Genomic profile of urine has high diagnostic sensitivity compared to cytology in non‐invasive urothelial bladder cancer

Cytology is widely conducted for diagnosis of urothelial bladder cancer; however, its sensitivity is still low. Recent studies show that liquid biopsies can reflect tumor genomic profiles. We aim to investigate whether plasma or urine is more suitable for detecting tumor‐derived DNA in patients with early‐stage urothelial bladder cancer. Targeted sequencing of 71 genes was carried out using a total of 150 samples including primary tumor, urine supernatant, urine precipitation, plasma and buffy coat from 25 patients with bladder cancer and five patients with cystitis and benign tumor. We compared mutation profiles between each sample, identified tumor‐identical mutations and compared tumor diagnostic sensitivities between urine and conventional cytology. We identified a total of 168 somatic mutations in primary tumor. In liquid biopsies, tumor‐identical mutations were found at 53% (89/168) in urine supernatant, 48% (81/168) in urine precipitation and 2% (3/168) in plasma. The high variant allele fraction of urine was significantly related to worse clinical indicators such as tumor invasion and cytological examination. Although conventional cytology detected tumor cells in only 22% of non‐invasive tumor, tumor diagnostic sensitivity increased to 67% and 78% using urine supernatant and precipitation, respectively. Urine is an ideal liquid biopsy for detecting tumor‐derived DNA and more precisely reflects tumor mutational profiles than plasma. Genomic analysis of urine is clinically useful for diagnosis of superficial bladder cancer at early stage.     

Ongoing and future directions in the management of metastatic colorectal cancer: Update on clinical trials

Metastatic colorectal cancer (mCRC) continues to show poor outcomes, with many patients exhausting effective standard-of-care therapy. To explore the current landscape of clinical trials for mCRC, we reviewed over 600 clinical trials that are currently ongoing for mCRC patients. Immunotherapeutic agents form approximately 39% (includes monoclonal antibodies, viruses, vaccines, and immunomodulators) of all agents and targeted therapy forms 45% (tyrosine kinase inhibitors, epigenetic modulators, and others) of all agents being investigated for mCRC.     

Dietary patterns and risk of recurrence and progression in non‐muscle‐invasive bladder cancer

The association of dietary factors with urinary bladder cancer prognosis has scarcely been investigated, and results of studies conducted to date are inconsistent. We investigated whether empirically derived dietary patterns are associated with risks of recurrence and progression in non‐muscle‐invasive bladder cancer (NMIBC) patients. Data from 595 newly diagnosed NMIBC patients from an ongoing prospective cohort study were used to derive dietary patterns using exploratory factor analysis. Factor scores were calculated and then categorized in sex‐specific tertiles. Multivariable‐adjusted proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the associations between tertiles of adherence to the dietary patterns and risks of recurrence and progression. We identified four dietary patterns: “fruits and vegetables,” “Western,” “low‐fat,” and “Tex‐Mex.” Patients in the highest tertile of adherence to the Western pattern experienced a 1.48 times higher risk of recurrence (95% CI 1.06–2.06) compared to patients in the lowest tertile. No statistically significant associations of a Western diet with risk of progression or of the other dietary patterns with risk of recurrence and progression were found. Overall, we found that adherence to a Western diet was associated with a higher risk of recurrence but further studies are needed to confirm our findings.     

Combination chemotherapy of docetaxel, ifosfamide and cisplatin (DIP) in patients with metastatic urothelial cancer: a preliminary report

OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicity of a new combination chemotherapy of docetaxel, ifosfamide and cisplatin (DIP) in the treatment of metastatic urothelial cancer. METHODS: Fourteen patients (nine male and five female; aged 59-82 years) with metastatic urothelial carcinoma, including five patients who have a history of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) chemotherapies, received the combination of docetaxel 60 mg/m(2) on day 1, and ifosfamide 1.0 g/m(2) and cisplatin 20 mg/m(2) on days 2-6 and repeated every 21 days, to a maximum of six cycles. Eligibility criteria included performance status (World Health Organization) 0-3; normal bone marrow and liver function; and no symptomatic peripheral neuropathy. RESULTS: Ten of the 14 patients (72%) demonstrated a partial response (PR), with durations of response ranging from 3 to 12 months [median 6.5 months; 95% confidence interval (CI), 4.1-8.7 months]. The response rate of the five patients with MVAC-refractory cancer was 80% with median duration of response 5.5 months, comparable with that of the cases without previous MVAC therapies. Grade 3-4 granulocytopenia occurred in 10 cases (71%), resulting in three episodes (21%) of febrile neutropenia. Grade 3 thrombocytopenia was observed in five cases (36%). No toxic death was observed. Grade 2 peripheral neuropathy was identified in one case. CONCLUSIONS: This pilot study demonstrated that DIP is an effective regimen for the treatment of metastatic urothelial cancer, and warrants further investigation.     

