A Multi-Gene Signature of Non-Muscle-Invasive Bladder Cancer Identifies Patients Who Respond to Immunotherapies Including Bacillus Calmette-Guérin and Immune Checkpoint Inhibitors.

Approximately 75% of bladder cancer cases originate as non-muscle-invasive bladder cancer (NMIBC). Despite initial diagnosis, NMIBC commonly recurs, with up to 45% advancing to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for high-risk NMIBC typically includes procedures like transurethral resection and, depending on recurrence risk, intravesical chemotherapy or immunotherapy such as Bacillus Calmette-Guérin (BCG). However, persistent shortages of BCG necessitate alternative first-line treatments. We aim to use a multi-gene signature in high-risk NMIBC patients to determine whether patients may benefit from immune checkpoint inhibitors (ICIs) as an alternative to BCG and to evaluate their clinical utility. The multi-gene signature obtained from the three independent NMIBC cohorts was applied to stratify the UROMOL2016 cohort (n = 476) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis using a machine learning algorithm was performed in six independent cohorts including the BRS (n = 283) cohort treated with BCG and the IMvigor210 (n = 298) clinical trials treated with PD-L1 inhibitors. Based on consensus cluster analysis, NMIBC patients in the UROMOL2016 cohort were classified into three classes exhibiting distinguished characteristics, including DNA damage repair (DDR). Survival analysis showed that the NMIBC-DDR class had the highest rates of disease progression (progression-free survival, p = 0.002 by log-rank test) in the UROMOL cohort and benefited from BCG and ICIs (respectively, p = 0.02 and p = 0.03 by log-rank test). This study suggests that the multi-gene signature may have a role in identifying high-risk NMIBC patients and improving the responsiveness of ICIs. Additionally, we propose immunotherapy as a new first-line treatment for patients with high-risk NMIBC because of the shortage of BCG supply. It is important to help more patients prioritize cancer immunotherapy.

Does Small Aneurysm Size (<10 mm) Predict Complete Occlusion After Flow Diversion? A Surpass Evolve Single-Center Study.

BACKGROUND: Long-term safety and efficacy outcomes of Surpass Evolve flow diverter (SEFD) in treatment of intracranial aneurysms are lacking. Factors predicting complete aneurysm occlusion are elusive in literature. METHODS: A retrospective review of all consecutive aneurysms treated with SEFD from February 2020 to July 2022, at a single comprehensive stroke center. RESULTS: Fifty-one patients with 80 aneurysms were included. Mean target aneurysm size was 5.6 mm and mean neck-width 3.42 mm. Small aneurysms (<10 mm) were 75% (n=60), while 25% were >10 mm. Unruptured were 71 (88.7%), previously ruptured were 8 (10%), and partially thrombosed 2.3% (n=1). Mean SEFDs used per patient were 1.07 and 40% (n=22) procedures were performed transradially. Mean procedure time was 59.1 minutes. The technical success rate for device deployment was 100%. Raymond Roy (RR) class I occlusion at 6 month (n=73) was seen among 56.2% (n=41), at 1 year (n=35) among 85.7% (n=30) and at 2 year (n=18) among 88.8% (n=16) aneurysms. Aneurysm size <10 mm significantly predicted RR-I occlusion outcome (odds ratio [OR]: 2.16; confidence interval [CI]: 0.02-4.29) at 6 months. Age, gender, smoking status, hypertension, location of aneurysm, and rupture status did not predict RR-I occlusion outcome. No mortality or permanent neurological morbidity was observed in the cohort. Major complications seen in 7.2% (n=4) patients were stent thrombosis (n=1, 1.8%), carotid-cavernous fistula (n=1, 1.8%) and transient ischemia in 2 (3.6%). Non-flow limiting stenosis was observed in 3 (5.4%) patients. CONCLUSION: SEFD gives good aneurysm occlusion rates with favorable long-term safety profile and low rate of thromboembolic complications. Small aneurysm size (<10 mm) was associated with complete aneurysm occlusion at 6-month angiographic follow-up. CLINICAL IMPACT: As Surpass Evolve is a newer generation Flow diverter of the Stryker Surpass FDs, with its improved design and applicability in intracranial aneurysms, we believe that more physicians will be encouraged to use this device worldwide.

