Predictive prognostic value of glomerular C3 deposition in IgA nephropathy.

BACKGROUND: IgAN is the most common primary glomerulonephritis worldwide. However, the pathogenesis of IgAN remains unknown. Currently, there is evidence that C3 deposition plays a role in disease development. This study aimed to investigate clinical, pathological features, and prognosis of adult IgAN patients with C3 deposition, as well as explore the role of complement activation in disease progression. METHODS: A total of 821 patients with biopsy-proven IgAN were included in this study. Patients were divided into three different groups according to their C3 deposition intensity. Clinical and pathological characteristics were compared between groups. Logistic analysis was used to estimate the relationship between C3 deposition and the Oxford scoring system. Univariate and multivariate Cox proportional hazard regression models were used to analyze the effect of the presence of C3 deposits on the prognosis of patients with IgA nephropathy. Kaplan-Meier survival analysis was used to evaluate the cumulative incidence of renal progression between groups. RESULTS: Patients with C3 deposition exhibited more severe clinical and pathological features and had a higher score according to the Oxford scoring system. With the increasing intensity of C3 deposition, patients present more hematuria, crescents, heavier interstitial inflammatory cell infiltration and a higher score on segmental sclerosis lesions. Logistic regression identified a positive relationship between C3 deposition and histopathology. Univariate and multivariate Cox regression indicated that C3 deposition was an independent risk factor for IgAN severity. The Kaplan-Meier survival curves indicated that patients with positive C3 deposition had a worse prognosis compared to those without C3 deposition. CONCLUSIONS: Patients with positive glomerular C3 deposition presented with more severe clinical and histopathological characteristics and a higher score on the Oxford scoring system. With the increasing intensity of C3 deposition, IgAN patients were more likely to present with high level of microscopic hematuria, fibrous crescents, interstitial inflammatory cell infiltration, and a higher score on segmental sclerosis lesions. C3 deposition at the time of renal biopsy is likely an independent risk factor for IgA nephropathy severity and progression.

IgA nephropathy with acute kidney disease: Characteristics, prognosis, and causes.

BACKGROUND: The clinical manifestations and prognosis of IgA nephropathy (IgAN) are diverse. Some patients may present with kidney dysfunction lasting shorter than 3 months and meet the acute kidney disease (AKD) criteria. This study aimed to investigate the clinicopathological features, causes and prognosis of newly diagnosed cases of IgAN with AKD. METHODS: 1320 IgAN patients diagnosed via kidney biopsy between January 2012 and June 2018 were included in this retrospective study, with a median follow-up period of 35 months. We analyzed the clinicopathological, etiological variables, as well as short-term and long-term prognosis. The main outcome was a composite event of 40% decline in eGFR, kidney failure or death. RESULTS: Incidence of AKD was 8.8% in the newly diagnosed IgAN patients, and was found to be an independent risk factor affecting the short-term (HR, 7.1; 95% CI, 2.3-22.2; P = 0.001) and long-term (HR, 1.8; 95% CI, 1.2-2.6; P = 0.006) prognosis, respectively. The most common cause of AKD was malignant hypertension-related AKD (MHT-AKD; 24.1%), followed by hematuria-related AKD (H-AKD; 12.9%), nephrotoxic-drug-exposure-related AKD (NTDE-AKD; 12.1%) and crescents-related AKD (C-AKD; 11.2%). The patients in AKD group had more severe clinicopathological characteristics and poor short-term and long-term prognosis than non-AKD group. In subgroup analysis, the MHT-AKD had the worst 5 years survival rate, followed by NTDE-AKD and C-AKD, whereas H-AKD had the best survival rate. CONCLUSIONS: AKD is not rare among IgAN patients, and is an independent risk factor for short-term and long-term prognosis. IgAN patients with AKD resulting from different causes have different prognosis.

Apatinib plus 5-fluorouracil as a third or subsequent-line treatment option for metastatic colorectal cancer: a phase-II, single-arm, prospective study.

