Comprehensive analysis of m6 A methylome and transcriptome by Nanopore sequencing in clear cell renal carcinoma.

N6 -methyladenosine (m6 A) is the most prevalent epigenetic modification on eukaryotic messenger RNAs. Recent studies have focused on elucidating the key role of m6 A modification patterns in tumor progression. However, the relationship between m6 A and transcriptional regulation remains elusive. Nanopore technology enables the quantification of m6 A levels at each genomic site. In this study, a pair of tumor tissues and adjacent normal tissues from clear cell renal cell carcinoma (ccRCC) surgical samples were collected for Nanopore direct RNA sequencing. We identified 9644 genes displaying anomalous m6 A modifications, with 5343 genes upregulated and 4301 genes downregulated. Among these, 5224 genes were regarded as dysregulated genes, encompassing abnormal regulation of both m6 A modification and RNA expression. Gene Set Enrichment Analysis revealed an enrichment of these genes in pathways related to renal system progress and fatty acid metabolic progress. Furthermore, the χ2 test demonstrated a significant association between the levels of m6 A in dysregulated genes and their transcriptional expression levels. Additionally, we identified four obesity-associated genes (FTO, LEPR, ADIPOR2, and NPY5R) among the dysregulated genes. Further analyses using public databases revealed that these four genes were all related to the prognosis and diagnosis of ccRCC. This study introduced the novel approach of employing conjoint analysis of m6 A modification and RNA expression based on Nanopore sequencing to explore potential disease-related genes. Our work demonstrates the feasibility of the application of Nanopore sequencing technology in RNA epigenetic regulation research and identifies new potential therapeutic targets for ccRCC.

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.

Efficacy and safety of surgery in renal carcinoma patients 75 years and older: a retrospective analysis.

OBJECTIVE: To investigate the efficacy and complications of surgical treatment in patients with renal cell carcinoma aged ≥ 75 years. METHODS: From January 2009 to May 2019, we assessed 166 patients aged 75 years and older, who either had radical nephrectomy (RN) or partial nephrectomy (PN) as treatments for diagnosed renal cell carcinoma. Patients were divided into one group of patients aged 75-79 years and the second group of patients ≥ 80 years. The complications and survival were compared between the two groups. RESULTS: All 166 patients were successfully operated on. Differences between the two groups were statistically significant in intraoperative and postoperative complications and Clavien-Dindo score of ≥ 1 (P = 0.02, P < 0.001, P = 0.001). Univariate analysis revealed no significant correlation between a Clavien-Dindo score ≥ 1 versus gender, body mass index (BMI), lack of symptoms, KPS, baseline GFR, postoperative GFR, tumor size, tumor location, surgical method, and transfusion or no transfusion (ALL P > 0.05). Multifactor analysis showed that age ≥ 80 years, partial nephrectomy, and operation time were independent predictors of a Clavien-Dindo score ≥ 1. No significant difference was found in OS between the two groups, (P < 0.0001), and no significant difference in CSS (P = 0.056). There was no significant difference in OS and CSS between the RN and PN groups (P = 0.143, P = 0.281, respectively). CONCLUSIONS: According to our findings, the overall safety of surgical therapy for elderly patients with renal cell carcinoma is adequate. PN should be carefully examined, especially over the age of 80. To select suitable patients based on an assessment of the tumor's complexity and patients' physical condition, such as age, underlying diseases and other conditions, technical feasibility, balance of benefits and a case-by-case.

Prognostic value of the ratio of maximum to minimum diameter of primary tumor in metastatic clear cell renal cell carcinoma.

BACKGROUND: Several models and markers were developed and found to predict outcome of advanced renal cell carcinoma. This study aimed to evaluate the prognostic value of the ratio of maximum to minimum tumor diameter (ROD) in metastatic clear cell renal cell carcinoma (mccRCC). METHODS: Patients with mccRCC (n = 213) treated with sunitinib from January 2008 to December 2018 were identified. Cutoff value for ROD was determined using receiver operating characteristic. Patients with different ROD scores were grouped and evaluated. Survival outcomes were estimated by Kaplan-Meier method. RESULTS: The optimal ROD cutoff value of 1.34 was determined for progression free survival (PFS) and overall survival (OS). Patients in ROD ≥ 1.34 group had shorter PFS (9.6 versus 17.7 months, p < 0.001) and OS (25.5 versus 32.6 months, p < 0.001) than patients in ROD < 1.34 group. After adjustment for other factors, multivariate analysis showed ROD ≥ 1.34 was an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.006). Patients in ROD ≥ 1.34 group presented higher proportions of pT3/4 stage (89.2% versus 10.8%, p = 0.021), WHO/ISUP grade III/IV (72.0% versus 28.0%, p = 0.010), tumor necrosis (71.0% versus 29.0%, p = 0.039), sarcomatoid differentiation (79.1% versus 20.9%, p = 0.007), poor MSKCC risk score (78.4% versus 21.6%, p < 0.001) and poor IMDC risk score (74.4% versus 25.6%, p < 0.001) than ROD < 1.34 group. CONCLUSION: Primary tumor with higher ROD was an independently prognostic factor for both PFS and OS in patients with mccRCC who received targeted therapy. Higher ROD was also associated with high pT stage, high WHO/ISUP grade, sarcomatoid features, tumor necrosis, poor MSKCC and IMDC risk score.