Stepwise molecular mechanisms responsible for chemoresistance in bladder cancer cells.

Chemotherapy resistance is an obstacle to cancer therapy and is considered a major cause of recurrence. Thus, understanding the mechanisms of chemoresistance is critical to improving the prognosis of patients. Here, we have established a stepwise gemcitabine-resistant T24 bladder cancer cell line to understand the molecular mechanisms of chemoresistance within cancer cells. The characteristics of the stepwise chemoresistance cell line were divided into 4 phases (parental, early, intermediate, and late phases). These four phase cells showed increasingly aggressive phenotypes in vitro and in vivo experiments with increasing phases and revealed the molecular properties of the biological process from parent cells to phased gemcitabine-resistant cell line (GRC). Taken together, through the analysis of gene expression profile data, we have characterized gene set of each phase indicating the response to anticancer drug treatment. Specifically, we identified a multigene signature (23 genes including GATA3, APOBEC3G, NT5E, MYC, STC1, FOXD1, SMAD9) and developed a chemoresistance score consisting of that could predict eventual responsiveness to gemcitabine treatment. Our data will contribute to predicting chemoresistance and improving the prognosis of bladder cancer patients.

Secretory SERPINE1 Expression Is Increased by Antiplatelet Therapy, Inducing MMP1 Expression and Increasing Colon Cancer Metastasis.

Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.

YAP1 activation is associated with the progression and response to immunotherapy of non-muscle invasive bladder cancer.

BACKGROUND: Despite the availability of several treatments for non-muscle-invasive bladder cancer (NMIBC), many patients are still not responsive to treatments, and the disease progresses. A new prognostic classifier can differentiate between treatment response and progression, and it could be used as a very important tool in patient decision-making regarding treatment options. In this study, we focused on the activation of Yes-associated protein 1 (YAP1), which is known to play a pivotal role in tumour progression and serves as a factor contributing to the mechanism of resistance to various relevant therapeutic agents. We further evaluated its potential as a novel prognostic agent. METHODS: We identified YAP1-associated gene signatures based on UC3-siYAP1 cells (n=8) and NMIBC cohort (n=460). Cross-validation was performed using 5 independent bladder cancer patient cohorts (n=1006). We also experimentally validated the changes of gene expression levels representing each subgroup. FINDINGS: The 976-gene signature based on YAP1-activation redefined three subgroups and had the benefits of Bacillus Calmette-Guérin (BCG) treatment in patients with NMIBC (hazard ratio 3.32, 95% CI 1.29-8.56, p = 0.01). The integrated analysis revealed that YAP1 activation was associated with the characterization of patients with high-risk NMIBC and the response to immunotherapy. INTERPRETATION: This study suggests that YAP1 activation has an important prognostic effect on bladder cancer progression and might be useful in the selection of immunotherapy. FUNDING: A funding list that contributed to this research can be found in the Acknowledgements section.

Transcriptomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence.

OBJECTIVES: Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. METHODS: This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. RESULTS: Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension). CONCLUSION: We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer.

E2F1 Promotes Progression of Bladder Cancer by Modulating RAD54L Involved in Homologous Recombination Repair.

DNA repair defects are important factors in cancer development. High DNA repair activity can affect cancer progression and chemoresistance. DNA double-strand breaks in cancer cells caused by anticancer agents can be restored by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Our previous study has identified E2F1 as a key gene in bladder cancer progression. In this study, DNA repair genes related to E2F1 were analyzed, and RAD54L involved in HRR was identified. In gene expression analysis of bladder cancer patients, the survival of patients with high RAD54L expression was shorter with cancer progression than in patients with low RAD54L expression. This study also revealed that E2F1 directly binds to the promoter region of RAD54L and regulates the transcription of RAD54L related to the HRR pathway. This study also confirmed that DNA breaks are repaired by RAD54L induced by E2F1 in bladder cancer cells treated with MMC. In summary, RAD54L was identified as a new target directly regulated by E2F1. Our results suggest that, E2F1 and RAD54L could be used as diagnostic markers for bladder cancer progression and represent potential therapeutic targets.

