CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical ...activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3
regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3
cells occurs in patients with cancer treated with anti-CTLA-4 therapies.
Quantitative IHC was used to evaluate the densities of intratumoral CD4
, CD8
, and FOXP3
cells in stage-matched melanoma (
= 19), prostate cancer (
= 17), and bladder cancer (
= 9) samples treated with ipilimumab and in paired melanoma tumors (
= 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (
= 5) treated with ipilimumab.
Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4
and CD8
cells without significantly changing or depleting FOXP3
cells within the tumor microenvironment.
Anti-CTLA-4 immunotherapy does not deplete FOXP3
cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
Unlocking bladder cancer Berdik, Chris
Nature (London),
11/2017, Letnik:
551, Številka:
7679
Journal Article
Recenzirano
Odprti dostop
The diagnostics, treatment and five-year survival rates for bladder cancer are largely unchanged since the 1990s. Research into cancer genomics, risk factors and immune therapies could hold the key ...to progress against this malignant disease.
The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiome has been linked to many urological disorders. We tested the hypothesis that the urinary microbial ...composition may be different between men with or without bladder cancer in catheter collected urines, bladder washouts and midstream voided urines, and may be dependent on tumor staging.
Liquid samples were collected from male patients with bladder cancer, and sex and age matched nonneoplastic controls. Total DNA was extracted and processed for 16S rRNA gene sequencing. Bioinformatic analysis for microbial classification was performed to assess diversity and variations.
The urinary microbiome associated with catheter collected urine samples of patients with bladder cancer was characterized by a significantly increased abundance of
(p=0.04) and
(p=0.03), and decreased
(p=0.03) compared to controls, with differences exacerbating with disease progression. Compared to catheterized urines, bladder cancer washouts showed the specific increase of some taxa, like
(p=0.014), whereas midstream urines were enriched in
(p <0.0001),
(p <0.0001),
(p=0.038) and
(p <0.0001).
The bladder is colonized by endogenous bacteria and microbial modifications characterize the microbiome of patients with bladder cancer. Different microbial compositions can be characterized by changing sampling strategy. These results pave the way for exploring new diagnostic and therapeutic options based on the manipulation of the bacterial community.
Abstract Context and objective To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the screening, diagnosis, and markers of bladder cancer using an ...evidence-based strategy. Evidence acquisition A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to screening, diagnosis, markers, and pathology. Proceedings from the last 5 yr of major conferences were also searched. Evidence synthesis The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed. Conclusions Cystoscopy alone is the most cost-effective method to detect recurrence of bladder cancer. White-light cystoscopy is the gold standard for evaluation of the lower urinary tract; however, technology like fluorescence-aided cystoscopy and narrow-band imaging can aid in improving evaluations. Urine cytology is useful for the diagnosis of high-grade tumor recurrence. Molecular medicine holds the promise that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patient's tumor. The challenge remains to optimize measurement of these targets, evaluate the impact of such targets for therapeutic drug development, and translate molecular markers into the improved clinical management of bladder cancer patients. Physicians and researchers eventually will have a robust set of molecular markers to guide prevention, diagnosis, and treatment decisions for bladder cancer.
Immunotherapy has transformed the treatment of many solid tumors, with some patients deriving long-term benefit, but how to identify such patients remains unclear. Somatic mutations detected in ...circulating tumor DNA (ctDNA) from plasma can be an indicator of disease progression, response to therapy, and clonality of primary and metastatic lesions. Hence, ctDNA analysis can provide a valuable noninvasive and tumor-specific marker for longitudinal monitoring of tumor burden. We explored the use of ctDNA to predict survival on durvalumab, an anti-PD-L1 therapy.
Variant allele frequencies (VAF) of somatic mutations in 73 genes were assessed in ctDNA using targeted sequencing in a discovery cohort consisting of 28 patients with non-small cell lung cancer (NSCLC) and two validation NSCLC and urothelial cancer (UC) cohorts of 72 and 29 patients, respectively, to correlate ctDNA changes with clinical outcomes.
Somatic variants were detected in 96% of patients. Changes in VAF preceded radiographic responses, and patients with reduction in VAF at 6 weeks had significantly greater reduction in tumor volume, with longer progression-free and overall survival.
ctDNA VAF changes are strongly correlated with duration of treatment, antitumor activity, and clinical outcomes in NSCLC and UC. Early on-treatment reduction in ctDNA VAF may be a useful predictor of long-term benefit from immunotherapy. Prospective studies should validate these findings and the value of utilizing early changes in ctDNA for therapeutic decision making by identifying nonresponders to checkpoint inhibitor monotherapies and guiding combination therapies.