Novel cut-off values of time from diagnosis to systematic therapy predict the overall survival and the efficacy of targeted therapy in renal cell carcinoma: A long-term, follow-up, retrospective study.

OBJECTIVES: Metastatic renal cell carcinoma can occur synchronously or metachronously. We characterized the time from diagnosis to systematic therapy as a categorical variable to analyze its effect on the overall survival and first-line treatment efficacy of metastatic renal cell carcinoma patients. METHODS: We initially enrolled 949 consecutive metastatic renal cell carcinoma patients treated with targeted therapies retrospectively from December 2005 to December 2019. X-tile analysis was used to determine cut-off values of time from diagnosis to systematic therapy referring to overall survival. Patients were divided into different groups based on the time from diagnosis to systematic therapy and then analyzed for survival. RESULTS: Of 358 eligible patients with metastatic renal cell carcinoma, 125 (34.9%) had synchronous metastases followed by cytoreductive nephrectomy, and 233 (65.1%) had metachronous metastases. A total of 28 patients received complete metastasectomy. Three optimal cut-off values for the time from diagnosis to systematic therapy (months) - 1.1, 7.0 and 35.9 - were applied to divide the population into four groups: the synchro group (time from diagnosis to systematic therapy ≤1.0), early group (1.0 < time from diagnosis to systematic therapy ≤ 7.0), intermediate group (7.0 < time from diagnosis to systematic therapy < 36.0) and late group (time from diagnosis to systematic therapy ≥36.0). The targeted therapy-related overall survival (P < 0.001) and progression-free survival (P < 0.001) values were significantly different among the four groups. Patients with longer time from diagnosis to systematic therapy had better prognoses and promising efficacy of targeted therapy. With the prolongation of time from diagnosis to systematic therapy, complete metastasectomy was more likely to achieve and bring a better prognosis. CONCLUSIONS: The time from diagnosis to systematic therapy impacts the survival of metastatic renal cell carcinoma patients treated with targeted therapy. The cutoff points of 1, 7 and 36 months were statistically significant. The statistical boundaries might be valuable in future model establishment.

A novel nomogram can predict pathological T3a upstaged from clinical T1a in localized renal cell carcinoma.

HYPOTHESIS: Nomogram can be built to predict the pathological T3a upstaging from clinical T1a in patients with localized renal cell carcinoma before surgery. PURPOSE: Renal cell carcinoma (RCC) patients with clinical T1a (cT1a) disease who are upstaged to pathological T3a (pT3a) have reduced survivals after partial nephrectomy. We aimed to develop a nomogram-based model predicting pT3a upstaging in RCC patients with preoperative cT1a based on multiple preoperative blood indexes and oncological characteristics. MATERIALS AND METHODS: Between 2010 and 2019, 510 patients with cT1a RCC were individually matched according to pT3a upstaging and pathological T1a (pT1a) at a 1:4 ratio using clinicopathologic features. Least absolute shrinkage and selection operator regression analysis was used to identify the most important risk factor from 40 peripheral blood indicators, and a predictive model was established. Multivariate logistic regression analysis was performed with the screened blood parameters and clinical data to identify significant variables. Harrell's concordance index (C-index) was applied to evaluate the accuracy of the model for predicting pT3a upstaging in patients with cT1a RCC. RESULTS: Out of 40 blood indexes, the top ranked predictor was fibrinogen (FIB). Age, the ratio of the tumor maximum and minimum diameter (ROD), FIB, and tumor size were all independent risk factors for pT3a upstaging in multivariate analysis. A predictive ARFS model (Age, ROD, FIB, tumor Size) was established, and the C-index was 0.756 (95% CI, 0.681-0.831) and 0.712 (95% CI, 0.638-0.785) in the training and validation cohorts, respectively. CONCLUSIONS: Older age, higher ROD, increased FIB level, and larger tumor size were independent risk factors for upstaging. The ARFS model has a high prediction efficiency for pT3a upstaging in patients with cT1a RCC.