Transcriptional Profiling of Advanced Urothelial Cancer Predicts Prognosis and Response to Immunotherapy.

Recent investigations reported that some subtypes from the Lund or The Cancer Genome Atlas (TCGA) classifications were most responsive to PD-L1 inhibitor treatment. However, the association between previously reported subtypes and immune checkpoint inhibitor (ICI) therapy responsiveness has been insufficiently explored. Despite these contributions, the ability to predict the clinical applicability of immune checkpoint inhibitor therapy in patients remains a major challenge. Here, we aimed to re-classify distinct subtypes focusing on ICI responsiveness using gene expression profiling in the IMvigor 210 cohort (n = 298). Based on the hierarchical clustering analysis, we divided advanced urothelial cancer patients into three subgroups. To confirm a prognostic impact, we performed survival analysis and estimated the prognostic value in the IMvigor 210 and TCGA cohort. The activation of CD8+ T effector cells was common for patients of classes 2 and 3 in the TCGA and IMvigor 210 cohort. Survival analysis showed that patients of class 3 in the TCGA cohort had a poor prognosis, while patients of class 3 showed considerably prolonged survival in the IMvigor 210 cohort. One of the distinct characteristics of patients in class 3 is the inactivation of the TGFß and YAP/TAZ pathways and activation of the cell cycle and DNA replication and DNA damage (DDR). Based on our identified transcriptional patterns and the clinical outcomes of advanced urothelial cancer patients, we constructed a schematic summary. When comparing clinical and transcriptome data, patients with downregulation of the TGFß and YAP/TAZ pathways and upregulation of the cell cycle and DDR may be more responsive to ICI therapy.

Time-dependent change in pain threshold following neurolytic celiac plexus block.

Aim: To determine the long-term effect of ethanol relative to the re-occurrence of pain in postneurolytic celiac plexus block (NCPB) patients. Patients & methods: A noninterventional study on 31 patients who had undergone NCPB to illustrate the average change of pain score over time. Results: All NCPB patients reported a pain score decrease of 83.8% right after the procedure. 73% of patients reported 50-66% decrease in pain 80-100 days postprocedure. The temporal threshold for the return of pain scores to average preblock level was determined to be 103 post-NCPB procedure days. Conclusion: In this study, NCPB patients demonstrate return of pain to baseline subsequent to the analgesic effects of ethanol after a mean 103 days.

Pseudoprogression presenting as intestinal perforation in non-small cell lung cancer treated with anti-PD-1: A case report.

Pseudoprogression is not frequently observed in patients with non-small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. We report on a case of pseudoprogression, which was presented as intestinal perforation after pembrolizumab immunotherapy for NSCLC. A-54-year-old man with stage IV NSCLC received pembrolizumab therapy. The patient was admitted to our hospital because of acute abdominal pain and the computed tomography scan revealed diffuse wall thickening of the small bowel with free intraperitoneal air. Intestinal perforation was suspected and surgical resection was performed. Histological evaluation of the resected specimen showed infiltrated lymphocytes positive for CD3, CD8 with necrotic tumor cells, suggestive of an immune reaction. Although intestinal perforation after treatment with immune checkpoint inhibitors is rare, it can be an unusual presentation of pseudoprogression and clinicians should be aware of this possibility.

A Case of Acquired Amegakaryocytic Thrombocytopenia with Anti-c-mpl Autoantibody: Comparison with Idiopathic Thrombocytopenic Purpura.

Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare disease that causes severe bleeding. The pathogenesis and treatment of AAMT have not yet been defined. We report the case of a 60-year-old woman diagnosed with AAMT, who presented with severe thrombocytopenia, gastroin-testinal bleeding, and significantly reduced bone marrow megakaryocytes. The patient was treated with methylprednisolone, cyclosporin, and intravenous immunoglobulin. After 2 weeks of treatment, her platelet count started to increase, and her bone marrow megakaryocyte count had normalized 3 months after diagnosis. At the time of diagnosis, the patient was seropositive for anti-c-mpl antibody but was seen to be seronegative once the platelet count recovered. In contrast, anti-c-mpl antibodies were not detected in the serum of 3 patients with idiopathic thrombocytopenic purpura. This case study suggests that anti-c-mpl antibody plays an important role in the development of AAMT, and that intensive immunosuppressive treatment is required for autoantibody clearance and recovery of megakaryocyte count.

Identification of mTOR inhibitor-resistant genes in cutaneous squamous cell carcinoma.

PURPOSE: The PI3K/AKT/mTOR pathway is frequently activated in various squamous cell carcinomas (SCCs). Although mTOR inhibitors are suggested as effective treatments in immunosuppressed patients with metastatic SCC, they are still not proven to be favorable in treating skin SCC patients not undergoing immunosuppressive therapy. Moreover, the exact mechanism of the mTOR signaling pathway in SCC has not yet been identified. In this study, we aimed to determine the genes associated with mTOR inhibitors in skin SCC. MATERIALS AND METHODS: The identification of cell viability according to concentration of everolimus and Western blot was done. To analyze the global gene expression profiles, A431 and HSC-1 cells were treated with dimethyl sulfoxide (DMSO) or 100 nM of everolimus for 72 hours. Furthermore, differentially expressed genes (DEGs) were identified using Affymetrix analysis. To identify the gene network associated with everolimus resistance in SCC cells, pathway analysis was performed using the Ingenuity Pathway Analysis (IPA) tool. RESULTS: The effects of cell death with respect to the mTOR inhibitor concentration were observed in the HSC-1 cell line; however, the mTOR inhibitor did not show effective cytotoxic activity in the A431 cell line. p-mTOR concentration also diminished with respect to everolimus concentrations in the HSC-1 cell line. Moreover, the microarray results showed that the MYC/CCND1/TP73/NUPR1/SBD/ERBB2/CDKN2B genes were related to mTOR inhibitor resistance. However, CCND1 gene overexpression was most closely related to mTOR inhibitor resistance. CONCLUSION: We identified mTOR inhibitor resistance genes, and our findings may help select therapeutic targets in skin SCC.

Long-term Survival after Repeated Local Therapy and Salvage Chemotherapy for Recurrent Metastases from Gastric Cancer: a Case Report and Literature Review.

We report a rare case of long-term survival in a patient who received local therapy and salvage chemotherapy for recurrent metastases, along with a literature review. A 65-year-old male patient underwent subtotal gastrectomy for advanced gastric adenocarcinoma. Six months after gastrectomy, 2 metastatic intra-abdominal lymph node enlargements were detected, which were treated with radiotherapy. At 55 months after gastrectomy, an abdominal wall mass was detected, which was treated by surgical resection. The patient received 5-fluorouracil/leucovorin/irinotecan chemotherapy for 27 months before and after radiotherapy and docetaxel chemotherapy for 6 months after surgical resection of the abdominal wall metastasis. At the last visit, 7.8 years since the initial resection of the primary gastric cancer and 6.2 years since detection of the first metastases, the patient was disease-free and required no further chemotherapy. This case suggests that repeated local therapy offers potential for long-term survival in a carefully selected subset of patients with recurrent metastases.

Chronic kidney disease in the BCR-ABL1-negative myeloproliferative neoplasm: a single-center retrospective study.

