Biomarkers guiding the neoadjuvant use of immune checkpoint inhibitors (ICBs) are needed for patients with localized muscle invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline, and the induction of tertiary lymphoid structures post-pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.
Long recognized to confer an extremely poor prognosis, sarcomatoid dedifferentiation of renal cell carcinoma (sRCC) is a tumor phenotype that is finally beginning to be better understood on the molecular and genetic levels. With an overall incidence that ranges from 1 to 32% depending on associated RCC subtype, the survival of sarcomatoid RCC patients rarely exceeds 2 years. The main reasons for its poor outcome include its aggressive biology, its tendency to present at an advanced or metastatic stage at the time of diagnosis, its high rate of tumor recurrence after nephrectomy, and its limited response to systemic therapies. Molecular pathology studies suggest that sarcomatoid dedifferentiation originates from a focal epithelial-mesenchymal transition (EMT) arising in the carcinomatous component of the tumor. It is hoped that the growing understanding of the molecular biology of sRCC will soon make it possible to adapt treatments based on the identification of actionable tumor alterations. The deliberate inclusion of these patients in the multicenter clinical trials of immune, targeted and combination therapies is a necessary next step in pioneering future treatment strategies.
contributed equally to this work and are equal first authors. J.-J.P. and B.E. contributed equally to this work and are equal senior authors. ObjectiveTo evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function. Patients and MethodsPatients with cT2aN0NxM0 clear-cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7-10 mg, was administered twice daily, for 2-6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib. ConclusionNeoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.
Introduction: Knowledge of the anatomy of the male pelvic floor is important to avoid damaging the pelvic floor muscles during surgery. We set out to explore the structure and innervation of the smooth muscle of the whole pelvic floor using male fetuses. Material and Methods: We removed en-bloc the entire pelvis of three male fetuses. The specimens were serially sectioned before being stained with Masson's trichrome and hematoxylin and eosin, and immunostained for smooth muscles, and somatic, adrenergic, sensory and nitrergic nerve fibers. Slides were digitized for 3D reconstruction. Accepted Article Results: We individualized a middle compartment that contains smooth muscle (SM) cells. This compartment is in close relation with the levator ani muscle (LAM), rectum, and urethra. We describe a posterior part of the middle compartment posterior to the rectal wall and an anterior part anterior to the rectal wall. The anterior part is split into 1) a centro-levator area of SM cells localized between the right and left LAM, 2) an endo-levator area that upholsters the internal aspect of the LAM, and 3) an infra-levator area below the LAM. All these areas are innervated by autonomic nerves coming from the inferior hypogastric plexus. The core and the infra-levator area receive the cavernous nerve and nerves supplying the urethra. Conclusion: We thus demonstrate that these muscular structures are smooth and under autonomic influence. These findings are relevant for the pelvic surgeon, and especially the urologist, during radical prostatectomy, abdominoperineal resection and intersphincteric resection.
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