Efficacy and safety of oncolytic viruses in advanced or metastatic cancer: a network meta-analysis.

BACKGROUND: Oncolytic viruses (OVs) have shown prospects in advanced and metastatic cancer, and many clinical trials have been carried out. To compare OV therapies comprehensively and provide a categorized profile and ranking of efficacy and safety, a network meta-analysis was conducted. METHODS: A total of 5948 studies were screened and 13 randomized controlled trials with 1939 patients, of whom 1106 patients received OV therapies, comparing four OVs (NTX-010, pexastimogene devacirepvec (Pexa-Vec), talimogene laherparepvec (T-VEC), and pelareorep) were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: objective response rate (ORR) and grade ≥ 3 adverse events. RESULTS: Compared to systemic treatments alone, talimogene laherparepvec (T-VEC) (OR 7.00, 95% CI 1.90-26.00) and T-VEC plus systemic treatment (2.90, 0.80-11.00) showed better objective response rates (ORRs), whereas Pexa-Vec 1 * 109 pfu plus systemic treatment (0.91, 0.26-3.00) and pelareorep plus systemic treatment (1.10, 0.61-2.00) were found to be comparable. The grade ≥ 3 adverse event ranking of the treatments from worst to best was as follows: T-VEC (ranking probability 24%), Pexa-Vec 1 * 109 pfu plus systemic treatment (21%), Pexa-Vec 1 * 109 pfu (17%), T-VEC plus systemic treatment (13%), pelareorep plus systemic treatment (13%), systemic treatments (18%), Pexa-Vec 1 * 108 pfu (12%), and NTX-010 (20%). CONCLUSIONS: Compared with other oncolytic virus therapies for patients with advanced or metastatic cancer, T-VEC and T-VEC plus systemic treatment appear to provide the best ORR therapy in terms of monotherapy and combination respectively, but should be given with caution to grade ≥ 3 adverse events. Conversely, combining OVs with chemotherapy or target agents was demonstrated not to improve efficacy compared with chemotherapy or target agents alone. Combining OV therapies with immune-checkpoint inhibitors, instead of chemotherapy or target agents, tended to provide better ORRs without causing severe adverse events. This study will guide treatment choice and optimize future trial designs for investigations of advanced or metastatic cancer.

Characteristics, dynamic changes, and prognostic significance of TCR repertoire profiling in patients with renal cell carcinoma.

The co-evolving tumour cells and the systemic immune environment are mutually dysregulated. Tumours affect the immune response in a complex manner. For example, although lymphocytes are mobilized in response to tumours, their function is impaired by tumour progression. This study aimed to explore how the baseline and dynamic renal cell carcinoma (RCC) tumour burdens affect the T-cell repertoire, and whether the baseline T-cell receptor ß-chain (TCRB) diversity predicts prognosis. To characterise the TCRB repertoire, the baseline and follow-up peripheral TCRB repertoires of 45 patients with RCC and 2 patients with benign renal disease patients were examined using high-throughput TCRB sequencing. To explain the significance of TCRB diversity, 56 peripheral leukocyte samples from 28 patients before and after surgery were subjected to transcriptome sequencing. To validate the results, an advanced RCC patient's sample was subjected to single-cell RNA sequencing (scRNA, 10x Genomics). Higher TCRB diversity was found to be correlated with a higher lymphocyte-to-neutrophil ratio, especially indicating more naïve T cells. High-baseline TCRB diversity predicted a better prognosis for stage IV patients, and different tumour burdens exerted distinct effects on the immune status. The pre-operative TCRB diversity was significantly higher in benign and stage I (low tumour burden) RCC patients than in stage IV (high tumour burden) patients. After the tumour burden of advanced patients was mostly relieved, we observed that the TCRB diversity was restored, T-cell exhaustion was reduced, and naïve T-cells were mobilized. It was demonstrated that the circulating TCRB repertoire could reflect the immune status and predict prognosis, and to some extent that cytoreductive nephrectomy (CN) reduces the burden of the immune system in advanced patients, which might provide a good opportunity for immunotherapy. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

High PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor in urothelial carcinoma.