Background/Aims: Renal complications related to BCR-ABL1-negative myeloproliferative neoplasms (MPNs) have not been examined fully in Asian populations. METHODS: We analyzed estimated glomerular filtration rate (eGFR) and its changes with time retrospectively in patients with BCR-ABL1-negative MPN from 2005 to 2015. RESULTS: The prevalence of chronic kidney disease (CKD) was 11% (6.6% having stage 3 and 4.4% having stage 4). In a linear regression analysis of eGFR versus time (years), overall, patients showed increased eGFR (mL/min/1.73 m2) by 0.51 (95% confidence interval [CI], -0.30 to 1.33; p = 0.22). Patients with polycythemia vera (PV), and those treated with hydroxyurea, showed statistically significant increases in eGFR (1.59; 95% CI, 0.28 to 2.90; p = 0.02 in PV; and 1.55; 95% CI, 0.56 to 2.54; p = 0.02 in treatment with hydroxyurea). In total, 17 patients (20.5%) showed rapid loss of eGFR (< -3 mL/min/1.73 m2 per year). This rapid loss in eGFR was associated with a higher incidence of kidney disease (23.5% vs. 6.1%, p = 0.05) and a higher percentage of patients with high neutrophil (> 7.0 × 109 /L) and high monocyte (> 0.7 × 109 /L) counts (76.5% vs. 50%, p = 0.05; 52.9% vs. 28.8%, p = 0.06, respectively). More patients had high serum lactate dehydrogenase (> 500 U/L) levels (52.9% vs. 25.8%, p = 0.03) at diagnosis. Conclusions: CKD is prevalent in patients with BCR-ABL1-negative MPN. Active cytoreductive therapy has the potential to improve kidney function in BCR-ABL1-negative MPN.

C-C motif chemokine receptors in gastric cancer.

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-associated mortality worldwide. Despite recent advances in molecular and clinical research, patients with gastric cancer at an advanced stage have a dismal prognosis and poor survival rates, and systemic treatment relies predominantly on traditional cytotoxic chemotherapy. To improve patients' quality of life and survival, an improved understanding of the complex molecular mechanisms involved in gastric cancer progression and treatment resistance, and of its clinical application in the development of novel targeted therapies, is urgently required. Chemokines are a group of small chemotactic cytokines that interact with seven-transmembrane G-protein-coupled receptors, and this interaction serves a crucial role in various physiological processes, including organ development and the host immune response, to recruit cells to specific sites in the body. There is also accumulating evidence that chemokines and chemokine receptors (CCRs) contribute to tumor development and progression, as well as metastasis. However, research regarding the functional roles of chemokines and their receptors in cancer is dynamic and context-dependent, and much remains to be elucidated, although various aspects have been explored extensively. In gastric cancer, C-C motif CCRs are involved in the biological behavior of tumor cells, including the processes of growth, invasion and survival, as well as the epithelial-mesenchymal transition. In the present review, attention is given to the clinical relevance of C-C motif CCRs in the development, progression, and metastasis of gastric cancer, particularly CCR7 and CCR5, which have been investigated extensively, as well as their potential therapeutic implications.

VIP (etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma.

We retrospectively reviewed outcomes of treatment with VIP (combination of etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma (STS).We analyzed the medical records of patients with advanced or relapsed STS who had undergone VIP treatment as second-line or more chemotherapy between January 2000 and December 2015. The patients were treated with a combination of etoposide (100 mg/m for 5 days), ifosfamide (2000 mg/m for 2 days), and cisplatin (20 mg/m for 5 days) once every 4 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and nonresponder groups (responders showed a tumor response to any prior systemic chemotherapy before VIP).Twenty-four patients with a median age of 50 years (range: 20-68 years) were treated with VIP. Eleven (45.8%) patients were male and 7 (29.2%) received 2 or more chemotherapy regimens before VIP. Median PFS was 3.7 months (95% confidence interval [CI], 1.3-6.1 months) and median OS was 10.0 months (95% CI, 6.6-13.5). The overall response rate was 37.5%, and the disease control rate was 50%. The responder group showed better PFS (7.7 months vs 3.0 months; P = 0.101) and significantly improved OS (11.0 months vs 8.8 months; P = 0.039) compared to those of nonresponders. All patients reported some grade of hematological toxicity. The most frequently encountered hematological toxicity was neutropenia (any grade, 77.7%; grade 3 or 4, 74.0%).VIP might be effective in patients with previously treated STS.