Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

[A real-world study of the clinical application of the Paris system for reporting urinary cytology in cancer hospital].

Objectives: To evaluate the clinical value of the Paris system for reporting urinary cytology (TPS) in the diagnosis of urothelial carcinoma (UC). Methods: A total of 1 744 cytological diagnostic records (from 751 cases) were collected retrospectively. All specimens were voided urines and histopathology as the gold standard. The sensitivity and specificity of urinary cytological diagnosis of UC and risk of high grade malignant (ROHM) in each diagnostic category were compared. Results: There were 360 cases with histopathology. The percentage of negative for high-grade urothelial carcinoma (NHGUC) was 30.1% (226/751), atypical urothelial cells (AUC) was 29.8% (224/751), suspicious for high-grade urothelial carcinoma (SHGUC) was 16.8% (126/751), high grade urothelial carcinoma (HGUC) was 21.2% (159/751), and non-urothelial malignancy (NUM) was 2.1% (16/751). The histpathologic ROHM corresponding to each cytological diagnosis category were 27.3% for NHGUC, 32.7% for AUC, 74.7% for SHGUC, 96.6% for HGUC and 100.0% for NUM, respectively. ROHM of SHGUC was significantly higher than that of AUC group, and the difference between the two groups was statistically significant (P＜0.001). ROHM of HGUC group was significantly higher than that of SHGUC group, and the difference was statistically significant (P＜0.001). With SHGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 76.7% (165/215) and 85.7% (18/21), and with HGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 53.0% (114/215) and 100.0% (21/21), respectively. Conclusions: Urine cytology has high sensitivity and specificity in the diagnosis of HGUC. The malignant risk of TPS varies with different diagnosis category. The high malignant risk population in cancer hospital leads to the relatively high malignant proportion and ROHM in each diagnosis category. Urinary cytology TPS reporting system is helpful to clinical management and has good clinical application value.

[Application value of domestic single-port robot in nephron sparing surgery].

Objective: To explore the application value of the domestic precision ®single-port robotic system in nephron sparing surgery. Methods: The clinical data of patients with renal masses underwent nephron sparing surgery using the domestic precision ®single-port robotic system at the PLA General Hospital, Gulou Hospital Affiliated to Nanjing University School of Medicine, Zhongnan Hospital of Wuhan University and the First Affiliated Hospital of Nanchang University from September to November 2023 were retrospectively included. Perioperative clinical data, pathological examination results, and postoperative complications were summarized. Results: A total of 12 patients were included, including 8 males and 4 females, with 26-75 (56±16) years. Body mass index (BMI) was (25.1±2.7) kg/m2. There were 6 cases on the left side and 6 case on the right side. The surgical approach was transabdominal in 9 cases and retroperitoneal in 3 case. The maximum diameter of the lesions was (2.7±0.7) cm, the warm ischemia time [M (Q1, Q3)] was 19 (15, 26) minutes, the surgical time was 180 (149, 216) minutes, and the intraoperative blood loss was 50 (28, 100) ml. Postoperative visual analogue scale (VAS) was (2.9±1.5) points. Postoperative pathology revealed malignant renal clear cell carcinoma in 9 cases, with nuclear grading of 3 cases for Grade 1, 3 cases for Grade 2, and 3 cases for Grade 3. Eight cases of pathological TNM staging were pT1aN0M0 and 1 case was pT3aN0M0, with no cancer at the resection margin. Three cases showed benign renal vascular smooth muscle lipoma. There were no postoperative blood transfusions and no complications such as fever, urine leakage and poor wound healing. Conclusion: The prliminary experience reveals that the domestic precision ®single-port laparoscopic robotic system has good clinical application value in urological nephron sparing surgery.

[Emerging and comparative genomic analysis of a novel plasmid carrying blaKPC-2 in Citrobacter freundii].