Aims: To explore the prognostic value of high PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (TIIC) in urothelial carcinoma (UC). Patients & methods: 162 UC specimens were evaluated for PD-L1 expression on TIIC and TC with the SP263 assay. High PD-L1 expression was defined as ≥25% staining. Results: High PD-L1 expression on TC in UC patients with stage T1-4 disease was associated with poor overall survival. However, high PD-L1 expression on TIIC in UC patients with stage T1-4 disease revealed favorable disease-free and overall survival; more significant differences were observed in patients with stages T2-4. Multivariate analysis revealed that high PD-L1 expression on TIIC was an independent prognostic predictor for better disease-free and overall survival. Conclusion: High PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in UC.

Lay abstract Bladder cancer is the tenth most common form of cancer worldwide, and urothelial carcinoma is the most common type of bladder cancer. PD-L1 is a protein that can be expressed on the surface of many tissue types, including tumor cells (TC) and tumor-infiltrating immune cells (TIIC). PD-L1 can help the tumor evade the body's natural immune defense system. The expression of PD-L1 not only related to the response of immunotherapy but is also associated with the prognosis in bladder cancer. However, the prognostic significance of PD-L1 expression on TC and TIIC remains controversial. This study drew a conclusion that high PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in urothelial carcinoma.

Long-term survival and prognostic factors for locally advanced renal cell carcinoma with renal vein tumor thrombus.

BACKGROUND: Previous related studies have mainly focused on renal cell carcinoma (RCC) with venous tumor thrombus, specifically inferior vena cava tumor thrombus with renal vein tumor thrombus (RVTT). However, only a few studies have focused on postoperative long-term survival of RCC patients exclusively with RVTT. Our aim was to investigate the independent prognostic factors for locally advanced RCC with RVTT in China. METHODS: Patients with locally advanced RCC with RVTT were enrolled for the study from January 2000 to December 2015. All patients underwent radical nephrectomy. Survival analysis was estimated using Kaplan-Meier. Univariable and multivariable survival analyses were performed using COX. Patients were divided into high-risk, middle-risk, and low-risk groups based on independent prognostic factors and then analyzed for survival. RESULTS: One hundred twenty-eight consecutive patients (103 men & 25 women) were enrolled with a median age of 61 years. Thrombi were all graded 0 using the Mayo system, of which 23 were friable. None of the thrombi detached during surgery. 121 patients were successfully followed up, with a median follow-up period of 47 months. Median overall survival was 127 months (95%CI: 101-153). The 5-year and 10-year cancer-specific survival (CSS) rate was 67.9 and 57.0%. 59 patients had recurrence with median time of 40 months. Friable thrombus, paraneoplastic syndrome (PNS), modified Fuhrman grade 3/4 and perirenal fat invasion were independent prognostic factors (p < 0.05). The 5-year CSS for the Low-risk group (no factors) was 100%, Middle-risk group (1-2 factors) was 68.6%, while the High-risk group (3-4 factors) was 0%. CONCLUSIONS: After radical surgery, RCC patients with RVTT had a relatively fair prognosis except for patients with friable thrombus, PNS, higher modified Fuhrman grade and perirenal fat invasion.

Nucleus-Aware Self-Supervised Pretraining Using Unpaired Image-to-Image Translation for Histopathology Images.

Self-supervised pretraining attempts to enhance model performance by obtaining effective features from unlabeled data, and has demonstrated its effectiveness in the field of histopathology images. Despite its success, few works concentrate on the extraction of nucleus-level information, which is essential for pathologic analysis. In this work, we propose a novel nucleus-aware self-supervised pretraining framework for histopathology images. The framework aims to capture the nuclear morphology and distribution information through unpaired image-to-image translation between histopathology images and pseudo mask images. The generation process is modulated by both conditional and stochastic style representations, ensuring the reality and diversity of the generated histopathology images for pretraining. Further, an instance segmentation guided strategy is employed to capture instance-level information. The experiments on 7 datasets show that the proposed pretraining method outperforms supervised ones on Kather classification, multiple instance learning, and 5 dense-prediction tasks with the transfer learning protocol, and yields superior results than other self-supervised approaches on 8 semi-supervised tasks. Our project is publicly available at https://github.com/zhiyuns/UNITPathSSL.

MSNSegNet: attention-based multi-shape nuclei instance segmentation in histopathology images.

