[Objective] To explore the expression of Nectin-4 in invasive bladder urothelial carcinoma (BUC) tissue and its clinical significance, so as to provide reference for clinical diagnosis and treatment of BUC. [Methods] Nectin-4 expression in 60 cases of invasive BUC and 40 cases of chronic inflammation of bladder mucosa was detected with immunohistochemical staining (IHC) and RNAscope.The results of the two methods were analyzed and compared, and the relationship between the two methods and the clinicopathological characteristics of invasive BUC was discussed.The correlation between the protein expression of Nectin-4 in BUC tissues, human epidermal growth factor receptor 2 (Her-2) and programmed death factor ligand 1 (PD-L1) was analyzed. [Results] The positive protein expression rates of Nectin-4 detected by IHC were 78.33%(47/60) and 17.50% (7/40) in the invasive BUC group and inflammatory group, respectively, while the positive mRNA expression rates of Nectin-4 detected by RNAscope were 83.33% (50/60) and 12.50% (5/40), respectively.The Kappa values of Nectin-4 in the invasive BUC group and inflammatory group were 0.732 and 0.610, respectively, with general consistency.The protein expression of Nectin-4 in invasive BUC was correlated with muscular invasion, histological grade, vascular thrombus, lymph node metastasis and clinical stage (P<0.05). The mRNA expression of Nectin-4 in invasive BUC was correlated with max tumor diameter, muscular invasion, histological grade, vascular thrombus, lymph node metastasis and clinical stage (P<0.05). The high expression of Nectin-4 in invasive BUC was positively correlated with the expression of Her-2 (P=0.002), but not with the expression of PD-L1 (P>0.05). [Conclusion] Nectin-4 is highly expressed in invasive BUC, and is usually associated with the pathological parameters of poor prognosis.Detection of Nectin-4 expression will help to guide clinical diagnosis and treatment.

To improve the understanding of clinicians on the diagnostic criteria and treatment principlis of pulmonary alveolar proteinosis(PAP),which is a rare respiratory disease.European Respiratory Society published the first edition guidelines for PAP,including a systematic review of the literature and the application of the grading of recommendations,assessment,development and evaluation(GRADE)approach to assess the certainty of evidence and the strength of recommendations.Five questions of patient,intervention,comparison,outcome(PICO)and two narrative questions were developed.Recommendations and evidence-based evidence were given,including management of PAP,whole lung lavage,granulocyte-macrophage colony-stimulating factor(GM-CSF)therapy,rituximab,plasma exchange,and lung transplantation.In addition,recommendations were given for the use of GM-CSF antibody testing,bronchoalveolar lavage,and lung biopsy.This study is to interpret the main content of the guideline.

Objective:To investigate the clinical features and therapeutic efficacy of patients with hereditary leiomyomatosis and renal cell carcinoma(RCC) syndrome-associated RCC (HLRCC-RCC) in China.Methods:The clinical data of 119 HLRCC-RCC patients with fumarate hydratase (FH) germline mutation confirmed by genetic diagnosis from 15 medical centers nationwide from January 2008 to December 2021 were retrospectively analyzed. Among them, 73 were male and 46 were female. The median age was 38(13, 74) years. The median tumor diameter was 6.5 (1.0, 20.5) cm. There were 38 cases (31.9%) in stage Ⅰ-Ⅱand 81 cases (68.1%) in stage Ⅲ-Ⅳ. In this group, only 11 of 119 HLRCC-RCC patients presented with skin smooth muscle tumors, and 44 of 46 female HLRCC-RCC patients had a history of uterine fibroids. The pathological characteristics, treatment methods, prognosis and survival of the patients were summarized.Results:A total of 86 patients underwent surgical treatment, including 70 cases of radical nephrectomy, 5 cases of partial nephrectomy, and 11 cases of reductive nephrectomy. The other 33 patients with newly diagnosed metastasis underwent renal puncture biopsy. The results of genetic testing showed that 94 patients had FH gene point mutation, 18 had FH gene insertion/deletion mutation, 4 had FH gene splicing mutation, 2 had FH gene large fragment deletion and 1 had FH gene copy number mutation. Immunohistochemical staining showed strong 2-succinocysteine (2-SC) positive and FH negative in 113 patients. A total of 102 patients received systematic treatment, including 44 newly diagnosed patients with metastasis and 58 patients with postoperative metastasis. Among them, 33 patients were treated with tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI), 8 patients were treated with bevacizumab combined with erlotinib, and 61 patients were treated with TKI monotherapy. Survival analysis showed that the median progression-free survival (PFS) of TKI combined with ICI was 18 (5, 38) months, and the median overall survival (OS) was not reached. The median PFS and OS were 12 (5, 14) months and 30 (10, 32) months in the bevacizumab combined with erlotinib treatment group, respectively. The median PFS and OS were 10 (3, 64) months and 44 (10, 74) months in the TKI monotherapy group, respectively. PFS ( P=0.009) and OS ( P=0.006) in TKI combined with ICI group were better than those in bevacizumab combined with erlotinib group. The median PFS ( P=0.003) and median OS ( P=0.028) in TKI combined with ICI group were better than those in TKI monotherapy group. Conclusions:HLRCC-RCC is rare but has a high degree of malignancy, poor prognosis and familial genetic characteristics. Immunohistochemical staining with strong positive 2-SC and negative FH can provide an important basis for clinical diagnosis. Genetic detection of FH gene germ line mutation can confirm the diagnosis. The preliminary study results confirmed that TKI combined with ICI had a good clinical effect, but it needs to be confirmed by the results of a large sample multi-center randomized controlled clinical study.