Background: For metastatic colorectal cancer (mCRC) patients for whom at least 2 lines of previous standard therapies have failed, the prognosis is often unfavorable due to very limited subsequent treatment options. We sought to explore the efficacy of apatinib, an oral small-molecule vascular endothelial growth factor receptor-2 inhibitor, plus 5-fluorouracil (5-FU) as a third- or subsequent-line treatment for mCRC. Methods: In this phase-II, single-arm, prospective study, the eligible patients had been histologically confirmed to have adenocarcinoma of the colon or rectum for which at least 2 previous regimens of standard therapies had failed. All the patients were treated with a daily dose of 250 mg of apatinib, in combination with capecitabine, Tegafur Gimeracil Oteracil Potassium Capsule (S-1), or 5-FU, until disease progression, unacceptable toxicity, or consent withdrawal. Results: From June 2017 to April 2018, 16 patients were enrolled in this study. Among them, 4 achieved partial response, 7 had stable disease, and 5 had progression disease, resulting in an objective response rate of 25.00% [95% confidence interval (CI): 7.27-52.38%], and a disease control rate of 68.75% (95% CI: 41.34-88.98%). The median progression-free survival (PFS) was 4.83 months (95% CI: 2.17-8.90 months), and the median overall survival (OS) was 9.10 months (95% CI: 5.59-15.18 months). The common treatment-related adverse events (AEs) were hand-foot syndrome (56.25%), hypertension (37.50%), proteinuria (37.50%), gingival bleeding (18.75%) and abdominal pain (18.75%). Grade 3 AEs, including hand-foot syndrome (18.75%), hypertension (12.50%), and proteinuria (12.50%), were observed in 7 patients. Conclusions: The combination regimen of apatinib plus 5-FU had encouraging anti-tumor efficacy, and is a feasible third- or subsequent-line treatment option for mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT03210064.

Normotensive and hypertensive Immunoglobulin a nephropathy with ischemic renal injury: clinicopathological characteristics and prognosis.

OBJECTIVES: This study aimed to investigate the clinicopathological characteristics and prognosis of normotensive and hypertensive IgAN patients with ischemic renal injury. METHODS: A total of 344 cases of IgAN with ischemic renal injury were included in the study, including 99 normotensive IgAN patients (28.8%) and 245 hypertensive IgAN patients (71.2%). In addition, 467 IgAN patients without ischemic renal injury were included as controls, including 205 normotensive patients and 262 hypertensive patients. Clinicopathological and prognostic data were collected and analyzed. RESULTS: Compared with patients without ischemic renal injury, IgAN patients with ischemic renal injury displayed a higher proportion of hypertention, a higher proportion of ischemic glomerulosclerosis, tubular atrophy/interstitial fibrosis and vascular lesions (all p < .05). There was no significant difference in cumulative survival between the normotensive IgAN patients groups (Log-rank χ2 = 0.479; p = .489). Furthermore, ischemic renal injury was not a risk factor for end-point events in normotensive IgAN patients (HR = 1.103; 95% CI: 0.279-4.365; p = .889). There was lower cumulative survival in hypertensive IgAN patients with ischemic renal injury (Log-rank χ2 = 11.352, p = .001). Moreover, ischemic renal injury was a risk factor for end-point events in hypertensive IgAN patients (HR = 1.889; 95% CI: 1.124-3.178; p = .016). CONCLUSIONS: Ischemic renal injury can occur in normotensive IgAN patients. Although the pathological changes may not affect the long-term prognosis of normotensive IgAN patients, the prognosis for hypertensive IgAN patients remains poor. Therefore, increased attention should be paid to the clinical management of ischemic lesions in hypertensive IgAN patients.

Development and validation of a predictive model for determining clinically significant prostate cancer in men with negative magnetic resonance imaging after transrectal ultrasound-guided prostate biopsy.

BACKGROUND: The interpretation of negative magnetic resonance imaging (MRI) screening results for clinically significant prostate cancer (csPCa) (International Society of Urological Pathology grade ≥group 2) is debatable and poses a clinical dilemma for urologists. No nomograms have been developed to predict csPCa in such populations. In this study, we aimed to develop and validate a model for predicting the probability of csPCa in men with negative MRI (PI-RADS score 1-2) results after transrectal ultrasound-guided systematic prostate biopsy. METHODS: The development cohort consisted of 728 patients with negative MRI results who underwent subsequent prostate biopsy at our center between January 1, 2014 and December 31, 2017. The patients' clinicopathologic data were recorded. The Lasso regression was used for data dimension reduction and feature selection, then multivariable binary logistic regression was used to build a predictive model with regression coefficients. The model was validated in an independent cohort of 334 consecutive patients from January 1, 2018 and June 30, 2020. The performance of the predictive model was assessed with respect to discrimination, calibration, and decision curve analysis. RESULTS: The predictors incorporated in this model included age, history of previous negative prostate biopsy, prostate specific antigen density (PSAD), and lower urinary tract symptoms, with PSAD being the strongest predictor. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.875 (95% confidence interval, 0.816-0.933) and good calibration (unreliability test, p = .540). Decision curve analysis demonstrated that the model was clinically useful. CONCLUSION: This study presents a good nomogram that can aid pre-biopsy risk stratification for the detection of csPCa, and that may help inform biopsy decisions in patients with negative MRI results.

