[Several key and difficult issues related to the grading of urothelial carcinoma of urinary bladder].

Grading and staging are the most important prognostic factors for both non-invasive and invasive urothelial carcinomas, and are also one of the most common difficulties encountered by pathologists in the daily diagnostic practice of urothelial carcinoma. Recently, the International Society of Urological Pathology organized a survey and questionnaire conference on various issues related to the diagnosis, grading, and staging of urothelial carcinoma, and ultimately formed a series of consensus opinions. This article briefly summarizes the consensus opinions of this series, and combines them with the current pathological diagnosis status of urothelial carcinoma in China. It briefly comments on how to apply this series of consensus opinions in the daily diagnostic practice of pathologists, deeply understand relevant diagnostic problems, and carry out relevant clinical pathological research to further solve problems.

[Significance of TERT promoter mutation in differential diagnosis of non-invasive inverted urothelial lesions of bladder].

Objective: To investigate the gene mutation of telomerase reverse transcriptase (TERT) promoter in inverted urothelial lesions of the bladder and its significance in differential diagnosis. Methods: From March 2016 to February 2022, a total of 32 patients with inverted urothelial lesions diagnosed in Department of Pathology at Qingdao Chengyang People's Hospital and 24 patients at the Affiliated Hospital of Qingdao University were collected, including 7 cases of florid glandular cystitis, 13 cases of inverted urothelial papilloma, 8 cases of inverted urothelial neoplasm with low malignant potential, 17 cases of low-grade non-invasive inverted urothelial carcinoma, 5 cases of high-grade non-invasive inverted urothelial carcinoma, and 6 cases of nested subtype of urothelial carcinoma were retrospectively analyzed for their clinical data and histopathological features. TERT promoter mutations were analyzed by Sanger sequencing in all the cases. Results: No mutations in the TERT promoter were found in the florid glandular cystitis and inverted urothelial papilloma. The mutation rates of the TERT promoter in inverted urothelial neoplasm with low malignant potential, low grade non-invasive inverter urothelial carcinoma, high grade non-invasive inverted urothelial carcinoma and nested subtype urothelial carcinoma were 1/8, 8/17, 2/5 and 6/6, respectively. There was no significant difference in the mutation rate of TERT promoter among inverted urothelial neoplasm with low malignant potential, low-grade non-invasive inverted urothelial carcinoma, and high-grade non-invasive inverted urothelial carcinoma (P>0.05). All 6 cases of nested subtype of urothelial carcinoma were found to harbor the mutation, which was significantly different from inverted urothelial neoplasm with low malignant potential and non-invasive inverted urothelial carcinoma (P<0.05). In terms of mutation pattern, 13/17 of TERT promoter mutations were C228T, 4/17 were C250T. Conclusions: The morphology combined with TERT promoter mutation detection is helpful for the differential diagnosis of bladder non-invasive inverted urothelial lesions.

[Clinicopathological and molecular diagnostic features of early-onset gastric cancer: a study based on data from a single-center dedicated gastric cancer database].

Objective: To clarify the clinicopathological, especially molecular, features of early-onset gastric cancer with the aim of informing analysis of treatment strategies. Methods: In this retrospective case-control study, we examined data from a dedicated gastric cancer database in Zhongshan Hospital affiliated to Fudan University. The original cohort comprised 2506 patients with gastric cancer who had undergone gastrectomy in Zhongshan Hospital Fudan University from July 2020 to October 2021, including 198 with early-onset gastric cancer (aged ≤45 years) and 2,308 with non-early gastric cancer. We used a simple random sampling method to select 396 of the 2,308 patients aged >45 years (ratio of 1:2) as the control group and then compared molecular diagnostic data and clinicopathological features of the two groups. Results: The median age was 39 years in the early-onset gastric cancer group, while 66 years in the control group. The clinicopathological features of early-onset gastric cancer included female predominance (59.1% [117/198] vs. 27.8% [110/396], χ2=54.816, P<0.001), less comorbidity (32.3% [64/198] vs. 57.1% [226/396], χ2=32.355, P<0.001), poorer differentiation (93.9% [186/198] vs. 74.5% [295/396], χ2=30.777, P<0.001) and higher proportion of diffuse type (40.4% [80/198] vs. 15.9% [63/396], χ2=69.639, P<0.001), distant metastasis (7.1% [14/198] vs. 2.8% [11/396], χ2=6.034, P=0.014). Regarding treatment, distal gastrectomy was more commonly performed than proximal gastrectomy (55.1% [109/198] vs. 47.0% [186/396], 1.5% [3/198] vs. 8.3% [33/396], χ2=11.644, P=0.003). Family history of gastric cancer, TNM stage, tumor size, lymph node dissection, nerve invasion, nodes harboring metastases, range of lymph node dissection, digestive tract reconstruction procedure, implementation of laparoscopic surgery, combined resection, and preoperative treatment did not differ significantly between the two groups (all P>0.05). Molecular diagnosis showed there was a smaller percentage of mismatch repair deficiency in the early-onset gastric cancer than in the control group (1.0% [2/198] vs. 10.1% [40/396], χ2=16.301, P<0.001), and a higher rate of positivity for Claudin 18.2 (77.8% [154/198] vs. 53.0% [210/396], χ2=5.442,P<0.001). HER-2 and Epstein-Barr virus positivity rates did not differ significantly between the two groups. Conclusion: Early-onset gastric cancer is a distinct type of gastric cancer with a high degree of malignancy, and treatment targeting Claudin 18.2 may be effective.