Objective:To investigate the efficacy of different treatment modes for locoregional recurrence after nephrectomy in patients with renal cell carcinoma.Methods:A total of 106 patients with locoregional recurrence after nephrectomy without distant metastasis (77 males and 29 females) admitted to Sun Yat-sen University Cancer Center from October 2001 to July 2020 were retrospectively analyzed. The median age was 51 (40, 60) years old. Radical nephrectomy was performed in 90 patients with primary tumor and partial nephrectomy was performed in 16 patients. Pathological diagnosis showed that 54 cases were clear cell carcinoma and 52 cases were non-clear cell carcinoma. 53 cases were in stage T 1-2 and 53 cases in stage T 3-4. The median diameter of recurrent lesions was 3.2 (2.0, 6.3) cm, and the median number was 2 (1, 4). The recurrence sites were divided into renal fossa recurrence (33 cases), renal fossa±retroperitoneal lymph node recurrence (38 cases), and intra-abdominal spread (35 cases). The median duration from primary surgery to local recurrence was 14.8 (7.3, 35.8) months. Two treatment groups were identified as systemic therapy alone (Group A) and local therapy with or without systemic therapy (Group B). The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) between Group A and Group B. The Cox model was used to perform univariate and multivariate analysis. Results:Of all the 106 patients, 33 patients were in Group A and 73 patients were in Group B. In Group A, 29 patients (87.9%) received targeted therapy, and 4 patients (12.1%) received targeted therapy combined with immunotherapy. In Group B, 34 patients (46.6%) received surgery or ablation and 39 patients (53.4%) received SBRT, of which 62 patients (84.9%) received concurrent systemic therapy. Among them, 58 patients (93.5%) received targeted therapy, and 4 patients (6.5%) received targeted therapy combined with immunotherapy. The median follow-up period was 29.0 (15.4, 45.9) months, 64 patients progressed on tumor including 28 patients died. The median PFS and OS were 15.6 (7.1, 35.2) months and 66.9 (37.8, not reached) months. The median PFS of Group A and Group B were 7.6(5.0, 17.2)months and 22.2(9.6, 63.9)months respectively ( P=0.001), median OS of Group A and Group B were 45.7 (23.4, 62.8)months and 71.0(50.6, not reached)months respectively, and the 2-year OS were 70.6% and 85.5% in Group A and Group B respectively ( P=0.023). The univariate analysis showed local therapy with or without systemic therapy was significantly reduced 56% risk of tumor progression ( HR=0.44, P=0.003) and reduced 60% risk of death ( HR=0.40, P=0.028). The multivariate analysis showed that the OS was associated with ECOG score( HR=10.20, 95% CI 4.13-25.30, P<0.001)and local therapy( HR=0.23, 95% CI 0.09-0.58, P=0.002). Conclusion:Compared with systemic therapy alone, local therapy with or without systemic therapy can effectively improve the PFS and OS of patients with locoregional recurrence after nephrectomy.