Bladder cancer is a heterogeneous disease with a variable natural history. At one end of the spectrum, low-grade Ta tumors have a low progression rate and require initial endoscopic treatment and ...surveillance but rarely present a threat to the patient. At the other extreme, high-grade tumors have a high malignant potential associated with significant progression and cancer death rates. In the Western world, bladder cancer is the fourth most common malignancy in men and the eighth most common in women. In Europe and the United States, bladder cancer accounts for 5% to 10% of all malignancies in men. The risk of developing bladder cancer at <75 years of age is 2% to 4% for men and 0.5% to 1% in women compared with the risk of lung cancer, for example, which is 8% in men and 2% in women. For the geographic and temporal comparison of bladder cancer incidence, it is crucial to separate the low-grade from the high-grade tumors. In epidemiologic studies on risk factors for bladder cancer, it is important to distinguish the low-grade Ta tumors from high-grade carcinoma in situ (CIS) and tumors >T1. Current studies do not support the routine screening for bladder cancer. However, prospective long-term studies are required to evaluate the benefits of bladder cancer screening, particularly in those at high risk. After assessing all available evidence, the Epidemiology and Diagnosis Committee has made recommendations on various diagnostic issues, including pathologic evaluation, urinary cytology, and imaging studies. Optimal resection techniques, role of repeat transurethral resection in high-grade T1 tumors, random bladder biopsy, and prostatic urethral biopsy are discussed, and appropriate recommendations are made according to the strength of available evidence.
Circ-ITCH is a circRNA generated from several exons of itchy E3 ubiquitin protein ligase (ITCH) and tumor suppressor served as a sponge for certain miRNAs targeting their parental transcripts of ...ITCH. However, the role of circ-ITCH in bladder cancer (BCa) was not reported. In the present study, we investigated the role of circ-ITCH in BCa.
Quantitative real-time PCR was used to detect the expression of circ-ITCH and survival analysis was adopted to explore the association between circ-ITCH expression and the prognosis of BCa. BCa cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion, cell cycle and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effect of circ-ITCH in BCa. Biotin-coupled probe pull down assay, Biotin-coupled miRNA capture, Fluorescence in situ hybridization and Luciferase reporter assay were conducted to confirm the relationship between the circ-ITCH and the microRNA.
In the present study, we found that circ-ITCH, is down-regulated in BCa tissues and cell lines. BCa patients with low circ-ITCH expression had shortened survival. Enforced- expression of circ-ITCH inhibited cells proliferation, migration, invasion and metastasis both in vitro and in vivo. Mechanistically, we demonstrated that circ-ITCH up-regulates the expression of miR-17 and miR-224 target gene p21 and PTEN through 'sponging' miR-17 and miR-224, which suppressed the aggressive biological behaviors of BCa.
circ-ITCH acts as a tumor suppressor by a novel circ-ITCH/miR-17, miR-224/p21, PTEN axis, which may provide a potential biomarker and therapeutic target for the management of BCa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the efficacy and safety of RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, in patients with HER2
locally advanced or metastatic urothelial ...carcinoma (mUC) refractory to standard therapies.
This was a phase II, open-label, multicenter, single-arm study of patients with HER2
(IHC status 3+ or 2+) locally advanced or mUC who previously failed at least one line of systemic chemotherapy. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee (BIRC). The secondary endpoint included progression-free survival (PFS), disease control rate, duration of response, overall survival (OS), and safety.
Forty-three patients were enrolled. The median follow-up was 20.3 months. The overall confirmed ORR as assessed by the BIRC was 51.2% 95% confidence interval (CI), 35.5%-66.7%. Similar responses were observed in prespecified subgroups, such as those with liver metastasis and those previously treated with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. The median PFS and OS were 6.9 months (95% CI, 5.6-8.9) and 13.9 months (95% CI, 9.1-NE), respectively. The most common treatment-related adverse events (TRAE) were hypoesthesia (60.5%), alopecia (55.8%), and leukopenia (55.8%). Twenty-five (58%) patients experienced grade 3 TRAEs, including hypoesthesia (23.3%) and neutropenia (14.0%). No grade 4 or grade 5 TRAEs occurred.
RC48-ADC demonstrated a promising efficacy with a manageable safety profile in patients with HER2
locally advanced or mUC who had failed at least one line of systemic chemotherapy.
BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that ...delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.
In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.
Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3–4 study drug-related adverse event (two 1% of 157 patients, both grade 3), and there were no treatment-related deaths.
Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.
FKD Therapies Oy.
Muscle-invasive bladder cancer (MIBC) is the second most common genitourinary malignancy, and is associated with high morbidity and mortality. Recently, molecular subtypes of MIBC have been ...identified, which have important clinical implications.
In the current study, we tried to predict the molecular subtype of MIBC samples from conventional histomorphology alone using deep learning.
Two cohorts of patients with MIBC were used: (1) The Cancer Genome Atlas Urothelial Bladder Carcinoma dataset including 407 patients and (2) our own cohort including 16 patients with treatment-naïve, primary resected MIBC. This resulted in a total of 423 digital whole slide images of tumor tissue to train, validate, and test the deep learning algorithm to predict the molecular subtype.
Various accuracy measurements including the area under the receiver operating characteristic curves were used to evaluate the deep learning model. A sliding window approach to visualize classification was used. Class activation maps were used to identify image features that are most relevant to call a specific class.
The deep learning model showed great performance in the prediction of the molecular subtype of MIBC patients from hematoxylin and eosin (HE) slides alone—similar to or better than pathology experts. Using different visualization techniques, we identified new histopathological features that were most relevant to our model.
Deep learning can be used to predict important molecular features in MIBC patients from HE slides alone, potentially improving the clinical management of this disease significantly.
In patients with bladder cancer, a computer program found changes in the appearance of tumor tissue under the microscope and used these to predict genetic alterations. This could potentially benefit patients.
By using a comprehensive deep learning model, we were able to predict the molecular subtype of muscle-invasive bladder cancer from conventional histopathological slides alone, with good to excellent performance.
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