was limited to NSCLC (p < 0.01) and was absent in melanoma. Weight loss (WL) and reduced skeletal muscle mass were observed in patients within all BMI categories. WL was associated with shorter survival in multivariable analysis in both tumour sites (p < 0.01), and for NSCLC, BMI lost significance when WL was included (p = 0.13). In models further adjusted for CT-defined skeletal muscle mass, WL retained significance for both tumour types (p < 0.01), and reduced skeletal muscle only for NSCLC (p = 0.02) was associated with shorter survival. WL retained significance when biomarkers (lactate dehydrogenase enzyme, albumin and derived neutrophil to lymphocyte ratio) were added to the multivariable model., Conclusions: The so-called 'obesity paradox', counterintuitive association between high BMI and longer survival, vanished when controlling for confounders, such as type of cancer, and manifestations of depletion (WL and reduced skeletal muscle mass)., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pr Robert reported consultant advisory for BMS, Novartis, MSD, AstraZeneca, Pierre Fabre, Sanofi, Roche and co-founder of Robonexus outside submitted work. Dr Planchard reported consulting advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Janssen, Abbvie, honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Janssen, Abbvie outside submitted work, Clinical trials research as principal or co-investigator (Institutional financial interests) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen, Abbvie outside submitted work and travel, accommodations, expenses from AstraZeneca, Roche, Novartis, Pfizer. Dr Routier reported consultant advisory for BMS, Novartis, Roche, clinical trials research principal or co-investigator for BMS, Novartis, Roche, Merck-Serono, MSD, Idera, Iovance, Regeneron, Debiopharm, Replimune outside submitted work and travel accommodations, expenses from BMS, Novartis, MSD. Dr Champiat reported consulting advisory role for Advisory Board: Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Ellipses Pharma, Oncovita, Seagen, UltraHuman, reported honoraria from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, Janssen, Merck, Novartis and Roche and was principal investigator of clinical trials for Abbvie, Amgen, Cytovation, Eisai, Imcheck Therapeutics, Molecular Partners Ag, Merck, Ose Pharma, Pierre Fabre, Sanofi Aventis, Sotio A.S, Transgene. Dr Michot: Principal/sub-Investigator of Clinical trials for Amgen, Astex, AstraZeneca, Medimmune, Roche, Sanofi, Xencor, BMS, Seattle Genetics, Regeneron. Pr Lambotte: paid expert testimony and consultancy fees from BMS France, MSD, Astra Zeneca; expert testimony for Janssen., Gilead. Pr Marabelle has worked as a clinical investigator and has participated to scientific advisory boards or has consulted for the following companies commercialising anti-PD(L)1 antibodies: Bristol Myers Squibb, Merck Sharp & Dohme, Astra Zeneca, Roche/Genentech, Sanofi, Merck Serono and Pfizer. No other disclosures were reported., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Many intratumoural (IT) immunotherapies are currently developed in the clinic with the aim of overcoming primary and secondary resistance and/or to limit on-target/off-tumour toxicities of immune checkpoint targeted therapies. This study aimed to describe the feasibility, safety and efficacy of IT immunotherapy treatments., Design: This retrospective single-centre study included the first 100 consecutive patients enrolled in Gustave Roussy's Human IntraTumoral-ImmunoTherapy (HIT-IT) program. Patient characteristics, target description, image guidance, safety and response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded. Predictive factors of complications and responses were analysed. Survival was also reported., Results: From 09/2015 to 05/2020, 100 patients had 115 tumours injected during 423 treatment cycles. Most frequent primary tumour arose from the skin (n = 49), digestive track (n = 4) or head and neck (n = 8). Injected tumours' mean diameter was 37 ± 23 mm, and a median number of 4 IT injections per patient (interquartile range:3-5) were performed. Targeted tumours for IT injections were superficial lymph nodes (36.5%), subcutaneous lesions (25.2%), liver tumours (20.9%) and others (17.4% including tumour sites such as deep lymph nodes or lung). Most patients (72%) received systemic immunotherapy in combination with HIT-IT. Procedure- and drug-related adverse events (AEs) occurred in 11.3% and 33.3% of the treatment cycles, respectively. Only 3 procedure-related AEs were grade-3 (0.7%); and no grade-4 or 5 occurred. Among all cycles, 7 grade-3 and 1 grade-5 drug-related AEs were reported. Complete and partial responses were achieved for 5% and 18% of patients, respectively, while stable disease was the best response for 11%. Patients receiving HIT-IT as a 1st-line treatment (24%), or