The long‐term outcome of treated high‐risk nonmuscle‐invasive bladder cancer

BACKGROUND:

The treatment of high‐risk nonmuscle‐invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single‐center series.

METHODS:

The authors reviewed all patients with primary, high‐risk NMIBC at their institution from 1994 to 2010. Outcomes were matched with clinicopathologic data. Patients who had muscle invasion within 6 months or had insufficient follow‐up (<6 months) were excluded. Correlations were analyzed using multivariable Cox regression and log‐rank analysis (2‐sided; P < .05).

RESULTS:

In total, 712 patients (median age, 73.7 years) were included. Progression to muscle invasion occurred in 110 patients (15.8%; 95% confidence interval [CI], 13%‐18.3%) at a median of 17.2 months (interquartile range, 8.9‐35.8 months), including 26.5% (95% CI, 22.2%‐31.3%) of the 366 patients who had >5 years follow‐up. Progression was associated with age (hazard ratio [HR], 1.04; P = .007), dysplastic urothelium (HR, 1.6; P = .003), urothelial cell carcinoma variants (HR, 3.2; P = .001), and recurrence (HR, 18.3; P < .001). Disease‐specific mortality occurred in 134 patients (18.8%; 95% CI, 16.1%‐21.9%) at a median of 28 months (interquartile range, 15‐45 months), including 28.7% (95% CI, 24.5%‐33.3%) of those who had 5 years of follow‐up. Disease‐specific mortality was associated with age (HR, 1.1; P < .001), stage (HR, 1.7; P = .003), dysplasia (HR, 1.3; P = .05), and progression (HR, 5.2; P < .001). Neither progression nor disease‐specific mortality were associated with the receipt of bacillus Calmette‐Guerin (P > .6).

CONCLUSIONS:

Within a program of conservative treatment, progression of high‐risk NMIBC was associated with a poor prognosis. Surveillance and bacillus Calmette‐Guerin were ineffective in altering the natural history of this disease. The authors concluded that the time has come to rethink the paradigm of management of this disease. Cancer 2012. © 2012 American Cancer Society.     

Treatment of muscle‐invasive bladder cancer: A systematic review

There is uncertainty regarding the use of bladder‐sparing alternatives to standard radical cystectomy, optimal lymph node dissection techniques, and optimal chemotherapeutic regimens. This study was conducted to systematically review the benefits and harms of bladder‐sparing therapies, lymph node dissection, and systemic chemotherapy for patients with clinically localized muscle‐invasive bladder cancer. Systematic literature searches of MEDLINE (from 1990 through October 2014), the Cochrane databases, reference lists, and the ClinicalTrials.gov Web site were performed. A total of 41 articles were selected for review. Bladder‐sparing therapies were found to be associated with worse survival compared with radical cystectomy, although the studies had serious methodological shortcomings, findings were inconsistent, and only a few studies evaluated currently recommended techniques. More extensive lymph node dissection might be more effective than less extensive dissection at improving survival and decreasing local disease recurrence, but there were methodological shortcomings and some inconsistency. Six randomized trials found cisplatin‐based combination neoadjuvant chemotherapy to be associated with a decreased mortality risk versus cystectomy alone. Four randomized trials found adjuvant chemotherapy to be associated with decreased mortality versus cystectomy alone, but none of these trials reported a statistically significant effect. There was insufficient evidence to determine optimal chemotherapeutic regimens. Cancer 2016;122:842–51 . © 2016 American Cancer Society.     

Contemporary use of perioperative cisplatin‐based chemotherapy in patients with muscle‐invasive bladder cancer

BACKGROUND:

Level I evidence indicates that neoadjuvant cisplatin‐based chemotherapy, in combination with radical cystectomy (RC), is associated with a significant survival advantage for patients with muscle‐invasive bladder cancer. Despite this, neoadjuvant chemotherapy is not uniformly used. Our objective was to determine the patterns of utilization of neoadjuvant chemotherapy in patients undergoing RC for muscle invasive bladder cancer in a contemporary cohort in a tertiary care center.

METHODS:

A retrospective review was performed of patients with bladder cancer who underwent RC between 2003 and 2008 at our institution. Clinical stage, pathologic stage, renal function, and perioperative chemotherapy treatments were tabulated. Primary outcome measures were the type and use of neoadjuvant chemotherapy among eligible patients. Secondary measures were the utilization patterns of adjuvant chemotherapy, renal function, pathologic outcomes, and disease specific and overall survival. Reasons for nonutilization of chemotherapy were also examined.