SOX17 Antagonizes the WNT Signaling Pathway and is Epigenetically Inactivated in Clear-Cell Renal Cell Carcinoma.

BACKGROUND: SRY-box containing gene 17 (SOX17) was reported to be a candidate tumor suppressor gene in multiple tumors. Little is known about its role in clear-cell renal cell carcinoma (ccRCC). This study aims to identify the epigenetic regulation and tumor-suppressive function of SOX17 in ccRCC. PATIENTS AND METHODS: Fifty-five human ccRCC tissue samples, ten adjacent non-malignant kidney tissue samples, 20 paired paraffin section tissues and seven RCC cell lines were obtained. Immunohistochemistry (IHC) and real-time PCR were used to examine the expression of the target genes at the mRNA and protein levels. The methylation of SOX17 was analyzed using methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) assay. The functions of SOX17 were examined by using CCK8, colony formation, wound healing assay and Matrigel invasion assays. Luciferase assay was used to analyze the function of SOX17 in the WNT signaling pathway. RESULTS: We investigated the SOX17 expression in ccRCC tissues and adjacent non-malignant kidney tissues using PCR and IHC. The expression of SOX17 was lower in ccRCC tissues. Next, we analyzed the DNA promoter methylation of SOX17 in 55 human ccRCC tissues, 10 adjacent non-malignant kidney tissues and RCC cell lines using MSP. DNA methylation of the SOX17 promoter region occurred in 60% of ccRCC tissues and 10% of adjacent non-malignant kidney tissues. In vitro experiments showed that SOX17 suppressed the proliferation of RCC cells. Furthermore, SOX17 inhibited the migration of RCC cells as shown in the wound healing and migration assays. In addition, we found that SOX17 overexpression affected the WNT signaling pathway by downregulating c-myc and cyclinD1. CONCLUSION: In summary, our study showed that SOX17 is downregulated in ccRCC and the loss of SOX17 expression is regulated via epigenetic mechanisms in ccRCC. In addition, SOX17 negatively regulates the WNT signaling pathway and function as a tumor suppressor in ccRCC.

External Validation of the International IgA Nephropathy Prediction Tool.

BACKGROUND AND OBJECTIVES: The International IgA Nephropathy Network recently developed and externally validated two models to predict the risk of progression of IgA nephropathy: full models without and with race. This study sought to externally validate the International IgA Nephropathy Prediction Tool in a large, independent, and contemporary cohort in China. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 1373 patients with biopsy-confirmed primary IgA nephropathy from The First Affiliated Hospital of Zhengzhou University from January 2012 to May 2018 and calculated predicted risks for each patient. The outcomes of interest were a 50% decline in eGFR or kidney failure. We assessed the performance of both models using discrimination (concordance statistics and Kaplan-Meier curves between subgroups), calibration (calibration plots), reclassification (net reclassification improvement and integrated discrimination improvement), and clinical utility (decision curve analysis). RESULTS: The median follow-up was 29 months (interquartile range, 21-43 months; range, 1-95 months), and 186 (14%) patients reached the kidney outcomes of interest. Both models showed excellent discrimination (concordance statistics >0.85 and well separated survival curves). Overall, the full model without race generally underestimated the risk of primary outcome, whereas the full model with race was well calibrated for predicting 5-year risk. Compared with the full model without race, the full model with race had significant improvement in reclassification, as assessed by the net reclassification improvement (0.49; 95% confidence interval, 0.41 to 0.59) and integrated discrimination improvement (0.06; 95% confidence interval, 0.04 to 0.08). Decision curve analysis showed that both full models had a higher net benefit than default strategies, and the model with race performed better. CONCLUSIONS: In this study, both full models demonstrated remarkable discrimination, acceptable calibration, and satisfactory clinical utility. The relatively short follow-up time may have limited the validation of these models.

Prevalence, clinicopathological features, and prognosis in upper tract urinary carcinoma patients with severe preoperative chronic kidney disease.