Objective: To explore the drug resistance mechanism and gene structure characteristics of a carbapenemase-producing novel incompatibility group plasmid pNY2385-KPC from Citrobacter freundii. Methods: A multi-drug resistant strain was obtained from urine samples of patients with fever in the emergency ward of Li Huili Hospital, Ningbo Medical Center. Bacterial species was preliminary identified and finally confirmed by 16S rRNA gene amplification and the average nucleotide identity alignment, respectively. The minimum inhibitory concentrations of the antimicrobial agents were determined by VITEK 2 Compact System. The complete genome sequence was obtained by "third-generation" sequencing methods, and then detailed annotation of gene function and comparative genomic analysis of plasmid structure were carried out by BLASTP/BLASTN, RefSeq, ConservedDomains, ResFinder, Isfinder, etc. Results: The pNY2385-KPC carried by citrobacter freundii NY2385 belonged a novel incompatibility group, and contained blaKPC-2 and conjugative transfer (type Ⅳ secretory system, T4SS) genes, which could induce conjugative transfer. A total of 15 plasmids of the same type as pNY2385-KPC were retrieved by NCBI, which were from Citrobacter freundii, and the rest were from Serratia marcescens, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Raoultella planticola and other bacteria, and were broad-host-range plasmids. The sequence comparative analysis of all 6 of the novel plasmid from Citrobacter freundii showed that the structure of the novel plasmid had certain conserved property, with Tn6296 variant structure carrying blaKPC-2, and plasmid pCF1807-3 had both repApNY2385-KPC and repAIncX8. Conclusion: The pNY2385-KPC type plasmids in Citrobacter freundii carried blaKPC-2 resistance gene, which were divided into two subtypes: repApNY2385-KPC single replicator and repApNY2385-KPC/repAIncX8 complex replicator, belonging to broad-host-range plasmids. And as a mobile genetic element, the plasmids promote the spread of blaKPC-2.

[Tumor cell-based glycolytic metabolism and single-cell sequencing of urinary exfoliated cells for the diagnosis and molecular profiling of urothelial carcinoma].

Objective: To explore the diagnostic values of HK2 testing and single-cell sequencing in the urothelial carcinoma (UC). Methods: The qualified urine specimens of 265 suspected UC patients or postoperative patients from the Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China were collected. Both exfoliative cytology and HK2 testing were performed on clinically suspected UC or postoperative patients. The performance of diagnostic cytology and HK2, including consistency, sensitivity, specificity, positive predictive value and negative predictive value, was evaluated based on histopathological, clinical and imaging diagnosis. Isolated HK2 metabolically abnormal cells were subject to single-cell sequencing to verify the reliability of HK2 detection performance and to explore the molecular characteristics of UC. Results: The concordance rate of HK2 testing and cytology for detecting UC was 90.3% (102/113, Kappa=0.604). Compared with cytology, the sensitivity of HK2 was significantly higher (85.2% versus 75.6%, P=0.024). The detection sensitivity of combined HK2 testing and cytology was increased to 91.1%. HK2 testing was significantly more sensitive than cytology for diagnosing UC in the upper urinary tract (81.8% versus 65.5%, P=0.022). It was also more sensitive than cytology for diagnosing early-stage UC (82.6% versus 69.5%, P=0.375) and low-grade UC (69.6% versus 47.8%, P=0.125). Single-cell sequencing of the ten patients, whose samples were positive for HK2, demonstrated highly concordant copy number variations (CNVs) in tumor cells from the same UC patient, with heterogeneity in CNV profiles among different patients. Deletion of chromosome 8p was found in 3 of the 4 urine samples of renal pelvis UC. The 2 patients with benign lesions had no CNVs in all sequenced cells. Conclusions: The test for abnormal urinary glycolytic HK2 metabolism can assist urine cytology to improve the sensitivity of UC diagnosis, and it provides a novel and reliable approach for early detection of upper urinary tract UC and lower grade UC. Meanwhile, this study has preliminarily revealed the feasibility of single-cell sequencing in urinary samples, which is expected to improve the diagnostic specificity of HK2 testing.

[Exploration and thinking on functional preservation after orthotopic neobladder construction].

The concept of functional preservation after orthotopic neobladder construction has gradually attracted attention. Reconstruction of urine storage and voiding is the basic function preservation of orthotopic neobladder. Clinical exploration mainly focuses on the optimization of neobladder reconstruction methods and procedures, and there is still a lack of summary of existing surgical characteristics and high-quality functional comparative studies. For strictly selected patients, on the basis of tumor control and standardized postoperative rehabilitation guidance, most patients with preserved nerve can retain satisfied sexual function after surgery. The protection of neurovascular bundle and ancillary structures combined with postoperative exercise is crucial to the improvement of urinary continence. According to the characteristics of patients, choosing the appropriate urinary diversion methods and function preserving can help patients establish a normal life style after surgery and improve their self-image and quality of life.

[Clinical study of brush liquid-based cytology combined with automatic immunohistochemistry in the classification and diagnosis of lung cancer].

