Bladder Cancer最新文献

Background: Chromatin modifying enzymes, mainly through post translational modifications, regulate chromatin architecture and by extension the underlying transcriptional kinetics in normal and malignant cells. Muscle invasive bladder cancer (MIBC) has a high frequency of alterations in chromatin modifiers, with 76% of tumors exhibiting mutation in at least one chromatin modifying enzyme [1]. Additionally, clonal expansion of cells with inactivating mutations in chromatin modifiers has been identified in the normal urothelium, pointing to a currently unknown role of these proteins in normal bladder homeostasis.

Objective: To review current knowledge of chromatin modifications and enzymes regulating these processes in Bladder cancer (BCa).

Methods: By reviewing current literature, we summarize our present knowledge of external stimuli that trigger loss of equilibrium in the chromatin accessibility landscape and emerging therapeutic interventions for targeting these processes.

Results: Genetic lesions in BCa lead to altered function of chromatin modifying enzymes, resulting in coordinated dysregulation of epigenetic processes with disease progression.

Conclusion: Mutations in chromatin modifying enzymes are wide-spread in BCa and several promising therapeutic targets for modulating activity of these genes are currently in clinical trials. Further research into understanding how the epigenetic landscape evolves as the disease progresses, could help identify patients who might benefit the most from these targeted therapies.

Background: The COVID-19 pandemic has disrupted regular health care with potential consequences for non-COVID diseases like cancer. To ensure continuity of oncological care, guidelines were temporarily adapted.

Objective: To evaluate the impact of the COVID-19 outbreak on bladder cancer care in the Netherlands.

Methods: The number of bladder cancer (BC) diagnoses per month during 2020-2021 was compared to 2018-2019 based on preliminary data from the Netherlands Cancer Registry (NCR). Additionally, detailed data were retrieved from the NCR for the cohort diagnosed between March 1^st-May 31^st 2020 (first COVID wave) and 2018-2019 (reference cohort). BC diagnoses, changes in age and stage at diagnosis, and time to first-line treatment were compared between both periods. Changes in treatment were evaluated using logistic regression.

Results: During the first COVID wave (week 9-22), the number of BC diagnoses decreased by 14%, corresponding with approximately 300 diagnoses, but increased again in the second half of 2020. The decline was most pronounced from week 13 onwards in patients≥70 years and patients with non-muscle invasive BC. Patients with muscle-invasive disease were less likely to undergo a radical cystectomy (RC) in week 17-22 (OR = 0.62, 95% CI = 0.40-0.97). Shortly after the start of the outbreak, use of neoadjuvant chemotherapy decreased from 34% to 25% but this (non-significant) effect disappeared at the end of April. During the first wave, 5% more RCs were performed compared to previous years. Time from diagnosis to RC became 6 days shorter. Overall, a 7% reduction in RCs was observed in 2020.

Conclusions: The number of BC diagnoses decreased steeply by 14% during the first COVID wave but increased again to pre-COVID levels by the end of 2020 (i.e. 600 diagnoses/month). Treatment-related changes remained limited and followed the adapted guidelines. Surgical volume was not compromised during the first wave. Altogether, the impact of the first COVID-19 outbreak on bladder cancer care in the Netherlands appears to be less pronounced than was reported for other solid tumors, both in the Netherlands and abroad. However, its impact on bladder cancer stage shift and long-term outcomes, as well as later pandemic waves remain so far unexamined.

Background: Pre-operative risk assessment in radical cystectomy (RC) is an ongoing challenge especially in elderly patients.

Objective: To evaluate the ability of comorbidity indices and their combination with clinical parameters in machine learning models to predict mortality and morbidity after RC.

Methods: In 392 patients who underwent open RC, complication and mortality rates were reported. The predictive values of the age-adjusted Charlson Comorbidity index (aCCI), the Elixhauser Index (EI), the Physical Status Classification System (ASA) and Gagne's combined comorbidity Index (GCI) were evaluated using regression analyses. Various machine learning models (Gaussian naïve bayes, logistic regression, neural net, decision tree, random forest) were additionally investigated.