In clinical research, the segmentation of irregularly shaped nuclei, particularly in mesenchymal areas like fibroblasts, is crucial yet often neglected. These irregular nuclei are significant for assessing tissue repair in immunotherapy, a process involving neovascularization and fibroblast proliferation. Proper segmentation of these nuclei is vital for evaluating immunotherapy's efficacy, as it provides insights into pathological features. However, the challenge lies in the pronounced curvature variations of these non-convex nuclei, making their segmentation more difficult than that of regular nuclei. In this work, we introduce an undefined task to segment nuclei with both regular and irregular morphology, namely multi-shape nuclei segmentation. We propose a proposal-based method to perform multi-shape nuclei segmentation. By leveraging the two-stage structure of the proposal-based method, a powerful refinement module with high computational costs can be selectively deployed only in local regions, improving segmentation accuracy without compromising computational efficiency. We introduce a novel self-attention module to refine features in proposals for the sake of effectiveness and efficiency in the second stage. The self-attention module improves segmentation performance by capturing long-range dependencies to assist in distinguishing the foreground from the background. In this process, similar features get high attention weights while dissimilar ones get low attention weights. In the first stage, we introduce a residual attention module and a semantic-aware module to accurately predict candidate proposals. The two modules capture more interpretable features and introduce additional supervision through semantic-aware loss. In addition, we construct a dataset with a proportion of non-convex nuclei compared with existing nuclei datasets, namely the multi-shape nuclei (MsN) dataset. Our MSNSegNet method demonstrates notable improvements across various metrics compared to the second-highest-scoring methods. For all nuclei, the D i c e score improved by approximately 1.66 % , A J I by about 2.15 % , and D i c e obj by roughly 0.65 % . For non-convex nuclei, which are crucial in clinical applications, our method's A J I improved significantly by approximately 3.86 % and D i c e obj by around 2.54 % . These enhancements underscore the effectiveness of our approach on multi-shape nuclei segmentation, particularly in challenging scenarios involving irregularly shaped nuclei.

MRI evaluation of vesical imaging reporting and data system for bladder cancer after neoadjuvant chemotherapy.

BACKGROUND: The Vesical Imaging-Reporting and Data System (VI-RADS) has demonstrated effectiveness in predicting muscle invasion in bladder cancer before treatment. The urgent need currently is to evaluate the muscle invasion status after neoadjuvant chemotherapy (NAC) for bladder cancer. This study aims to ascertain the accuracy of VI-RADS in detecting muscle invasion post-NAC treatment and assess its diagnostic performance across readers with varying experience levels. METHODS: In this retrospective study, patients with muscle-invasive bladder cancer who underwent magnetic resonance imaging (MRI) after NAC from September 2015 to September 2018 were included. VI-RADS scores were independently assessed by five radiologists, consisting of three experienced in bladder MRI and two inexperienced radiologists. Comparison of VI-RADS scores was made with postoperative histopathological diagnosis. Receiver operating characteristic curve analysis (ROC) was used for evaluating diagnostic performance, calculating sensitivity, specificity, and area under ROC (AUC)). Interobserver agreement was assessed using the weighted kappa statistic. RESULTS: The final analysis included 46 patients (mean age: 61 years ± 9 [standard deviation]; age range: 39-70 years; 42 men). The pooled AUC for predicting muscle invasion was 0.945 (95% confidence interval (CI): 0.893-0.977) for experienced readers, and 0.910 (95% CI: 0.831-0.959) for inexperienced readers, and 0.932 (95% CI: 0.892-0.961) for all readers. At an optimal cut-off value ≥ 4, pooled sensitivity and specificity were 74.1% (range: 66.0-80.9%) and 94.1% (range: 88.6-97.7%) for experienced readers, and 63.9% (range: 59.6-68.1%) and 86.4% (range: 84.1-88.6%) for inexperienced readers. Interobserver agreement ranged from substantial to excellent between all readers (k = 0.79-0.92). CONCLUSIONS: VI-RADS accurately assesses muscle invasion in bladder cancer patients after NAC and exhibits good diagnostic performance across readers with different experience levels.

Downstaging guided neoadjuvant strategy shift and bladder preservation in locally advanced bladder cancer: A case report.