[Outcomes of fluoroscopy-free hip arthroscopy technique in the treatment of femoroacetabular impingement syndrome].

Objective: To evaluate the effect of fluoroscopy-free technique in the arthroscopic treatment of femoroacetabular impingement syndrome (FAIS). Methods: A retrospective cohort study. Clinical data of FAI patients treated with hip arthroscopy in the No.4 Medical Center, PLA General Hospital from October 2018 to December 2021 were retrospectively analyzed. The patients were divided into two groups according to the surgical procedure: the fluoroscopy group and the fluoroscopy-free group. The operation time and modified Harris hip score (mHHS), international hip outcome tool (iHOT12) and visual analogue scale (VAS) of hip joint pain before and after the operation were observed and compared between the two groups. And the incidence of surgical complications in the two groups were compared too. Results: A total of 460 patients (213 males and 247 females) [aged (32.6±8.3) years (15-67 years)] with valid follow-up were included in this study. There were 275 cases in the fluoroscopy-free group and 185 cases in the fluoroscopy group. The operation time was shorter in the fluoroscopy-free group when compared with that in the fluoroscopy group, and the difference was statistically significant [(93.36±12.54) min vs (115.62±6.03) min, P<0.001]. In both groups, the VAS scores decreased and the mHHS scores and iHOT12 scores improved significantly at the last follow-up when compared with those before the operation (all P<0.001); however, there was no significant difference in the scores between the two groups (all P>0.05). The complication rate in the fluoroscopy-free group was 10.18% (28/275), and it was 10.81%(20/185) in the fluoroscopy group (P=0.829). Conclusion: Fluoroscopy-free hip arthroscopy technique for FAI can avoid radiation and shorten the operation time, but it does not increase the incidence of complications with reliable clinical outcomes.

Genistein attenuates renal ischemia-reperfusion injury via ADORA2A pathway.

BACKGROUND: Studies have shown oxidative stress and apoptosis are the main pathogenic mechanisms of renal ischemia/reperfusion (IR) injury (IRI). Genistein, a polyphenolic non-steroidal compound, has been extensively explored in oxidative stress, inflammation and apoptosis. Our research aims to reveal the potential role of genistein on renal IRI and its potential molecular mechanism both in vivo and in vitro. METHODS: In vivo experiments, mice were pretreated with or without genistein. Renal pathological changes and function, cell proliferation, oxidative stress and apoptosis were measured. In vitro experiments, overexpression of ADORA2A and knockout of ADORA2A cells were constructed. Cells proliferation, oxidative stress and apoptosis were analyzed. RESULTS: Our results in vivo showed that the renal damage induced by IR was ameliorated by genistein pretreatment. Moreover, ADORA2A was activated by genistein, along with inhibition of oxidative stress and apoptosis. The results in vitro showed that genistein pretreatment and ADORA2A overexpression reversed the increase of apoptosis and oxidative stress in NRK-52E cells induced by H/R, while the knockdown of ADORA2A partially weakened this reversal from genistein treatment. CONCLUSIONS: Our results demonstrated that genistein have a protective effect against renal IRI by inhibiting oxidative stress and apoptosis via activating ADORA2A, presenting its potential use for the treatment of renal IRI.

