Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

Prognosis and Clinicopathological Characters of Adult TFEB-Altered Renal Cell Carcinoma: A Single Center Experience of 18 Cases.

INTRODUCTION: TFEB-altered renal cell carcinoma (RCC) is a rare entity characterized by the rearrangement of the TFEB gene or TFEB amplified. The therapeutic implications and long-term survival of TFEB-altered RCC remain unclear, especially for metastatic cases. MATERIALS AND METHODS: The current study initially enrolled 7604 consecutive RCC patients at our center and a total of 248 patients were selected for FISH and immunohistochemistry (IHC) analysis. Eventually, eighteen TFEB-altered RCC patients were identified. We then reported the clinical, morphological, IHC, and radiological features of these cases. RESULTS: The median age at initial diagnosis was 45 years, ranging from 18 years to 66 years. The majority of the TFEB-altered RCC patients were male (61.1%), with localized disease (T1-2N0M0, 77.8%). The median split TFEB fluorescent signal was 24%, ranging from 15%-80%. The morphological characteristics of TFEB-altered RCC were variable, with acinar, papillary, solid, or nest patterns. IHC and magnetic resonance imaging features of TFEB-altered RCC were nonspecific. Nine patients with localized disease received partial nephrectomy and five patients with localized disease received radical nephrectomy. During the median follow-up of 67 months, no signs of recurrence or metastasis were found in these patients. Two patients had distant metastasis and received axitinib plus PD-1 immunotherapy. One of them died at 40-month follow-up and another still alive at 88-month follow-up. CONCLUSION: TFEB-altered RCC is an extremely rare variant, exhibited mixed morphological characteristics. The radiological feature lack specificity, resembling clear cell RCC or papillary RCC. Genetic analyses including FISH analysis is crucial in the diagnosis of TFEB-altered RCC. For localized TFEB-altered RCC, both radical nephrectomy and partial nephrectomy conferred satisfactory prognosis. For metastatic TFEB-altered RCC, immunotherapy-based drug combinations could be a promising treatment strategy.

Dynamic alteration and prognostic significance of tumor-associated CD68+ and CD68+ PD-L1- macrophages in muscle-invasive bladder cancer treated with neoadjuvant chemotherapy.

BACKGROUND: The current study aimed to investigate the dynamic alteration and prognostic significance of tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and PD-L1 status of immune cells in muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy (NAC). METHODS: Multiplex immunofluorescence staining was performed to examine CD68+ TAM, CD4+ T cell, CD8+ T cell, FOXP3+ Treg cell, and PD-L1 expression in paired MIBC tissues (n = 54) before and after NAC. Patients were then divided into definite responders (DR), (≤pT1) and incomplete responders (IR). RESULTS: There was no significant difference between DR and IR cohorts for the immune cell infiltration levels at the baseline status. Tobacco history was identified to be associated with worse NAC efficacy. CD68+ (stroma area: p = 0.025; tumor area: p = 0.028; total area: p = 0.013) and CD68+ PD-L1- (stroma area: p = 0.035; tumor area: p = 0.013 total area: p = 0.014) TAMs infiltration levels decreased significantly after NAC, while there was no significant difference of CD68+ PD-L1+ and TILs. The infiltration of CD68+ (p = 0.033), CD68+ PD-L1- (p = 0.033), and CD68+ PD-L1+ (p < 0.001) TAMs in stroma area were significantly associated with poorer disease-free survival rate (DFS) of MIBC patients. CONCLUSION: CD68+ and CD68+ PD-L1- TAMs infiltration levels decreased significantly after NAC and pre-treatment TAM infiltration levels were independent prognostic factors for MIBC patients. While there was no sufficient evidence demonstrating that pre-treatment TILs or TAMs could predict response to NAC in MIBC patients.

Disease Management of Clinical Complete Responders to Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer: A Review of Literature.

Muscle-invasive bladder cancer (MIBC) is an aggressive disease requiring active management. Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is considered the standard treatment paradigm for MIBC patients, which could result in significant perioperative mortality and morbidity, as well as the significant alteration of the quality of life (QOL). Notably, multimodal bladder-preserving treatment strategies have been recommended for highly selected patients. Pathologic complete response (pCR) after NAC is a powerful prognostic indicator of survival for patients with MIBC. Clinical complete response (cCR) is then introduced as a complementary endpoint for pCR to assess disease status preoperatively. Bladder preservation strategy for patients who achieve cCR following NAC is emerging as a new treatment concept. However, the efficiency of the conservative strategy remains controversial. In this state-of-the-art review, we discuss the advantages and limitations of cCR and the feasibility and safety of bladder preservation strategy in highly selected MIBC patients who achieve cCR following NAC. We conclude that a conservative strategy can be considered a reasonable alternative to RC in carefully selected cCR MIBC patients, leading to acceptable oncological outcomes.