BACKGROUND: Studies regarding the prevalence and factors associated with severe pre-operative chronic kidney disease (CKD) in upper tract urinary carcinoma (UTUC) patients were rare due to the low prevalence of UTUC. We conducted the present study to investigate the prevalence, clinicopathological features, and prognosis in UTUC patients with severe preoperative CKD. METHODS: The study included 731 patients with UTUC treated with radical nephroureterectomy (RNU) in a large Chinese center. Estimated glomerular filtration rate (eGFR) was calculated by re-expressed Modification of Diet in Renal Disease (MDRD) formulas for the Chinese population. Severe preoperative CKD was defined as CKD stage 4-5 (eGFR <30 mL/min). Relationships of CKD stage 4-5 with clinicopathological characteristics, overall survival (OS), cancer-specific survival (CSS), contralateral recurrence-free survival and intravesical recurrence (IVR)-free survival were analyzed. RESULTS: A total of 73 (10.0%) patients presented severe preoperative CKD in this cohort. Multivariate logistic analysis indicated that female gender (OR =1.791; 95% CI: 1.018-3.150; P=0.043), lower BMI (OR =0.452; 95% CI: 0.262-0.778; P=0.004), concomitant bladder tumor (OR =2.944; 95% CI: 1.360-6.373; P=0.006), lower pathological T stage (OR =0.578; 95% CI: 0.339-0.984; P=0.043), tumor necrosis (OR =2.764; 95% CI: 1.411-5.416; P=0.003), and exposure of aristolochic acid (AA) (OR =3.115; 95% CI: 1.536-6.316; P=0.002) were significantly related to severe CKD. Multivariate Cox's regression analysis showed that severe preoperative CKD was significantly associated with worse OS (HR =1.840; 95% CI: 1.150-2.944; P=0.011) and worse contralateral recurrence-free survival (HR =3.269; 95% CI: 1.607-6.650; P=0.001), while no statistical difference in terms of CSS or IVR-free survival were noticed. CONCLUSIONS: Female gender, lower BMI, concomitant bladder tumor, lower pathological T stage, exposure of AA, and tumor necrosis were independently associated with severe preoperative CKD in UTUC patients. UTUC patients with severe preoperative CKD possess worse OS and higher possibility of contralateral upper urinary tract recurrence.

Role of lymph node dissection in the management of upper tract urothelial carcinomas: a meta-analysis.

BACKGROUND: Lymph node dissection (LND) is not routinely performed during radical nephroureterectomy (RNU) in upper tract urothelial carcinomas (UTUC) and the role of LND has been controversial. We aim to investigate whether patients with LND had improved survival in UTUC patients. METHODS: We performed a systematic literature search of PubMed, Embase, and Cochrane library for citations published prior to January 2016, describing LND performed among UTUC patients and conducted a standard meta-analysis of survival outcomes. RESULTS: Eleven eligible studies containing 7516 patients satisfied the inclusion criteria. Pooled HRs for cancer-specific survival (CSS) and recurrence-free survival (RFS) were 1.17 (P = 0.18) and 1.33 (P = 0.19) respectively. However, the patients in the LND group had more advanced tumour stages and grades (P < 0.001). Further subgroup analysis showed that among muscle-invasive UTUC patients, the pooled HR for CSS and RFS were 1.10 (P = 0.42) and 0.92 (P = 0.72) respectively. Besides, no difference was found in CSS and RFS between pN0 and pNx individuals in overall populations and in patients with muscle-invasive UTUC, while pN+ patients had significantly worse prognosis when compared to pN0 patients. CONCLUSIONS: LND during RNU allows more accurate staging and prediction of survival, but it remains uncertain whether LND independently improves survival in patients with UTUC. However, standard use of LND should be further investigated in a multi-center, prospective evaluation to obtain a definitive statement regarding this matter.

[Ileal ureteric replacement for iatrogenic long segment ureteric injuries].

OBJECTIVE: To investigate the efficacy of ileal ureteric replacement in the treatment of iatrogenic long segment ureteric injuries. METHODS: The hospital records of 9 cases with iatrogenic long segment ureteric injuries during Aug. 2010 to Sept. 2014 treated with ileal ureteric replacement were retrospectively reviewed and followed-up postoperatively. The patients included 3 males and 6 females with a median age of 40 years. The length of injury segment was 13-25 cm (median 20 cm). The etiology of the iatrogenic injury was urological surgery (n=6), gynecological surgery (n=2) and general surgery (n=1), respectively. The ureter stent was removed in 1-2 month postoperatively in all the 9 cases. RESULTS: All the operations were successful. The operation time was 203-394 min, with the average of (278.1±68.8) min. The bleeding volume was 10-1 000 mL, with the median of 200 mL. The mean length of hospital stay was (16.8±7.5) days. Four minor complications (Grade I-II) developed, including 3 ileus (33.3%) and 1 proximal anastomotic leakage (11.1%). The median follow-up time was 11 months, serum creatinine decreased or remained stable in 8 patients (88.9%). Three patients (33.3%) developed mild hydronephrosis and short-time urinary tract infection was seen in 1 patient (11.1%). Metabolic acidosis was not detected during the follow-up. CONCLUSION: Ileal ureteric replacement is a safe and effective method in patients with complex or difficult iatrogenic long segment ureteric injuries.