[Clinicopathological characteristics of Klinefelter syndrome: a testicular biopsy analysis of 87 cases].

Objective: To investigate the clinicopathological characteristics of testicular biopsies from Klinefelter syndrome (KS) patients. Methods: The testicular biopsy specimens of 87 patients with KS (a total of 107 biopsy specimens) were collected from the Department of Pathology, Peking University Third Hospital, Beijing, China from January 2017 to July 2022. All patients were diagnosed as KS by peripheral blood karyotyping analysis. The testicular histopathologic features, testicular volume and hormone levels were evaluated retrospectively. The histopathologic analysis was used to assess the quantity and morphology of Leydig cells, the spermatogenic state of seminiferous tubules, the thickening of the basement membrane of seminiferous tubules and the changes of stroma. Results: Leydig cell proliferative nodules were seen in 95.3% (102/107) of KS testicular biopsy tissues. The eosinophilic inclusion bodies and lipofuscin in Leydig cells were found in 52.3% (56/107) and 57.9% (62/107) of specimens, respectively. The Sertoli cell only seminiferous tubules and the hyalinized tubules were found in 66.4% (71/107) and 76.6% (82/107) of the examined tissues, respectively. The tubules with complete spermatogenic arrest were found in 15.9% (17/107) of specimens, and 5.6% (6/107) of the specimens showed low spermatogenesis or incomplete spermatogenic arrest. In 85.0% (91/107) of the specimens, increased thick-walled small vessels with hyaline degeneration were identified. Conclusions: The most common features of KS testicular specimens are Leydig cell proliferative nodules, hyaline degeneration of seminiferous tubules and proliferation of thick-walled blood vessels. Testicular biopsy specimens of KS are rare. The pathologists can make a tentative diagnosis of KS based on the histological findings, combined with the ultrasound and laboratory results, which is helpful for further diagnosis and treatment of KS.

[IgG4-related diseases of retroperitoneum in urinary and male reproductive system: a clinicopathological analysis of eleven cases].

Objective: To analyze the clinicopathological features of IgG4-related diseases (RD) of retroperitoneum and the urinary and male reproductive system (IgG4-RUMR). Methods: A total of 11 IgG4-RUMR cases from January 2013 to March 2021 were retrospectively collected at Peking University Third Hospital and Shandong Provincial Hospital affiliated to Shandong First Medical University. The clinicopathologic features, laboratory and imaging findings were analyzed and scored according to the 2019 ACR/EULAR classification criteria for IgG4-RD. Results: The 11 patients (male:female is 9∶2; mean age 59 years, range from 44 to 83 years) were initially admitted to the Deparment of Urology/Kidney Transplantation (10 cases) and the Department of Oncology (1 case). All patients had urogenital disorders or imaging abnormalities. Three of the 11 patients had a history of IgG4-RD such as lacrimal gland engorgement, salivary gland engorgement and IgG4-associated pancreatitis. Abnormal retroperitoneal soft tissue and hydronephrosis were found in eight cases, while epididymal and spermatic cord masses were found in one case, simple renal mass in one case, and"benign prostatic hyperplasia"in one case. In the 10 patients tested for serum IgG4, the serum IgG4 level was 0.8-14.4 g/L. Histologically, all cases showed significant lymphoplasmacytic infiltration and storiform fibrosis, and some were accompanied by obliterative phlebitis. The number of IgG4 positive plasma cells was 12-155 per high-power field, and the IgG4/IgG ratio was 15%-77%. According to the 2019 ACR/EULAR IgG4-RD classification standard 11 cases scored 20-48 points, all of which met the diagnostic criteria of IgG4-RUMR. Therapeutically, the patient with a simple renal mass underwent partial nephrectomy. The patient with prostate lesion underwent transurethral resection of prostate and was initially diagnosed as nonspecific chronic prostatitis. Later, the patient was admitted again because of salivary gland swelling, and the pathologic diagnosis was amended. The patient with epididymal and spermatic cord masses participated in a clinical trial about retroperitoneal fibrosis. The remaining eight patients received symptomatic treatment such as adhesiolysis and stent placement. All the patients were subsequently treated with glucocorticoid/immunosuppressant and symptoms relieved. Conclusions: IgG4-RUMR is uncommon. In clinical practice, information from clinical, serologic, radiologic and pathologic evaluations must be integrated. IgG4-RUMR should be considered in the differential diagnosis of urinary and male reproductive diseases. The 2019 ACR/EULAR classification criteria for IgG4-RD, while relatively complex, are objective and practical in the diagnosis of IgG4-RUMR.

