Anti-HLA antibodies hamper successful transplantation, and activation of the complement cascade is involved in antibody-mediated rejection. We investigated whether the complement-binding capacity of ...anti-HLA antibodies plays a role in kidney-allograft failure.
We enrolled patients who received kidney allografts at two transplantation centers in Paris between January 1, 2005, and January 1, 2011, in a population-based study. Patients were screened for the presence of circulating donor-specific anti-HLA antibodies and their complement-binding capacity. Graft injury phenotype and the time to kidney-allograft loss were assessed.
The primary analysis included 1016 patients. Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had the lowest 5-year rate of graft survival (54%), as compared with patients with non-complement-binding donor-specific anti-HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P<0.001 for both comparisons). The presence of complement-binding donor-specific anti-HLA antibodies after transplantation was associated with a risk of graft loss that was more than quadrupled (hazard ratio, 4.78; 95% confidence interval CI, 2.69 to 8.49) when adjusted for clinical, functional, histologic, and immunologic factors. These antibodies were also associated with an increased rate of antibody-mediated rejection, a more severe graft injury phenotype with more extensive microvascular inflammation, and increased deposition of complement fraction C4d within graft capillaries. Adding complement-binding donor-specific anti-HLA antibodies to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 0.75; 95% CI, 0.54 to 0.97).
Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss.
Objectives
To evaluate the relationship between metabolic syndrome and the frequency and severity of lower urinary tract symptoms (LUTS).
Patients and Methods
In all, 4666 men aged 55–100 years ...consulting a general practitioner during a 12‐day period in December 2009 have been included in this observational study. LUTS were defined according to the International Prostate Symptom Score (IPSS) and metabolic syndrome with the National Cholesterol Education Program/Adult Treatment Panel III definition. We studied the correlation between metabolic syndrome and its individual components, and the severity of LUTS (IPSS and treatment for LUTS). Analyses were adjusted for body mass index, age, and prostate‐specific antigen level.
Results
Metabolic syndrome was reported in 51.5% of the patients and 47% were treated for LUTS. There was a significant link between metabolic syndrome and treated LUTS (P < 0.001). The risk of being treated for LUTS also increased with an increasing number of metabolic syndrome components present. Metabolic syndrome was positively correlated with the severity of the LUTS (P < 0.001) for overall IPSS and both voiding and storage scores (P < 0.001). Each component of the metabolic syndrome (except high‐density lipoprotein‐cholesterol) appeared as an independent risk factor of high IPSS and of LUTS treatment in multivariate analysis. Metabolic syndrome was positively correlated with prostate volume.
Conclusions
Our results suggest a significant relationship between LUTS linked to benign prostatic hyperplasia and metabolic syndrome, in terms of frequency and severity. The risk of being treated for LUTS also increased with an increasing number of metabolic syndrome components present. The prevention of such modifiable factors by the promotion of dietary changes and regular physical activity practice may be of great importance for public health.
Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are ...based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4.
Tumor specimens were obtained from patients from two separate cohorts: One from "Evita Pueblo" Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR.
Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased.
In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.
Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been ...directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in‐depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.
HLA-G:ILT2 has recently been positioned as a major immune checkpoint in urologic cancers. In clear cell renal cell carcinoma (ccRCC), tumor-infiltrating CD8+ T cells expressing ILT2 are a highly ...cytotoxic cell population, distinct from PD1+ T cells, and whose function is inhibited by HLA-G+ targets. Here we report that ILT2 receptor can also be expressed by CD4+ T cells in urologic cancer patients. In the course of deciphering the role of these ILT2+CD4+ T cells, we found a statistical association between the tumor context and these T cells, and a positive correlation between the levels of peripheral and intra-tumoral CD4+ILT2+ T cells. Phenotypic analyses revealed that CD4+ILT2+ T cells express memory T cell (CD27−CD28−CD57+) and cytotoxicity (Tbet+Perforin+KLRG1+NKp80+GPR56+) markers, consistent with a CD4+CTL phenotype. Functional assays showed that ccRCC-infiltrating CD4+ILT2+ T cells indeed have high cytolytic properties and therefore function as proper CD4+CTLs, but are selectively inhibited by HLA-G+ targets. Clinical relevance was provided by immunohistochemical analyses on ccRCC tumor lesions with HLA-G+ HLA class II+ tumor cells next to CD4+ T cell infiltrates. Our findings provide evidence supporting that ILT2+ T cells constitute a reservoir of intratumor cytotoxic T cells that is not targeted by the current checkpoint inhibitors, but could be by anti-HLA-G/anti-ILT2 antibodies as novel immunotherapy in HLA-G+ tumors.