not previously pre-treated with immunotherapy (53%) responded better, p = 0.001 and p = 0.004, respectively. From 1st cycle of IT, 12-month overall progression-free survival and overall survival were 21% (14-31%) and 57% (47-68%), respectively., Conclusions: This retrospective study, conducted on patients with cancer and treated within clinical trials at Gustave Roussy, demonstrates the feasibility and safety of the IT immunotherapy strategy., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lambros Tselikas received honoraria from the following companies: Amgen, Boston Scientific, Medincell, GE Healthcare, Guerbet, SIRTEX, Quantum Surgical, and received grants from BMS foundation and Terumo. Thierry de Baere, has consulted or received advisory fees from: AstraZeneca, Boston Scientific, Eisai, GE Healthcare, Guerbet, Johnson & Johnson, Medtronic, Nanobiotix, Roche, Terumo, Quantum surgical, Frédéric Deschamps, has received honoraria from: Ablatech, Boston Scientific, General Electric, Medtronic and Terumo. Capucine Baldini, reports research funding from BMS, honoraria from Sanofi, BMS, Astra Zeneca, and Abbvie Jean-Charles Soria, received honoraria from Astex, AstraZeneca, Bayer, Blend Therapeutics, Boehringer-Ingelheim, Clovis, Eli Lily, Gammamabs, Merus, Mission Therapeutics, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Symhogen, Tarveda; is a Gritstone stockholder and was an AstraZeneca full time employee from Sept 2017 to Dec 2019 and is an AMGEN full time employee since July 2021. Fabrice Barlesi, reports personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. Christophe Massard, has consulted or received advisory fees from: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi and Orion. Caroline Robert, has consulted for BMS, Pierre Fabre, Novartis, Amgen, Merck, MSD, Roche, Sanofi, Biothera, Ultimovacs. Stéphane Champiat, has received honoraria or consulted for the following companies: Amgen, AstraZeneca, BMS, Janssen, MSD, Novartis and Roche. Aurélien Marabelle, has participated to Scientific Advisory Boards or Consulted for the following companies: MSD, Astra Zeneca/Medimmune, Bayer, Pillar Partners, Bioncotech, Rigontec, Curevac, Servier, Amgen. Antoine Dardenne, , Matthieu Faron, , Samy Ammari, Siham Farhane, Steve Suzzoni, François-Xavier Danlos, Thibault Raoult, Sandrine Susini, Nael Al-Shatti, Severine Mouraud, Adrian Kobe, Alexandre Delpla, Charles Roux, have no conflict of interest to declare •No specific funding was obtained for this study. The Intratumoral programm of Gustave Roussy is partially funded by the Centre d’Investigation Clinique BIOTHERIS (CIC1428 INSERM), (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Hydatidosis is a zoonosis caused by Echinococcus granulosus . It's a real public health problem in Morocco. Muscle localization is unusual, even in endemic countries. We report a rarely described case of a hydatid cyst of the psoas muscle diagnosed in our laboratory., Case Report: The patient was a 32-year-old male, living in a rural area. He reported a contact with dogs. He was admitted in vascular surgery department for left hypochondrium pain, with heaviness of the left lower limb and appearance of varicose veins. Clinical examination has found a huge painful and hard mass of the left flank arriving to the hypogastrium with varicose veins of the left leg. An injected CT scan of the pelvic region showed a 189 x 137 mm cystic mass of the left psoas muscle reflowing left iliac vessels. This suggested hydatid cyst. No other localization was found. Hydatid serology was positive with an ELISA test and an indirect hemagglutination test. The patient underwent surgery to remove the mass. Several white vesicles of a few centimeters were found in the cyst and were sent to the parasitology laboratory. Microscopic examination has confirmed the presence of viable Echinococcus granulosus . The patient received albendazole 400 mg twice daily for only a month and was not seen for follow-up. One year after surgery, he showed the same symptoms of abdominal pain and heaviness. Recurrence of hydatid cysts in the same localization was diagnosed with ultrasound showing two hydatid cysts type 3 according to Gharbi classification., Discussion: Diagnosis of all hydatidosis localizations is based on epidemiological, clinical, and radiological data and confirmed by serology and parasitological examination of the surgical specimen. Surgery is then a diagnostic and therapeutic tool that cannot be bypassed since it allows the definitive elimination of the parasite and eviction of recurrence if it's well done. Conservative methods are related to recurrent cysts., Conclusion: Muscle hydatidosis is extremely rare but should not be forgotten when radiological and epidemiological data suggest it. It's a benign infection but can be severe and deadly if not appropriately treated., (Copyright © 2022 SFMTSI.)