[A case-control study of multiple myeloma patients with central nervous system involvement].

Objective: To investigate the treatment options for multiple myeloma patients with central nervous system involvement (CNS-MM) , as well as their clinical characteristics and prognostic factors. Methods: Between January 2011 and January 2022 our center diagnosed 18 people with CNS-MM. A retrospective analysis was done on the clinical information from the initial diagnosis and central nervous system involvement, and it was compared to 1∶3 matched newly diagnosed MM from the same period. Analysis was done on the clinical characteristics and survival rates of the two groups. Results: In patients with CNS-MM, the median time of onset was 14.2 (0.9-79.6) months and the median overall survival (OS) was 30.5 months from initial diagnosis and only 3.8 months in patients after CNS involvement. The CNS-MM patients showed more IgD type (P=0.010) , severer anemia (P=0.014) , a higher proportion of bone marrow plasma cells (P=0.013) , more extramedullary lesions (P=0.001) , and increased lactic dehydrogenase (LDH) (P=0.009) when compared to the control group. Lenalidomide or pomalidomide-based combinations had higher rates of hematology and CNS remission than bortezomib or daratumumab-based regimens (75.0% vs 16.7% , P=0.019) . Patients who received IMiD-based regimens and had 2 high-risk factors at initial diagnosis (high LDH and extramedullary lesions) had a significantly lower incidence of CNS-MM (P=0.026) . At the initial diagnosis, LDH (P=0.008, HR=7.319, 95% CI 1.663-32.219) and extramedullary lesions (P=0.006, HR=8.054, 95% CI 1.828-35.486) were independent risk factors for the occurrence of CNS-MM. Conclusion: Patients with CNS-MM had a poor prognosis. Patients with high LDH or extramedullary lesions at the time of the initial diagnosis are more likely to have CNS-MM. The prognosis of this patient may be improved by immunoregulator-based therapy.

[Clinical and pathological features of renal cell carcinoma with urinary tract tumor thrombus: 6 cases report and literature review].

OBJECTIVE: To investigate the clinical characteristics, diagnosis and treatment of renal cell carcinoma with urinary tract tumor thrombus. METHODS: From January 1, 2015 to December 31, 2019, patients with renal cell carcinoma complicated with urinary tract tumor thrombus who were hospitalized in the Peking University Third Hospital and Beijing Friendship Hospital, Capital Medical University were retrospectively analyzed. Meanwhile, we reviewed the literature, and the reported patients of renal cell carcinoma with urinary tract tumor thrombus were also included in our study. The basic information, clinical manifestations, treatment, pathological characteristics and follow-ups of all the patients were analyzed. RESULTS: In our study, 6 patients from the two hospitals and 16 patients from previous literature reports were included. There were 13 males and 9 females with an average age of 54.7 years (22-79 years). Fifteen patients had renal cell carcinoma on the left side, 6 on the right side, and 1 on the unknown side. Gross hematuria was the most common chief complaint, including 18 patients. One patient complained of weight loss, 1 patient complained of microscopic hematuria, and 1 patient was found by ultrasound examination. Tumor thrombus was classified as grade Ⅰ in 9 cases (the tumor embolus protruded into the renal pelvis, but did not reach the ureteropelvic junction), grade Ⅱ in 10 cases (the tumor embolus protruded into the ureter, but not into the bladder), and grade Ⅲ in 3 cases (the tumor embolus passed through the ureter and protruded into the bladder). Only 11 patients were diagnosed with renal cell carcinoma before operation. Radical nephrectomy was performed in 9 cases and nephroureterectomy in 12 cases. In pathological diagnosis, there were 15 cases of clear cell renal cell carcinoma, 1 case of papillary renal cell carcinoma, 1 case of chromophobe cell carcinoma, 1 case of mixed cell renal cell carcinoma, 4 cases of renal cell carcinoma with undetermined classification. Eleven patients were followed up for 3-31 months, and 3 patients had lung metastasis within 6 months. CONCLUSION: Renal cell carcinoma with urinary tract tumor thrombus is rare in clinic. It needs to be differentiated from renal pelvis carcinoma in diagnosis. The treatment principle can refer to general renal carcinoma. For locally advanced cases, complete resection is the best treatment, and its oncological prognosis needs more long-term and large-scale follow-up observation.