[Correlation of 41 loci of single nucleotide polymorphisms with testicular germ cell tumor].

Objective: To identify genetic susceptibility genes and the loci of their single nucleotide polymorphisms (SNPs) in patients with testicular germ cell tumor (TGCT) and provide some new ideas for the prediction, diagnosis and treatment of TGCT. METHODS: We identified 41 SNP loci of TGCT-related genetic susceptibility genes from the literature published abroad. Using the iMLDRTM genotyping technique, we examined the SNP loci of the genetic susceptibility genes in the blood samples from 76 TGCT patients (aged 16－68 years) and 148 healthy men (aged 22－61 years) in China and analyzed their correlation with TGCT. RESULTS: In China, TGCT was found to be correlated with the SNP loci rs2978381, rs10146204, rs12435857 and rs1256063 of the ESR2 gene, rs9397080 of the ESR1 gene, rs11202586 of the PTEN gene, rs2606345 and rs4646903 of the CYP1A1 gene, and rs1456432 of the CYP19A1 gene. CONCLUSIONS: The results of our study indicated some difference in the positive SNP loci of the TGCT patients between Chinese and foreign cohorts as well as in different groups in China.

Clinical Experience of Escalated Sunitinib Dose in Select Patients With Metastatic Renal Cell Carcinoma.

OBJECTIVE: Sunitinib is approved multinationally for the first-line treatment of metastatic renal cell carcinoma (mRCC). After mRCC progressed in patients, we escalated the sunitinib dose in selected patients and then retrospectively evaluated the efficacy and safety of dose-escalated sunitinib in these selected patients. METHODS: From January 2010 to January 2016, 288 patients with mRCC received sunitinib as first-line treatment. Treatment continued until radiologic progression occurred. When the disease progressed, 34 patients with mRCC who had mild or moderate adverse events and missed free second-line target therapy trials were escalated to sunitinib 50 mg once daily continuously. Dose-escalated treatment continued until the disease progressed again, the patient was unable to tolerate sunitinib, or the patient was willing to quit the sunitinib treatment. RESULTS: All 34 patients (median age, 55 years [range, 28-67 years]; 28 [82.4%] males; 6 [17.6%] females) with confirmed metastatic clear-cell RCC, received an escalated dose of sunitinib and were evaluated for toxicity and response. During treatment at the regular sunitinib dosage, 9 (26.5%) patients achieved partial response and 25 (73.5%) patients had a stable disease condition. With dose-escalated sunitinib, 2 (5.9%) patients achieved partial response, 27 (79.4%) patients had stable disease, and the disease still progressed in 5 (14.7%) patients. Tumor size was reduced in 10 (38.2%) patients. Median progression-free survival was 11.2 months (95% confidence interval [CI], 5.2-17.2 months) with the regular dose of sunitinib. During dose-escalated sunitinib treatment, the median progression-free survival was 4.1 months (95% CI, 2.3-5.9 months). Median overall survival was 25.0 months from the initiation of sunitinib treatment (95% CI, 16.0-34.0 months). During dose escalation, grade 3 adverse events consisted of hand-foot syndrome, fatigue, mucositis, and diarrhea. All grade 3 adverse events were relieved by supporting and symptomatic treatment. No grade 4 adverse events occurred. CONCLUSION: Sunitinib was efficacious in the treatment of mRCC. For patients who tolerated sunitinib well, the dosage could be cautiously increased to gain better treatment benefit.

Safety and efficacy of sunitinib for advanced non-clear cell renal cell carcinoma.