Results: The aCCI, ASA and GCI showed significant results for the prediction of complications (χ² = 8.8, p < 0.01, χ² = 15.7, p < 0.01 and χ² = 4.6, p = 0.03) and mortality (χ² = 21.1, p < 0.01, χ² = 25.8, p < 0.01 and χ² = 2.4, p = 0.04) after RC while the EI showed no significant prediction. However, areas under receiver characteristic curves (AUROCs) revealed good performance only for the prediction of mortality by the aCCI and ASA (0.81 and 0.78, CGI 0.63) while the prediction of complications was poor (aCCI 0.6, ASA 0.63, CGI 0.58). The combination of ASA, age, body mass index and sex in machine learning models showed a better prediction. Gaussian naïve bayes (0.79) and logistic regression (0.76) showed the best performance using a hold-out test set.

Conclusions: The ASA and aCCI show good prediction of mortality after RC but fail predicting complications accurately. Here, the combination of comorbidity indices and clinical parameters in machine learning models seems promising.

Background: The role of smoking in the prognosis of bladder cancer may significantly impact clinical management. It is also a considerable burden to Taiwan's economy and health of its citizens.

Objective: To search Taiwan's National Health Insurance Research Database to determine whether smoking affected overall and cancer-specific mortality of patients with bladder cancer.

Methods: We collected data on basic information, tumor stage, and comorbidities. Each smoking case was propensity score-matched by age, sex, and diagnosis year to one control individual among bladder cancer patients. The study comprised a never-smoke and an ever-smoke group, with each group including 4,728 patients after matching. We evaluated the association between smoking and mortalities in patients with bladder cancer. Cox proportional regression modeling was used to estimate hazard ratios (HRs) of overall and cancer-specific mortality rates. Stratified analysis was also performed to estimate risk ratios of overall and cancer-specific mortalities in bladder cancer patients with and without a history of smoking history among different subgroups.

Results: The overall and specific mortality ratio of patients who were ever smokers were 1.15-fold and 1.16-fold, respectively, compared with those of never smokers (overall: 95% confidence interval [CI], 1.06-1.26, P = 0.0014; specific: 95% CI, 1.03-1. 03, P = 0.0176). Patients with bladder cancer who smoked and had significantly higher overall and specific mortality rates were those with Charlson Comorbidity Index (CCI)≥3 (overall: P = 0.0119; specific: P = 0.0092), diabetes mellitus (DM; overall: P = 0.0046; specific: P = 0.0419), and non-muscle-invasive bladder cancer (NMIBC; overall: P = 0.0038; specific: P = 0.0014).

Conclusions: Overall and specific mortality rates were significantly higher in the ever-smoke group than in the never-smoke group. The ever-smoke group with male sex, CCI≥3, DM, and NMIBC had increased risks for overall and specific mortality.

Abstract

BACKGROUND:

Bladder cancer is the second most common urological cancer worldwide, with low early diagnosis and high mortality. The limited progress in diagnostics and treatment greatly impedes the survival of bladder cancer patients.

OBJECTIVE:

Potential therapeutic biomarkers are urgently needed for future clinical treatment.

METHODS:

We analyzed the sequencing data and corresponding clinicopathological features and survival information of bladder cancer patients in the TCGA database and identified a new zinc finger protein 485 gene, termed ZNF485, which is highly expressed in the tissues of bladder cancer patients and was verified in cells, animal models and tissue microarrays.

RESULTS:

We found that inhibition of ZNF485 in the bladder cancer cell lines T24 and 5637 obviously inhibited proliferation and promoted the apoptosis of cancer cells. Furthermore, wound healing and invasion assays showed that downregulation of ZNF485 significantly decreased the mobility and invasion of T24 and 5637 cells. In addition, ZNF485-shRNA transfection obviously inhibited tumor growth in nude mice. Immunohistochemical results of clinical samples showed that the expression level of ZNF485 protein in cancer tissues was higher than that in adjacent tissues. Mechanistic analysis identified possible downstream target genes.

CONCLUSIONS:

Taken together, the results provide evidence that ZNF485 is involved in bladder cancer proliferation and might be a potential therapeutic biomarker for the treatment of this disease

Abstract

BACKGROUND:

Effective maintenance therapy for urothelial carcinoma (UC) is needed to delay progression after first-line chemotherapy.