RESULTS:

Among 238 patients who underwent RC for bladder cancer, 145 had a preoperative clinical stage ≥T2. Only 17% (25 of 145) of these patients received cisplatin‐based neoadjuvant chemotherapy. The renal function was adequate (CrCl > 60 ml/min) in 97 (67%) of these patients. Patients who received neoadjuvant chemotherapy had higher p0 rates (29% vs 8%) than patients who did not receive neoadjuvant therapy. Advanced patient age, comorbidities, concerns over toxicity of chemotherapy, and the modest nature of benefit from neoadjuvant chemotherapy may explain why this treatment is not often used.

CONCLUSIONS:

Despite level I evidence, neoadjuvant cisplatin‐based chemotherapies continue to be underutilized in the management of bladder cancer, even at a high‐volume tertiary center. A prospective evaluation of management choices, including the patient and physician factors involved in the use of perioperative cisplatin‐based chemotherapy in bladder cancer, is indicated. Cancer 2011. © 2010 American Cancer Society.     

Profiling of extracellular vesicles of metastatic urothelial cancer patients to discover protein signatures related to treatment outcome

The prognosis of metastatic urothelial carcinoma (mUC) patients is poor, and early prediction of systemic therapy response would be valuable to improve outcome. In this exploratory study, we investigated protein profiles in sequential plasma‐isolated extracellular vesicles (EVs) from a subset of mUC patients treated within a Phase I trial with vinflunine combined with sorafenib. The isolated EVs were of exosome size and expressed exosome markers CD9, TSG101 and SYND‐1. We found, no association between EVs/ml plasma at baseline and progression‐free survival (PFS). Protein profiling of EVs, using an antibody‐based 92‐plex Proximity Extension Assay on the Oncology II^® platform, revealed a heterogeneous protein expression pattern. Qlucore bioinformatic analyses put forward a protein signature comprising of SYND‐1, TNFSF13, FGF‐BP1, TFPI‐2, GZMH, ABL1 and ERBB3 to be putatively associated with PFS. Similarly, a protein signature from EVs that related to best treatment response was found, which included FR‐alpha, TLR 3, TRAIL and FASLG. Several of the markers in the PFS or best treatment response signatures were also identified by a machine learning classification algorithm. In conclusion, protein profiling of EVs isolated from plasma of mUC patients shows a potential to identify protein signatures that may associate with PFS and/or treatment response.     

Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group

Purpose:The aim of the study was to evaluate the efficacyand safety of the combination of gemcitabine and ifosfamide as asecond-line treatment for advanced urothelial cancer. Patients and methods:Thirty-four patients with metastaticurothelial cancer previously treated with cisplatin (CDDP)/carboplatin(CBDCA) and/or taxanes-based chemotherapy were studied. Gemcitabine wasadministered at a dose of 800 mg/m² on days 1 and 8 andifosfamide at a dose of 2 g/m² on days 1 and 8 with adequateamount of Mesna, every three weeks. Hematopoietic growth factors weregiven between days 3 to 5 and 12 to 16 to maintain the treatmentschedule. Results:On an intent to treat basis, therewas one complete response (CR) (3%) (95% confidenceinterval (95% CI): 0% to 10%) and six partialresponses (PR) (18%) (95% CI: 7% to 34%),inducing an objective response rate (RR) of 21% (95% CI:9% to 38%); 12 (35%) patients achieved a stabledisease (SD) and 15 (44%) a progressive disease (PD). The mediantime to tumor progression (TTP) was four months (range, 0.52 to 21.6months) and the median survival nine months (range 0.52 to 28 months).This regimen also provided the opportunity for symptomatic improvementof pain, dysuria, haematuria and leg oedema. Grade 3–4 neutropeniawas experienced by 9 (27%) patients, grade 3–4 anemia by 6(18%) and grade 3–4 thrombocytopenia by 4 (12%). Sixpatients were hospitalized due to febrile neutropenia. Despite theprophylactic use of hematopoietic growth factors, 8 (23.5%)patients required dose reduction due to myelosuppression. Grade 3alopecia occurred in 14 (41%) patients, grade 3–4 nausea in1 (3%), grade 2 fever in 3 (9%), grade 2–3 diarrheain 2 ( 6%) and grade 2 allergic reaction in 1 (3%). Conclusion:We conclude that the combination of gemcitabineand ifosfamide is an active salvage regimen for the treatment ofurothelial cancer and that the treatment also has a tolerable toxicityprofile; it warrants further investigation in combination with CDDP inchemotherapy-naïve patients.