e16511 Background: Currently, targeted agents and immunotherapy are applied to local-regional recurrent renal cell carcinoma (LRRCC). The combination with systemic therapy and stereotactic radiotherapy (SBRT) is worth exploring. In the present study, we aimed to investigate the efficacy and safety profile of sintilimab plus axitinib combined with SBRT in the treatment for LRRCC. Methods: This was a single-arm, phase II study enrolled LRRCC patients (pts), for whom the SBRT can be safety applied for all the recurrent lesions visible on imaging. Eligible pts received sintilimab (200mg, day 1) and axitinib (5mg, bid, day 1-21) in a 21d cycle. SBRT (35-45Gy/5 fractions) was performed before the third administration of sintilimab. The primary endpoint was progression-free survival (PFS). Results: From Oct 2021 to Jan 2024, 19 pts with a median age of 58 (range: 33-74) were enrolled. Among them, 9 (47.37%) pts had clear cell carcinoma. Nine (47.37%) pts were IMDC intermediate (7 pts) or high risk, and 8 (42.11%) pts recurred in less than 1 year after surgery. Seven(36.84%) pts received at least one prior systemic therapy. Four (21.05%) pts had recurrence in the renal fossa, while 3(15.79%) pts in retroperitoneal lymph node, 2(10.53%) pts in retroperitoneal lymph node with renal fossa and 10(52.63%) pts in intra-abdominal soft tissue. With a median follow-up of 9.5 months (range: 3.0-27.1m), 18 pts were evaluable for response. The median tumor volume was 37.47cc (range: 2.44-493.19cc). The overall response rate was 55.56% with 4 complete responses and 6 partial responses per RECIST v1.1. The median time-to-response was 5 months. The local control rate and the disease control rate were 100% and 94.44%, respectively. The median PFS was not reached, and the 9-month PFS rate was 94.44%. All 19 pts were evaluable for toxicity. Any-grade treatment-related adverse events (TRAEs) occurred in 16(84.21%) pts. The most common TRAEs were albuminuria (8/19; 42.11%), nausea (8/19; 42.11%), hypertension (7/19; 36.84%), and diarrhea (7/19; 36.84%). Grade 3 or higher TRAEs occurred in 6/19(31.58%). Conclusions: Sintilimab plus axitinib combined with SBRT showed promising antitumor activity and manageable toxicity in pts with LRRCC. Clinical trial information: ChiCTR2100049523 .
Purpose Recurrent renal cell carcinoma(reRCC) is associated with poor prognosis and the underlying mechanism is not yet clear. A comprehensive understanding of tumor microenvironment (TME) of reRCC may aid in designing effective anticancer therapies, including immunotherapies. Single-cell transcriptomics holds great promise for investigating the TME, however, this technique has not been used in reRCC. Here, we aimed to explore the difference in the TME and gene expression pattern between primary RCC (pRCC) and reRCC at single-cell level. Experimental design We performed single-cell RNA sequencing analyses of 32,073 cells from 2 pRCC, 2 reRCC, and 3 adjacent normal kidney samples. 41 pairs of pRCC and reRCC samples were collected as a validation cohort to assess differences observed in single-cell sequencing. The prognostic significance of related cells and markers were studied in 47 RCC patients underwent immunotherapy. The function of related cells and markers were validated via in vitro and in vivo experiments. Results reRCC had reduced CD8 + T cells but increased cancer-associated fibroblasts (CAFs) infiltration compared with pRCC. Reduced CD8 + T cells and increased CAFs infiltration were significantly associated with a worse response from immunotherapy. Remarkably, CAFs showed substantial expression of LGALS1 (Gal1). In vitro, CAFs could induce CD8 + T cells apoptosis via Gal1. In vivo, knockdown of Gal1 in CAFs suppressed tumor growth, increased CD8 + T cells infiltration, reduced the proportion of apoptotic CD8 + T cells and enhanced the efficacy of immunotherapy. Conclusions We delineated the heterogeneity of reRCC and highlighted an innovative mechanism that CAFs acted as a suppressor of CD8 + T cells via Gal1. Targeting Gal1 combined with anti-PD1 showed promising efficacy in treating RCC.