•CD4+ILT2+ T cells are associated with tumoral context in urologic cancer patients.•Peripheral and intra-tumoral CD4+ILT2+ T cells are positively correlated.•CD4+ILT2+ T cells display a memory and cytotoxic phenotype, corresponding to CTLs.•CD4+ILT2+ T cells are found next to HLA-DR and HLA-G positive ccRCC tumor cells.•CD4+ILT2+ T cells are functional cytotoxic T cells but are inhibited by HLA-G.
Objective
To investigate the feasibility, efficacy, and safety of trimodal therapy (TMT) using a bifractionated split‐course hypofractionated radiotherapy (RT) for non‐metastatic muscle‐invasive ...bladder cancer (MIBC) in elderly patients.
Patients and Methods
We retrospectively reviewed the characteristics and outcomes of patients aged >75 years with non‐metastatic MIBC suitable or not for radical cystectomy (RC) and treated with transurethral resection of bladder tumour followed by concomitant radio‐chemotherapy (platinum salt and 5‐fluorouracil) at two institutions (Saint Louis Hospital, Paris, France and European Georges Pompidou Hospital, Paris, France) between 1990 and 2021. RT consisted of an adapted bifractionated split‐course hypofractionated RT. Acute toxicities were reported according to Common Terminology Criteria for Adverse Events version 5.0 and late toxicities were reported according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. The primary end‐point was overall survival (OS). Secondary end‐points included other survivals outcomes and safety.
Results
A total of 122 patients were identified, with a median (range) follow‐up of 51.1 (0.5–210.8) months. In all, 83.5% of patients completed radio‐chemotherapy. The OS rate was 61.7% at 3 years and 51.2% at 5 years. In multivariate analysis, the completion of RT and concomitant chemotherapy were significantly associated with better OS and cancer‐specific survival. For patients fit for RC, a complete histological response was achieved for 77 patients (91.7%) with radio‐chemotherapy and the bladder conservation rate was 90.5%. Acute and late Grade ≥3 toxicities were <5%.
Conclusion
Bifractionated split‐course hypofractionated RT with concomitant chemotherapy regimen appears to be well‐tolerated and effective. Trimodal treatment seems to be a curative option for elderly patients unfit for radical surgery compared with palliative care and may contribute to improved survival in these patients.
Despite proven efficacy, antimuscarinics are not frequently used for treating lower urinary tract symptoms in adult men, due to the perception of an increased risk of acute urinary retention (AUR). ...Men treated with α-blockers, 5α-reductase inhibitors, or their combinations have lower AUR incidence rates than the general symptomatic population. In the selected study population in this review (men with post-void residuals ≤200 mL), the risk of AUR with antimuscarinics with and/or without α-blockers may be increased during short-term treatment, but if patients do not develop AUR in the first 3 months, their subsequent risk is lower than in the untreated, symptomatic population.
Objectives
To compare the oncological outcomes of percutaneous cryoablation (PCA) vs robot‐assisted partial nephrectomy (RAPN) for the treatment of T1 renal tumours.