Background: We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425)., Methods: In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy., Results: A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4 + PD1 + OX40 + T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP + dendritic cells, CD3 + T cells and FOXP3 + Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4 + CXCR3 + CXCR5 - memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels., Conclusion: Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy., Trial Registration: ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered., (© 2022. The Author(s).)

Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience., (©2021 American Association for Cancer Research.)

Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach., (©2020 American Association for Cancer Research.)

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown., Experimental Design: The percentage of CD28 - , CD57 + , KLRG1 + among CD8 + T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP + CD8 + T cells were assessed in vitro ., Results: In the ICI discovery cohort ( N = 37), SIP cut-off was 39.5%, 27% of patients were SIP + . In the ICI validation cohort ( N = 46), SIP + status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP + status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8 + T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population ( N = 83), SIP + status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort ( N = 61), 11% of patients were SIP + . SIP status did not correlate with outcomes upon PCT., Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT. See related commentary by Salas-Benito et al., p. 374 ., (©2020 American Association for Cancer Research.)

To control estradiol (E2) formation, we are interested in synthesizing inhibitors of 17β-hydroxyteroid dehydrogenase type 1 (17β-HSD1). Since the results of docking experiments have shown that E2-lactone derivatives substituted in position 19 or 20 (E-ring) could generate interactions with the active site of the enzyme, we carried out their chemical synthesis. After having prepared the 16β,17β-γ-lactone-E2 in four steps starting from estrone (E1), we introduced the molecular diversity by adding a hydroxymethyl, a methylcarboxylate, a carboxy or an allyl group. The allyl derivative was used as a key intermediate to generate a hydroxyethyl side chain in α or β position. Two lactols were also obtained from two hydroxyalkyl lactones. Enzymatic assays revealed that lactone and lactol derivatives weakly inhibited 17β-HSD1 in homogenized HEK-293 cells overexpressing 17β-HSD1 (34-60% at 1 μM) and in intact T-47D cells expressing 17β-HSD1 (10-40% at 10 μM). This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors"., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [(14)C]-E1 (100 nM) into [(14)C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 µM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T47-D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [(14)C]-E1 (60 nM) into [(14)C]-E2 transformation at 1 and 10 µM, respectively.

Introduction: Uroflowmetry is the simplest urodynamic test to study the lower urinary tract. Uroflowmetry parameters, especially maximum flow rate, are important, but are difficult to interpret due to the lack of normal uroflowmetry data in children., Objective: The objective of this prospective clinical study was to evaluate normal uroflowmetry parameters in a prospective series of 202 children between the ages of 5 and 15 years., Materials and Methods: We prospectively studied uroflowmetry in a series of 202 children between the ages of 5 and 15 years. Children with voiding disorders, or a psychiatric or neurological illness were excluded. The following variables were determined: age, body surface area (BSA (m2)), maximum flow rate (Qmax (ml/s)), voided volume (V (ml)) and maximum flow time (TQmax (s))., Results: Qmax increased with age, V and BSA in both sexes and was greater in girls. In girls between the ages of 5 and 6 years, mean Qmax was 15.8 for a mean V of 173 and BSA less than 1.06 and, in girls between the ages of 13 and 15 years, mean Qmax was 26.2 for a mean V of 327 and BSA greater than 1.06. TQmax also increased with age, V and BSA and was greater in boys. In boys between the ages of 5 and 6 years, mean TQmax was 6.5 for a mean V of 174 and BSA less than 1.6 and, in boys between the ages of 13 and 15 years, mean TQmax was 7.4 for a mean V of 332 and BSA greater than 1.6. A positive correlation was demonstrated between age and uroflowmetry parameters and the most significant correlation was observed between age and Qmax in both sexes., Conclusion: This study on normal uroflowmetry parameters in children not presenting any voiding disorders demonstrated a significant difference, in both sexes, between Qmax and TQmax in relation to age, V and BSA. Uroflowmetry could therefore be useful in the diagnosis of infravesical obstruction.

Splenogonadal fusion is a rare congenital anomaly that is often discovered at operation or autopsy. The diagnosis is difficult, but could be based on preoperative scintigraphy and frozen section histological examination to avoid useless orchidectomy. It is a benign lesion, which must be distinguished from testicular tumour.

Benign mesenchymal tumors of the bladder are rare. Leiomyoma is the most common mesenchymal tumor of the bladder. We report a new case. A 50-year-old woman presented with total hematuria. Complementary investigations (ultrasonographic, intravenous urography) showed an intravesical solid mass, arising from the bladder dome. Cystoscopic examination suggested a benign tumor, which was confirmed by pathologic assessment of biopsy. Partial cystectomy was performed. Postoperative course was uneventful. Pathologic examination showed a leiomyoma. Leiomyoma of the urinary bladder is a rare benign tumor. Its prognosis is good, the treatment being exclusively surgical.