Objective:To evaluate the efficacy of first-line tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors (ICI) in metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC).Methods:The data of 87 metastatic FH-deficient RCC patients from West China Hospital ( n=44), Renji Hospital ( n=27) and Sun Yat-sen University Cancer Center (n=16) from Mar 2019 to Aug 2022 were retrospectively analyzed. The median age was 37(30, 47) years, the male to female ratio was 1.9∶1. The median size of tumor was 7.5(5.0, 10.0) cm. Sixty-one patients (70.1%) had germline FH mutations, and 26 patients (29.9%) had somatic FH mutations. Forty-nine patients (56.3%) metastasis disease at initial diagnosis, and 38 patients (43.7%) had metachronous metastasis. The most common site of metastasis was lymph node (41/87, 47.1%), followed by bone (33/87, 37.9%), liver (22/87, 25.3%), and lung (14/87, 16.1%). Fifteen patients (17.2%) had weak expression of FH protein and 59 patients (67.8%) had positive PD-L1 expression. The most common treatments were sintilimab plus axitinib (52/87, 59.8%), followed by pembrolizumab plus cabozantinib (7/87, 8.0%), tirelizumab plus axitinib (6/87, 6.9%), pembrolizumab plus axitinib (5/87, 5.7%), and toripalimab plus axitinib (4/87, 4.6%). Thirteen patients (13/87, 14.9%) received other ICI plus TKI combination treatments. Statistical analysis was conducted using R 4.2.3 software. Kaplan Meier survival curve was used to evaluate survival data, and log-rank test was used to compare differences between treatment groups. Results:The overall objective response rate (ORR) and disease control rate (DCR) of first-line TKI + ICI were 39.1% and 89.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 16.5 months and 71.0 months, respectively. For first-line sintilimab plus axitinib, the ORR and DCR were 44.2% and 92.3%, respectively. The median PFS was 17.3 months and the median OS was not reached for this combination treatment. The efficacy of first-line tirelizumab plus axitinib was inferior to other treatment strategies (median PFS: 4.0 vs. 16.6 months, P<0.001; median OS: 22.0 vs. 71.0 months, P=0.043). Subgroup analyses further showed that the efficacy of ICI+ TKI combination therapy was consistent in patients with different clinicopathologic and genomic features. However, patients with liver metastasis had shorter OS than those without liver metastasis (median OS: 26.3 vs. 71.0 months, P=0.021). Conclusion:First-line TKI + ICI is effective for metastatic FH-deficient RCC and can significantly prolong the survival of the patients.

Objective: To report the experience on the multi-disciplinary management of metastatic renal cell (mRCC) patients in a single center. Methods: Data of 168 mRCC patients treated by multi-disciplinary team (MDT) at Sun Yat-sen University Cancer Center from December 2007 to February 2019 was retrospectively analyzed.Three treatment groups were identified, including 76 patients with 55 males and 21 females, received anti-angiogenic agents alone (Group A), 66 patients with 55 males and 11 males, received anti-angiogenic agents plus local therapy (Group B)and 26 patients, with 19 males and 7 females, received anti-angiogenic agents plus immunotherapy and local therapy (Group C). The Sunitinib, Sorafenib, Axitinib were chosen for the TKI. The Pembrolizumab was used for immunotherapy. The stereotactic body radiation therapy and surgical excision were considered as the local therapy. The study aims to compare the age, gender, IMDC score, pathology, nbephrectomy, adverse events, progression-free survival and overall survival (OS). Results: Of all patients, the median follow-up duration was 23 months (ranging 6-117 cmonths). The PFS was 18.3 months and median OS was 33.5 months. The 2 years and 5 years survival rate was 66% and 35%, respectively. The median OS of Group A, B and C were 29.8 months, 44.6 months and not reached. 2y-OS was 58%, 67% and 89%, while 5y-OS 12%, 46% and 57%.There was no difference in age, gender, IMDC score, pathology, synchronous metastases or nephterectomy between the three groups. The prognostic result in TKI based combination therapy was superior to TKI therapy alone, which the 5y-OS was 51% and 11%, respectively. The prognostic result in group C's moderate-high risk mRCC patients was superior to group A and B. The median OS in TKI+ DC and CIK+ Pembrolizumab was 49.1 months and 53.1 months. On univariate analyses, IMDC score, nephrectomy and treatment group was associated with OS (P<0.05). On multivariate analyses, treatment group, nephrectomy was associated with OS (P<0.05). The risk of death of Group C decreased about 60% [HR 0.39 (0.17, 0.89), P=0.026]. 78 (46.4%) patients on TKI alone and 16 (61.5%) patients treated with TKI plus immunotherapy had Grade 3 or 4 adverse events. 16 (20.3%) patients had Clavien Ⅲ-Ⅳ toxicity after surgical procedures. 6 (5.7%) patients had Grade 3 toxiciy after SBRT. Conclusions Patients treated with combined therapy had better survival than those treated with anti-angiogenic agents alone. MDT approach could bring survival benefit to mRCC patients.