AIM: This study evaluated the safety and efficacy of sunitinib in the treatment of advanced non-clear cell renal cell carcinoma. METHODS: Thirty-seven Chinese patients with advanced non-clear cell renal cell carcinoma were enrolled from October 2008 to October 2013. Sunitinib monotherapy was administered in repeated 6-week cycles of daily oral administration of 50 mg for 4 weeks, followed by 2 weeks off. Computed tomography scan was used to evaluate the efficacy every two cycles. RESULTS: All 37 patients received sunitinib treatment according to the schedule and were evaluated for response and toxicity. Thirty (81.1%) patients underwent nephrectomy before sunitinib treatment and seven (18.9%) patients had kidney biopsy. Twenty-five patients were diagnosed with papillary renal cell carcinoma, two with spindle cell-type renal cell carcinoma, two with chromophobe renal cell carcinoma and eight with unclassified cell types. The disease control rate was 73.0%, with partial response in 5 (13.5%), stable disease in 22 (59.5%) and progression disease in 10 (27.0%), the best tumor response. The median progression-free survival (PFS) was 6 months and the median overall survival (OS) was 9 months. In patients with papillary renal cell carcinoma, the median PFS was 6 months and the median OS was 10 months. The most common adverse events were hand-foot syndrome, fatigue, leukopenia, anemia, thrombocytopenia, mucositis, edema and hypertension. All adverse events were ameliorated by supportive treatment, dose reduction or treatment interruption. CONCLUSION: Sunitinib was efficacious in the treatment of advanced non-clear cell renal cell carcinoma. Most adverse events were tolerable.

[Clinical significance of serum levels of endostatin in patients with clear cell renal cell carcinoma].

OBJECTIVE: To assess serum levels of endogenous endostatin in patients with clear cell renal cell carcinoma (CCRCC) and to determine the relationship of these levels to tumor stage, grade. METHODS: From March 2004 to October 2008, preoperative serum were obtained from 138 consecutive patients with CCRCC (73 patients in T1, 39 patients in T2, 20 patients in T3, and 6 patients in T4) and 40 healthy controls. Serum levels of endostatin were measured by sandwich-ELISA. Associations between circulating endostatin levels and clinicopathologic factors and clinical outcome were determined. RESULTS: Endostatin levels did not differ significantly between the patients with CCRCC (93.1 microg/L) and healthy controls (78.9 microg/L, P > 0.05). Serum levels of endostatin were significantly higher in the T2-4 CCRCC patients (107.2 microg/L) than those of the T1 patients (80.4 microg/L, P < 0.01). No significant difference was found in the endostatin levels among the T2-4 patients, or between healthy controls and the T1 patients. The serum endostatin concentration was significantly higher in the metastasis group (118.4 microg/L) than in the no metastasis group (89.5 microg/L, P < 0.05), but there was no significant difference between patients with distant metastasis group (122.0 microg/L) and lymph nodes metastasis (110.0 microg/L, P > 0.05). Patients with G3-4 tumors had significantly higher endostatin levels (111.8 microg/L) than those of patients with G1 (80.4 microg/L) and G2 tumors (86.2 microg/L, P < 0.01), but endostatin levels did not differ significantly between the two groups (P > 0.05). CONCLUSION: Preoperative serum levels of endostatin elevated in patients with CCRCC and associated with higher stage and grade.

High fidelity screening of regulatory sequences in apolipoprotein(a)-plasminogen cluster.

Identifying networks of gene expression regulation is one of the major tasks in the post-genomic era, this demands firstly high throughput identification of regulatory elements. Apolipoprotein(a)-plasminogen cluster is closely related to both atherosclerosis and thrombosis, and forms a link between the two systems. The mechanism regulating expression of this cluster, through which the balance between atherosclerosis and thrombosis is achieved, is far from been fully understood. Polymerase chain reaction based strategies for screening of regulatory sequences are both simple and efficient yet face severe problems of contamination and sequence mutations. In this work, entity self-competition electrophoresis mobility shift assay and differential library hybridization are introduced to overcome the problems. Cis-element candidates are picked out from a library generated from the screening region, thus avoiding the effect of repetitive amplifications. Sequence fidelity of the selected fragments is guaranteed and one by one identification of each fragment by self-competition is unnecessary. Using this method, 32 potential regulatory elements in apolipoprotein(a)-plasminogen gene cluster were found, including three of the four known DNase I hypersensitive sites in the cluster, attesting the efficiency of our method. We also find an intron-locating element, which is repeatedly screened out. A new in vivo electrophoresis mobility shift assay method based on in situ digestion of crosslinked chromatin DNA and southern hybridization is established for the detection of in vivo protein binding status in the intron region. The result supports our hypothesis that the element may play an important role in expression regulation or evolution of apolipoprotein(a) gene.