Objective: To explore the feasibility of bronchoscopic brushing liquid-based slide cytology combined with automatic immunocytochemistry (ICC) for pathological typing of lung cancer. Methods: A liquid-based thin-prep was prepared from 171 bronchoscopic brushing specimens of patients with pulmonary lesions. ICC was detected by automatic immunohistochemistry instrument while cytomorphological diagnosis was made. The results were compared with those of histopathological diagnosis. Results: Among 171 patients, 130 (76.0%) could be classified by cell morphology alone, including 31 squamous cell carcinomas, 44 adenocarcinomas and 55 small cell carcinomas; 162 (94.7%) could be classified by cell morphology combined with ICC, including 38 squamous cell carcinomas, 61 adenocarcinomas and 63 small cell carcinomas (P<0.001). According to the gold standard of histopathological diagnosis, the coincidence rate of cytomorphology combined with ICC was higher than that of cell morphology alone. The coincidence rate of squamous cell carcinoma was increased from 85.2% to 97.1% (P=0.093), adenocarcinoma from 92.5% to 98.0% (P<0.001), and small cell carcinoma from 96.1% to 98.3% (P=0.465). Conclusion: The combination of liquid-based thin-prep cytology and automatic immunohistochemistry can effectively improve the accuracy of pathological typing of brushing specimens under fiberoptic bronchoscopy, and provide more objective diagnostic results for clinical treatment.

[The application of conventional smears and liquid-based cytologic slides of lymphatic metastasis specimens of lung adenocarcinoma acquired by fine needle aspiration to detect the expression of anaplastic lymphoma kinase protein].

Objective: To explore the feasibility of conventional smears and liquid-based cytologic slides of lymphatic metastasis specimens of lung adenocarcinoma acquired by fine needle aspiration cytology (FNAC) to detect the expression of anaplastic lymphoma kinase (ALK/D5F3) by immunocytochemistry (ICC) analysis. Methods: The lymphatic metastasis specimens of 147 lung adenocarcinoma, including 100 liquid-based cytologic slides and 47 conventional smears, were collected in this study. ALK fusion protein was detected by Roche Ventana ICC technology, which was compared with the ALK fusion gene assessed by fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR). Results: The positive rate of ALK (D5F3) fusion protein in advanced lung adenocarcinoma acquired by FNAC was 11.6% (17/147), and 10.6% (5/47) and 12.0% (12/100) were reached in conventional smears and liquid-based cytologic slides, respectively.Among 147 cases, 57 cases including 17 positive cases and 40 negative cases were verified by RT-PCR and FISH. The whole coincidence rate reached 96.5% (55/57). The sensitivity and specificity of ALK (D5F3) fusion protein detected in lung adenocarcinoma acquired by FNAC were 94.1% (16/17) and 97.5% (39/40), respectively. The sensitivity and specificity were both 100% (5/5 of sensitivity and 10/10 of specificity) in conventional smears, while 91.7% (11/12) and 96.7% (29/30) in liquid-based cytologic slides. Conclusion: Conventional smears and liquid-based cytologic slides of FNAC samples can be used to perform ICC analysis of ALK (D5F3) expression in advanced lung adenocarcinoma, especially for patients who have no opportunity for surgery or whose resected samples are difficult to form cell block.

[Clinical features of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions-single-center study].

Objective: To analyze the clinical characteristics, treatment methods and prognosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 tRCC). Methods: From January 2007 to February 2018, 48 patients were diagnosed with Xp11.2 tRCC at Nanjing Drum Tower Hospital. The epidemiological features, treatment methods and long-term follow-up results were retrospectively reviewed. Results: Of the 48 patients, 20 cases were female and 28 cases were male, aged from 2 to 72 years. Gross hematuria and flank pain were the most frequent symptoms, which occurred on 14 cases and 8 cases respectively. The mean tumor size of 48 cases was (5.3±2.5)cm. Among the 34 cases who were classified as stageⅠ/Ⅱ, 14 cases received laparoscopic nephron-sparing surgery(NSS)and 20 cases received radical nephrectomy(RN). The other 14 cases who were classified as stage Ⅲ/Ⅳ received RN but one case received target therapy. On univariate analysis, tumor diameter, adjuvant treatment, AJCC stage, lymph node metastasis and vein tumor thrombosis showed association with progression-free survival (PFS) and overall survival (OS) (P<0.05). Multivariate analysis indicated that AJCC stage (P=0.023, 95% CI: 0.048-0.081)and vein tumor thrombosis (P=0.046, 95% CI: 1.004-1.590)were independent prognostic factors of PFS. Conclusions: Xp11.2 tRCC mainly occurs in females. RN was the major method for Xp11.2 tRCC. However, NSS can also receive satisficed results for stage T1a case. High AJCC stage and the occurrence of vein tumor thrombosis indicated poor prognosis.