OBJECTIVE:

To evaluate S-588410, a cancer peptide vaccine containing five human leukocyte antigen (HLA)-A ^*24:02-restricted epitope peptides derived from five cancer-testis antigens (DEPDC1, MPHOSPH1, URLC10, CDCA1, and KOC1) in chemotherapy-treated, clinically stable patients with advanced or metastatic UC

MATERIALS AND METHODS:

This open-label, international, phase 2 trial enrolled patients with UC who had completed≥4 cycles of first-line platinum-containing chemotherapy without disease progression. Forty-five HLA-A ^*24:02-positive patients received subcutaneous injections of S-588410 (Montanide ISA 51 VG with 1 mg/mL of each peptide) weekly for 12 weeks then once every 2 weeks thereafter for up to 24 months. Thirty-six HLA-A ^*24:02-negative patients did not receive S-588410 (observation group). The primary endpoint was the rate of cytotoxic T-lymphocyte (CTL) induction against≥1 of the peptides at 12 weeks.

RESULTS:

The CTL induction rate in the S-588410 group was 93.3% (p < 0.0001, one-sided binomial test with a rate of≤50% as the null hypothesis). The antitumor response rate was 8.9% in the S-588410 group and 0% in the observation group; median progression-free survival was 18.1 versus 12.5 weeks and median overall survival was 71.0 versus 99.0 weeks, respectively. The most frequent treatment-emergent adverse event was injection-site reactions (47 events, grades 1–3) reported in 93.3% (n = 42/45) of participants.

CONCLUSIONS:

S-588410 demonstrated a high CTL induction rate, acceptable safety profile, and modest clinical response, as maintenance therapy in participants with advanced or metastatic UC who had received first-line platinum-based chemotherapy (EudraCT 2013-005274-22).

Background: Pain is not well described in patients with locally advanced or metastatic urothelial cancer (la/mUC).

Objective: To characterize pain and assess the content validity of the Brief Pain Inventory Short Form (BPI-SF) worst pain item in patients with la/mUC receiving first-line treatment in the US.

Methods: Qualitative interviews were conducted in patients aged≥45 years with confirmed la/mUC, self-reported la/mUC-attributed pain before enrollment, and no major surgery≤3 months prior to being interviewed. Interview participants were asked open-ended questions about their la/mUC symptoms and pain. "Think aloud" cognitive debriefing was conducted for the BPI-SF worst pain item.

Results: Ten participants with laUC and six (38%) with mUC were interviewed. First-line treatments included cisplatin (n = 14; 88%) or carboplatin (n = 2; 13%). The average past-week worst pain score (0-10 scale) was 6.2 (range, 3-10); seven (44%) participants reported severe pain (score≥7). Pain was most frequently reported in the back (n = 14; 88%) and/or pelvic/lower abdominal area (n = 10; 63%). Pain impacted all participants' physical and daily activities; 81% reported it impacted their overall quality of life. All participants interpreted and completed the BPI-SF worst pain item without difficulty; 15 (94%) reported it was relevant to their la/mUC experience. Participants understood the 24-hour recall period; most supported daily (n = 13; 81%) or weekly (n = 14; 88%) assessment, preferring electronic administration using their phone (n = 14; 88%).

Conclusions: Pain attributed to la/mUC impacted physical and daily activities in all participants undergoing first-line treatment for la/mUC. Content validity was demonstrated for the BPI-SF worst pain item in this population.

Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC).

Objective: To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC).

Methods: We searched MEDLINE, Embase, Scopus and other sources. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model.

Results: We identified 24 studies. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15-1.82) and all-cause mortality at longest follow-up (OR 0.63; 95%CI 0.44-0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95%CI 0.13-0.80), anemia (OR 0.32; 95%CI 0.18-0.54), nausea and vomiting (OR 0.27; 95%CI 0.12-0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3-4 thrombocytopenia (OR 4.70; 95%CI 1.59-13.89) and a lower risk of nausea and vomiting (OR 0.05; 95%CI 0.01-0.31). Certainty in the estimates was very low for most outcomes.

Conclusions: Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.