Patients and Methods
We conducted ...a retrospective study in all patients treated by RAPN or PCA for malignant renal tumours in one of four centres between 2009 and 2016. Tumours were paired one by one using radiological tumour stage and RENAL nephrometry score (package matchit, R software version 3.2.2). Malignancy was confirmed by biopsy for all patients in the PCA group. Patient characteristics before and after matching and oncological results were compared between the two groups. Cox regression, adjusted for age, treatment type, histological type and margins, was used to identify factors associated with time to local recurrence. Positive margins were defined histologically in the RAPN group and radiologically in the PCA group.
Results
A total of 647 patients were identified; 470 underwent RAPN and 177 underwent PCA. After matching, there was no significant difference between the two groups (RAPN, n = 177; PCA, n = 177) with regard to tumour stage, RENAL nephrometry score, tumour size (27.6 vs 25.9 mm; P = 0.07) and gender ratio. Patients in the PCA group remained significantly older (69.9 vs 59.8 years; P < 0.001). The absolute recurrence rate was 2.8% in the RAPN group vs 8.4% in the PCA group (P = 0.03). The 5‐year recurrence‐free survival rate was 85% in the PCA group vs 95% in the RAPN group (log‐rank P = 0.02). In multivariate analysis, the presence of positive margins and the type of treatment were the two factors significantly associated with local recurrence (P < 0.001 and P = 0.046, respectively).
Conclusion
The local recurrence rate after PCA was significantly higher than after RAPN for T1 renal tumours. Incomplete treatment was the main criterion associated with recurrence. The recurrence rate may have been overestimated in the PCA group because of closer radiological follow‐up in these patients.
The establishment and maintenance of anti-tumor immune responses are the objectives of cancer immunotherapy. Despite recent promising advances, the effectiveness of these approaches has been limited ...by the multiple immunosuppressive mechanisms developed by tumors (checkpoint). The aim of the present study was to demonstrate intratumor heterogeneity at the levels of immune escape strategies and tumor-host relationships. We focused on well-known checkpoints such as PD1/PDL1 and on a new checkpoint involving HLA-G and its receptors ILT2/ILT4. A prospective study was performed on 19 renal-cell carcinoma patients that were included during hospitalization for surgical tumor resection. Different areas of the tumor were collected for each patient and subjected to both immunohistochemical and flow cytometry analysis. Immune cells from peripheral blood were concomitantly analyzed for each patient. Our results show the heterogeneous expression of PD1/PDL1 and HLA-G/ILT in the various areas of the same tumor. Intratumor heterogeneity was found both at tumor cell and infiltrating immune cell levels. From a clinical point of view, this work highlights the functional redundancies of checkpoints and the need to adapt personalized poly-immunotherapy.
Purpose
to assess the respective outcomes of patients with localized muscle-invasive bladder cancer (MIBC) treated by either radical cystectomy (RC) or trimodal treatment (TMT) depending on ...pathological response to previous neoadjuvant chemotherapy (NAC) assessed on cystectomy specimen or post-NAC transurethral resection (TURB) specimen, respectively.
Patient and methods
We retrospectively included all consecutive patients treated in one academic center with cisplatin-based NAC followed by RC or TMT for cT2-3N0M0 MIBC between 2014 and 2021. Primary endpoint was metastasis-free survival (MFS) in both treatment groups and according to pathological response to NAC. Local recurrence-free survival and conservative management failure (metastasis-free bladder-intact survival) for patients treated with TMT were assessed.
Results
104 patients were included, 26 treated with TMT and 78 with RC. The rate of complete pathological response was 47.4% in patients treated with RC (ypT0) and 66.7% in patients treated with TMT (ycT0). Median follow-up was 34.9 months. Four-year MFS was 72% in both treatment groups. Four-year MFS was 85% in both ypT0 RC patients and ycT0 TMT patients. ycT0 stage was associated with low rates of intravesical recurrence and conservative management failure.
Conclusion
Patients with post-NAC ycT0 stage treated with TMT have favorable oncological outcomes similar to those of ypT0 patients treated with RC. Assessment of complete histological response with TURB after NAC may help in selecting the best candidates for bladder preservation with TMT.
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