Background: The study of bladder preservation for muscle-invasive bladder cancer (MIBC) mainly focuses on the T2 stage, which remains difficult in the T3 and T4 stage. Pembrolizumab has been applied as neoadjuvant therapy followed by radical cystectomy for MIBC, gaining encouraging results in the phase II study. Disitamab vedotin, an antibody-drug conjugate (ADC), also achieved promising efficacy for refractory bladder cancer. However, the neoadjuvant therapy strategy of these drugs for bladder sparing remains further exploration. Case presentation: A patient with locally advanced MIBC at our institute underwent a neoadjuvant therapeutic regimen followed by transurethral resection of bladder tumor (TURBT) and concurrent chemoradiotherapy. In light of limited initial efficacy, we enacted an adaptive shift in the neoadjuvant treatment strategy, transitioning from a combination of gemcitabine, cis-platinum, and pembrolizumab to disitamab vedotin with pembrolizumab. This approach ultimately achieved bladder preservation, complete response, and a remarkable 1-year disease-free survival (DFS). Conclusion: Proactive evaluation in the early stages of tumor downstaging can serve as a guiding principle for neoadjuvant strategies. This is the first successful case of neoadjuvant pembrolizumab combined with disitamab vedotin and chemotherapy in MIBC patients achieving complete response and bladder preservation.

Cigarette smoking-related OLC1 overexpression associated with poor prognosis in bladder urothelial carcinoma.

AIMS: To explore the clinical significance of OLC1 and cigarette smoking in bladder urothelial carcinoma (UBC). MATERIALS AND METHODS: OLC1 mRNA expression was detected in 106 UBC samples by mRNA array or reverse real-time PCR. OLC1 protein expression in 114 UBC samples was detected by immunohistochemical staining. Wild-type C57BL/6J mice were injected with cigarette smoke condensate (n = 12) or exposed to cigarette smoke (n = 6) to investigate the correlations between cigarette smoking and OLC1 expression using mRNA array. KEY FINDINGS: The mRNA and protein expression of OLC1 were higher in tumor samples (p < 0.01) and significantly correlated with tumor stage (p < 0.05). OLC1 protein expression and smoking history were correlated with disease-free survival (p < 0.05). OLC1 expression was significantly elevated in smoking patients with higher smoking intensity on both mRNA and protein levels (p < 0.05). Cigarette smoke exposure experiments revealed that OLC1 mRNA overexpressed in bladder uroepithelium of mice. SIGNIFICANCE: OLC1 could serve as a potential prognosis biomarker of UBC, especially for smoking 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.

Cyclic Learning: Bridging Image-Level Labels and Nuclei Instance Segmentation.

Nuclei instance segmentation on histopathology images is of great clinical value for disease analysis. Generally, fully-supervised algorithms for this task require pixel-wise manual annotations, which is especially time-consuming and laborious for the high nuclei density. To alleviate the annotation burden, we seek to solve the problem through image-level weakly supervised learning, which is underexplored for nuclei instance segmentation. Compared with most existing methods using other weak annotations (scribble, point, etc.) for nuclei instance segmentation, our method is more labor-saving. The obstacle to using image-level annotations in nuclei instance segmentation is the lack of adequate location information, leading to severe nuclei omission or overlaps. In this paper, we propose a novel image-level weakly supervised method, called cyclic learning, to solve this problem. Cyclic learning comprises a front-end classification task and a back-end semi-supervised instance segmentation task to benefit from multi-task learning (MTL). We utilize a deep learning classifier with interpretability as the front-end to convert image-level labels to sets of high-confidence pseudo masks and establish a semi-supervised architecture as the back-end to conduct nuclei instance segmentation under the supervision of these pseudo masks. Most importantly, cyclic learning is designed to circularly share knowledge between the front-end classifier and the back-end semi-supervised part, which allows the whole system to fully extract the underlying information from image-level labels and converge to a better optimum. Experiments on three datasets demonstrate the good generality of our method, which outperforms other image-level weakly supervised methods for nuclei instance segmentation, and achieves comparable performance to fully-supervised methods.

Neutrophil extracellular traps primed intercellular communication in cancer progression as a promising therapeutic target.

In addition to the anti-infection response, neutrophils are linked to tumor progression through the secretion of inflammation components and neutrophil extracellular traps (NETs) formation. NET is a web-like structure constituted by a chromatin scaffold coated with specific nuclear and cytoplasmic proteins, such as histone and granule peptides. Increasing evidence has demonstrated that NETs are favorable factors to promote tumor growth, invasion, migration, and immunosuppression. However, the cell-cell interaction between NETs and other cells (tumor cells and immune cells) is complicated and poorly studied. This work is the first review to focus on the intercellular communication mediated by NETs in cancer. We summarized the complex cell-cell interaction between NETs and other cells in the tumor microenvironment. We also address the significance of NETs as both prognostic/predictive biomarkers and molecular targets for cancer therapy. Moreover, we presented a comprehensive landscape of cancer immunity, improving the therapeutic efficacy for advanced cancer in the future.