[Efficacy of NO regimen and NP regimen on advanced non-small cell lung cancer: a prospective randomized trial].

BACKGROUND & OBJECTIVE: Oxaliplatin (LOHP) is an effective drug in treatment of non-small cell lung cancer (NSCLC) with mild toxicities to gastrointestinal tract, kidney, and bone marrow. Cisplatin (DDP) plus vinorelbine (NVB) constitute the first-line regimen (NP regimen) for NSCLC. This study was to compare the short-term response, long-term outcome, and adverse events between advanced NSCLC patients received NO regimen (LOHP plus NVB) and NP regimen. METHODS: A total of 90 patients with advanced NSCLC were randomized into NO group (58 patients, 25 mg/m(2) of NVB, day 1 and day 8; 130 mg/m(2) of LOHP, day 1) and NP group (32 patients, 25 mg/m(2) of NVB, day 1 and day 8; 50 mg/m(2) of DDP, day 2 and day 3). The short-term response, long-term outcome, adverse events, and survival status of the 2 groups were observed. RESULTS: The response rates were 33.33% in NO group, and 35.48% in NP group, but no significant difference was detected between the 2 groups (P > 0.05). The clinical benefit response rate was significantly higher in NO group than in NP group (80.70% vs. 64.52%, P < 0.05). The median time to progression (TTP) was 17 weeks in NO group, and 15 weeks in NP group; the median time of remission was 21 weeks in NO group, and 19 weeks in NP group; the median survival time was 39 weeks in NO group, and 37 weeks in NP group; the 1-year survival rate was 37.93% in NO group, and 31.25% in NP group. No significant differences were detected between the 2 groups. The incidence rates of phlebitis and grade I-II peripheral neuritis were significantly higher in NO group than in NP group (77.59% vs. 50.00%, P<0.01; 43.10% vs. 15.63%, P<0.01). The incidence rate of grade III-IV nausea/vomiting was significantly higher in NP group than in NO group (31.25% vs. 3.45%, P<0.05). CONCLUSIONS: The efficacy of NO regimen on advanced NSCLC is similar to that of NP regimen, but the clinical benefit response rate is higher in NO group than in NP group. In short, NO regimen may be recommended as the first-line chemotherapy regimen for advanced NSCLC.

[Prospective randomized study of HMVP, MVP, and HVP regimens in treatment of advanced non-small cell lung cancer].

BACKGROUND & OBJECTIVE: Non-small cell lung cancer (NSCLC) is hyposensitive to the normal first and second-line chemotherapy regimens. Camptothecin derivative is becoming a hot point in the treatment of advanced NSCLC. The objective of this article was to evaluate the response, toxicity, and survival time of HMVP, MVP, and HVP regimens (detail in below) in the treatment of advanced NSCLC. METHODS: A total of 134 cases with advanced NSCLC was randomized into three groups: HMVP group [46 patients, hydroxycamptothecin (HCPT) 12 mg/m(2) from d1 to d5, mitomycin C (MMC) 6 mg/m(2) d1, vindesine (VDS) 2.5-3 mg/m(2) d1 and d8, cisplatin (DDP) 50 mg/m(2) d2 and d3], MVP group (44 patients, MMC, VDS and DDP were the same as HMVP group) and HVP group (44 patients, HCPT, VDS, DDP were the same as HMVP group). RESULTS: The response rates were 39.54% (17/43), 35.57% (15/42), and 26.19% (11/42) in HMVP, MVP, and HVP groups, respectively; no significant difference was detected among the three groups (P >0.05). No significant difference was detected in the median time of remission, median survival time, and 1-, 2-year survival rates among the three groups. Moreover, no significant difference was detected in grade III-IV leukopenia, grade III-IV thrombocytopenia, grade III-IV nausea and vomiting and grade III-IV constipation among the three groups. CONCLUSION: The response rate of MVP regimen is slightly lower than that of HMVP regimen, but HMVP regimen do not show obvious superiority. It may increase toxicities such as leukopenia, nausea/vomiting, and constipation. The response rate of HVP regimen is slightly lower than that of MVP regimen.