Objective:To evaluate the preliminary clinical efficacy and safety of stereotactic body radiation therapy (SBRT) in combination with targeted therapy for metastatic renal cell carcinoma (mRCC).Methods:Clinical data of 58 patients with mRCC who were treated with SBRT in combination with targeted therapy in Sun Yat-sen University Cancer Center from June 2013 to December 2018 were retrospectively analyzed. Among them, 79.3% patients were classified as intermediate or high risk according to International Metastatic Renal Cell Carcinoma Database Consortium Criteria. The median biologically equivalent dose (BED) was 147 Gy (67 to 238 Gy).Results:Overall, 32, 13, 7, 5 and 1 patients received SBRT for 1, 2, 3, 4 and 6 metastatic sites (105 lesions) and 71.4% of them were bone lesions. Targeted therapy was continued during SBRT. With a median follow-up of 9.4 months (range 2.7 to 40.1 months), 18 patients died. The 1-year local control rate was 97.4%. The 1-year progression-free survival was 50.3%. The 1-and 2-year overall survival was 72% and 53%. Approximately 85% patients experienced pain relief after SBRT. Patients who achieved complete or partial response after SBRT obtained better overall survival than those with stable disease or disease progression (1-year overall survival: 83% vs. 48%, P=0.021). In the whole cohort, 6 cases developed Grade Ⅲ adverse events, 4 of which were Grade Ⅲ myelosuppression, 1 case of Grade Ⅲ neuropathy and 1 case of radiation-induced skin injury. Conclusion:Preliminary study reveals that combined use of targeted therapy and SBRT is an efficacious and safe treatment of advanced mRCC.

Objective To investigate and analysis the epidemiological characteristics of a cluster epidemic of COIVD-19 in a collective workplace in Tianjin, evduate the prevention and control measures based on limited evidence and experience in early period of COVID-19 epidemic. Methods Descriptive research method was used to describe the distribution and other epidemiological characteristics of the cluster cases of COVID-19. Results Since the onset of the first index case on January 15, ten confirmed COVID-19 cases had occurred in the workplace, and the epidemic had spread from the workplace to 4 families, infecting 7 family members. The median age of 17 cases was 55 (19-79) years. All the 10 employee cases were males, and in 7 family cases, 3 were males and 4 were females. Of the employee cases, 8 worked in CW workshop and 2 worked in administrative office building. The median exposure-onset interval of all the cases was 4 (0-12) days, and the median exposure-onset interval was 4.5 days in the employee cases and 4 days in the family cases. The median onset-medical care seeking interval was 4 days in the non-isolated cases, 2.5 days in the cases with home isolation after onset, and 0.5 day in the cases with home isolation before onset. Conclusion The clustering of COVID-19 cases was observed in this workplace in Tianjin, which affected 4 families. In the early stage of the epidemic, accurate and rapid blocking and control measures can completely prevent the large-scale spread of COVID-19.