Background: Radical inguinal lymph node dissection (rILND) is the most available treatment to cure penile cancer (PC) with limited inguinal-confined disease. However, guidelines regarding acceptable boundaries of rILND are controversial, and consensus is lacking. We aimed to standardize the surgical boundaries of rILND with definite pathological evidence and explore the distribution pattern of inguinal lymph nodes (ILNs) in PC. Methods: A total of 414 PC patients from two centers who underwent rILND were enrolled. The ILN distribution was divided into seven zones anatomically for pathological examination. Student’s t test and Kaplan‒Meier survival analysis were used. Results: ILNs displayed a funnel-shaped distribution with high density in superior regions. ILNs and metastatic nodes present anywhere within the radical boundaries. Positive ILNs were mainly concentrated in zone I (51.7%) and zone II (41.3%), but there were 8.7 and 12.3% in inferior zones V and VI, respectively, and 7.1% in the deep ILNs. More importantly, a single positive ILN and first-station positive zone was detected in all seven regions. Single positive ILNs were located in zones I through VI in 40.4%, 23.6%, 6.7%, 18.0%, 4.5% and 1.1%, respectively, and 5.6% presented deep ILN metastasis directly. Conclusion: We established a detailed ILN distribution map and displayed lymphatic drainage patterns with definite pathological evidence using a large cohort of PC patients. Single positive ILNs and first-station metastatic zones were observed in any region, even directly with deep ILN metastasis. Only rILND can ensure tumor-free resection without the omission of positive nodes.
Radical/cytoreductive nephrectomy or nephron-sparing surgery may be thought to be not safe or unfeasible in some renal cell carcinoma (RCC) patients in which tumor is locally advanced or highly complicated. Neoadjuvant therapy may reduce the volume of the tumor, thus facilitates surgery. The aim the study is to evaluate the efficacy and safety of neoadjuvant combination of pazopanib or axitinib and PD-1-activated dendritic cell-cytokine-induced killer (PD-1/DC-CIK) cell immunotherapy in those patients.Data from 16 RCC patients who received neoadjuvant pazopanib (Group P, n=9) or axitinib (Group A, n=7) plus PD-1/DC-CIK cells immunotherapy were reviewed retrospectively. A total of 9 participants that were potential candidates for radical/cytoreductive nephrectomy (RN/CN) had locally advanced tumor and 5 participants with partial nephrectomy (PN) absolute indications had highly complicated tumors. The efficacy outcomes were based on volume changes of the primary tumor, lymph nodes, and tumor thrombus in 13 participants with complete computed tomography (CT) imaging. The treatment-related toxicities and surgical complications were also reported.With a median of 2.1 months treatment, the overall volume of the tumors decreased by a median of 42.30% [interquartile range (IQR): 19.37-66.78%]. Specifically, the median reduction of tumor volume was 88.77 and 15.50 cm3 in group P and group A, respectively (P=0.014). However, participants in Group P were more likely to experience grade 3 or 4 treatment-related adverse events (AEs) than those in Group A (44.4% vs. 0). Finally, all participants were candidates for appropriate surgery after neoadjuvant therapy (as assessed by the surgeon), and 10 participants accepted surgery, including 5 PN, 4 RN/CN, and 1 lymph node dissection. A solitary participant had Clavien grade IV acute renal failure required dialysis and another had grade II lymphatic leakage.Neoadjuvant combination of pazopanib or axitinib and PD-1/DC-CIK cells immunotherapy was well-tolerated and could effectively reduce the volume of tumors in locally advanced or highly complicated RCC patients.
Cystatin-C (Cys-C) has been studied as a valuable prognostic indicator in several malignancies. The goal of this study is to explore the expression and prognostic significance of Cys-C in clear cell renal cell carcinoma (CCRCC).Immunohistochemistry and western blot assays were performed to evaluate the level of Cys-C expression in CCRCC tissue. Expression levels of Cys-C in CCRCC tissue samples in relation to clinicopathological characteristics of the tumors were assessed. Their prognostic significance was analyzed by univariate and multivariate analyses. In addition, the expression of Cys-C in 786-O cell lines was inhibited by using CRISPR/Case9 and the effects of Cys-C knockout on 786-O cells in vitro were evaluated using MTT method, colony formation assay, cell cycle assay, and cell migration and invasive assay.The expression level of Cys-C was lower in CCRCC tissues (n = 253) than in paired adjacent non-cancerous tissues (n = 164) by immunohistochemistry (P < 0.001). Among the 253 patients, the results showed that patients with low Cys-C expression level in cancer tissue has longer overall survival (OS) than that with high Cys-C level. Furthermore, knockout of Cys-C in 786-O cell line has ability to suppress cell proliferation, induce G0/G1 phase arrest, inhibited cell invasion, decreased phosphorylation of ERK1/2, STAT-3 and enhanced phosphorylated JNK expression.A decrease in serum Cys-C is a favorable prognostic indicator for CCRCC patients. Inhibition of Cys-C suppressed RCC 786-O cell proliferation and invasion. These results indicated that Cys-C could serve as an ideal prognostic biomarker in patients with CCRCC.
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