[The efficacy and safety of daratumumab in relapsed and refractory multiple myeloma].

Objective: To investigate the efficacy and safety of daratumumab in relapsed and refractory multiple myeloma (RRMM) . Methods: The clinical characteristics, adverse reactions, efficacy, and prognosis of 46 patients with RRMM treated with daratumumab in Shanghai Changzheng Hospital from September 2017 to March 2020 were retrospectively analyzed. Results: All patients were treated with daratumumab-based regimen: 8 in the Dd group, 35 in the DRd group, and 3 in the DVd group. With a median follow-up of 9.6 months, the overall response rate (ORR) was 75% [complete remission (CR) rate 18.2% ] among the 44 patients available for evaluation. The ORRs of patients resistant to bortezomib, lenalidomide, and both were 70.6% , 69.2% , and 63.6% , respectively. The CR rates of patients resistant to bortezomib, lenalidomide, and both were 17.6% , 11.5% , and 13.6% , respectively. No significant difference was observed in ORR and CR rates among the three groups. The ORRs of the DRd, DVd, and Dd groups were 85.3% , 66.7% , and 28.6% , respectively (P=0.007) . The median PFS of 46 patients was 8.9 months, the median OS was not reached, and the 1-year OS rate was 74% . The median PFS and OS in the DRd group were longer than those in the Dd group (PFS: 14.4 months vs 2.0 months; OS: not reached vs 5.2 months) . After treatment with daratumumab, neutropenia is the most common hematological adverse reaction above grade 3. Non-hematological adverse reactions are mainly infusion-related adverse reactions and infections. Prognostic analysis showed that patients with extramedullary invasion had shorter PFS and OS compard with patients without extramedullary invasion (PFS: 5.7 vs 14.4 months, P=0.033; OS: 6.3 months vs not reached, P=0.029) . The OS of patients with an ECOG score of 3-4 was significantly shorter than patients with an ECOG score of 1-2 (5.9 months vs not reached, P=0.004) . Conclusion: Daratumumab-based regimens have good efficacy and safety in the treatment of RRMM.

[Clinicopathological characteristics and prognosis of young patients with upper tract urethelial carcinoma].

Objective: To investigate the clinicopathological characteristics and prognosis of the young patients with upper tract urothelial carcinoma (UTUC). Methods: The clinical data of 839 UTUC patients receiving radical nephroureterectomy at Peking University Third Hospital, Beijing, China from September 1999 to September 2019 were retrospectively analyzed. The patients were divided into the young (<55 years old, 107 cases) and elderly groups (≥55 years old, 732 cases). After the variables were balanced using propensity score matching, the patients were paired at a 1∶1 ratio. The clinicopathological characteristics and survival rates were compared between the two groups. Results: Compared with the elderly group, the young group had more males (P=0.047), a higher rate of smoking history (P=0.042), a higher rate of renal transplantation history (P<0.01), and fewer symptoms of hematuria (P=0.048). The 1-, 3-, and 5-year cancer specific survival (CSS) rates after surgery were 77.9%, 62.2%, 60.2% and 85.7%, 70.3%, 65.0% in the young and the elderly groups, respectively. The CSS and disease free survival (DFS) of young patients were shorter than those of elderly patients, but the difference was not significant either by subgroup analysis or propensity matching analysis (P>0.05). Young female patients had shorter CSS (P=0.034) and DFS (P=0.046) than elderly females. Perineural invasion (CSS, P=0.002; DFS, P<0.01) and extensive necrosis (CSS, P=0.041; DFS, P=0.001) were the independent risk factors of survival in young patients. Conclusions: Young UTUC patients are different from elderly ones in the frequencies of gender, smoking history, renal transplantation history, and first symptoms. Young female patients have a worse prognosis than elderly female ones. Perineural invasion and extensive necrosis could help clinicians to evaluate the prognosis of young UTUC patients.