Objective:To evaluate the efficacy and safety of Tyrosine Kinase Inhibitors (TKIs) combined with stereotactic body radiation therapy(SBRT) in the treatment of renal cell carcinoma (RCC) patients with bone metastasis.Methods:The clinical data of 80 RCC patients with bone metastasis in Sun Yat-sen University Cancer Center from April 2010 to April 2020 were analyzed retrospectively. Among them, 64 patients were medium or high risk according to the International Metastatic Renal Cell Carcinoma Database Consortium(IMDC) score. Twenty-four patients received TKI therapy alone(Group A), and the other 56 cases received TKIs combined with SBRT to bone metastastic lesions (Group B).Results:The median follow-up period was 20.7 months (4.8-115.6 months), 70 patients received second or third-line targeted drug therapy, and 4 patients in group A and 15 patients in group B received TKI plus immunotherapy. Fifty-four patients had symptoms of bone pain before radiotherapy, 46 patients were satisfied with the analgesic effect after SBRT treatment. Twelve patients got complete response (CR) after bone lesions, and 32 patients achieved partial response (PR). Forty patients died of disease progression during follow-up. The median OS was: 20.7 months vs not reached(Group A vs. Group B), and the 2-y OS and 5-y OS were 50% vs. 62%, and 19% vs. 56%, respectively ( P=0.006). There were only 2 patients (3.6%) had grade 3 SBRT related adverse events. Conclusions:SBRT combined with TKIs improved the quality of life and prolonged the overall survival of RCC patients with bone metastasis.

Objective:To evaluate the efficacy and safety of switch from prednisone (AA+ P) to dexamethasone (AA+ D) in metastatic castration-resistant prostate cancer patients (mCRPC) progressing on abiraterone plus prednisone.Methods:Between November 2016 and December 2019, 46 mCRPC patients were switched to AA+ D after progression on AA+ P at Sun Yet-sen University Cancer center. Median age was 72 years(50 to 89 years), with median androgen deprivation therapy (ADT) duration 14.6 months(2.1 to 168.5 months). PSA level at the time of diagnosis, the initiation of AA+ P treatment, the time of switch were 258.9 ng/ml, 56.6 ng/ml, 25.1 ng/ml, respectively. 42 (91.3%), 12(26.1%), 7(15.2%) patients had bone metastasis, lymph node metastasis, visceral metastasis, respectively. 28 patients had Gleason score ≥8, and 11 patients had Gleason score<8. The primary endpoint was progression free-survival (PFS). Secondary endpoints included PSA response rate of PSA decline ≥50% and ≥30% and safety. Patients were divided into different risk level groups according to PSA level at the time of switch and PFS on AA+ P.Results:The median follow-up of 46 patients was 4.9 months, 40 patients progressed at the last follow-up, the treatment was terminated in 1 patient because of cerebral infarction, 5 patients were still on the treatment of AA+ D. Median PFS on AA+ D of 46 patients was 3.7 (1.6-24.1) months. A total of 12 (26.1%) patients showed a PSA decline≥50% after treatment with AA+ D, and 21 (45.7%) patients showed a PSA decline ≥30%. The median PFS was 8.5 (2.7-24.1) and 3.0 (1.6-17.8) months for patients with PSA decline≥50% and PSA didn’t decline ≥50%, respectively. Four factors below were significantly associated with a longer PFS on AA+ D after steroid switch in univariate analysis: lower PSA level at the time of switch (<30 ng/ml, HR=0.30, 95% CI 0.14-0.64, P=0.002), longer ADT sensitivity duration (≥18 months, HR=0.55, 95% CI 0.28-1.06, P=0.045), longer AA+ P treatment PFS (≥8 months, HR=0.36, 95% CI 0.18-0.72, P=0.004), and greater PSA decline on AA+ D (≥50%, HR=0.30, 95% CI 0.17-0.75, P=0.007). The above mentioned factors were also independent prognostic factors associated with better PFS on AA+ D after steroid switch in multivariate analysis. Treatment with AA+ D was well tolerated in all patients, with no grade 3/4 toxicity reported. Conclusions:Switching from prednisone to dexamethasone is effective and safe in mCRPC patients progressing on abiraterone plus prednisone. Patients with lower PSA level at the time of switch, longer ADT sensitivity duration, longer AA+ P treatment PFS and greater PSA decline on AA+ D might gain better efficacy.