Radical cystectomy is curative in 80–85% of patients when offered early in the disease course.1 However, many patients seek alternatives in an attempt to preserve their bladder, or simply have too ...many comorbidities and are therefore ineligible for cystectomy, which carries substantial morbidity and mortality.2 Non-surgical treatments for BCG-unresponsive high-risk non-muscle-invasive bladder cancer have been suboptimal, including repeated BCG induction and maintenance therapy, intravesical chemotherapy,3 and device-assisted therapies aimed at improving the efficacy of intravesical treatment.4 Until recently, only intravesical valrubicin had been approved by the US Food and Drug Administration (FDA) for use in patients with carcinoma in situ in whom BCG therapy had failed.5 However, valrubicin use has been sporadic, due to its low availability and suboptimal efficacy, with only 21% patients achieving a complete response at 3 months' follow-up.6 In The Lancet Oncology, Stephen A Boorjian and colleagues present the results of a phase 3, single-arm study7 investigating a novel gene therapy, nadofaragene firadenovec (rAd-IFNα/Syn3), in the management of BCG-unresponsive urothelial carcinoma of the bladder. Intravesical administration of this recombinant adenovirus-expressing interferon alfa demonstrated a 3-month complete response rate of 59·6% in all enrolled and treated patients (53·4% complete response in patients with carcinoma in situ with or without Ta or T1 tumours, and 72·9% freedone from high-grade recurrence in those with high-grade Ta or T1 tumours only). ...well-designed single-arm phase 2–3 trials to compare novel therapies to pre-specified study endpoints have been accepted for the evaluation of treatments for this disease.10 However, outcome assessment in unblinded, single-arm trials can be prone to investigator bias, a fact that cannot be ignored.
Nanosensors based on the unique electronic properties of nanotubes and nanowires offer high sensitivity and have the potential to revolutionize the field of Point-of-Care (POC) medical diagnosis. The ...direct current (dc) detection of a wide array of organic and inorganic molecules has been demonstrated on these devices. However, sensing mechanism based on measuring changes in dc conductance fails at high background salt concentrations, where the sensitivity of the devices suffers from the ionic screening due to mobile ions present in the solution. Here, we successfully demonstrate that the fundamental ionic screening effect can be mitigated by operating single-walled carbon nanotube field effect transistor as a high-frequency biosensor. The nonlinear mixing between the alternating current excitation field and the molecular dipole field can generate mixing current sensitive to the surface-bound biomolecules. Electrical detection of monolayer streptavidin binding to biotin in 100 mM buffer solution is achieved at a frequency beyond 1 MHz. Theoretical modeling confirms improved sensitivity at high frequency through mitigation of the ionic screening effect. The results should promise a new biosensing platform for POC detection, where biosensors functioning directly in physiologically relevant condition are desired.
Nearly all existing nanoelectronic sensors are based on charge detection, where molecular binding changes the charge density of the sensor and leads to sensing signal. However, intrinsically slow ...dynamics of interface-trapped charges and defect-mediated charge-transfer processes significantly limit those sensors' response to tens to hundreds of seconds, which has long been known as a bottleneck for studying the dynamics of molecule-nanomaterial interaction and for many applications requiring rapid and sensitive response. Here we report a fundamentally different sensing mechanism based on molecular dipole detection enabled by a pioneering graphene nanoelectronic heterodyne sensor. The dipole detection mechanism is confirmed by a plethora of experiments with vapour molecules of various dipole moments, particularly, with cis- and trans-isomers that have different polarities. Rapid (down to ~0.1 s) and sensitive (down to ~1 ppb) detection of a wide range of vapour analytes is achieved, representing orders of magnitude improvement over state-of-the-art nanoelectronics sensors.
Summary Background Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important ...complications associated with these treatments for prostate cancer. Methods We did a population-based retrospective cohort study, in which we used administrative hospital data, physician billing codes, and cancer registry data for men who underwent either surgery or radiotherapy alone for prostate cancer between 2002 and 2009 in Ontario, Canada. We measured the 5-year cumulative incidence of five treatment-related complication endpoints: hospital admissions; urological, rectal, or anal procedures; open surgical procedures; and secondary malignancies. Findings In the 32 465 patients included in the study, the 5-year cumulative incidence of admission to hospital for a treatment-related complication was 22·2% (95% CI 21·7–22·7), but was 2·4% (2·2–2·6) for patients whose length of stay was longer than 1 day. The 5-year cumulative incidence of needing a urological procedure was 32·0% (95% CI 31·4–32·5), that of a rectal or anal procedure was 13·7% (13·3–14·1), and that of an open surgical procedure was 0·9% (0·8–1·1). The 5-year cumulative incidence of a second primary malignancy was 3·0% (2·6–3·5). These risks were significantly higher than were those of 32 465 matched controls with no history of prostate cancer. Older age and comorbidity at the time of index treatment were important predictors for a complication in all outcome categories, but the type of treatment received was the strongest predictor for complications. Patients who were given radiotherapy had higher incidence of complications for hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies at 5 years than did those who underwent surgery (adjusted hazard ratios 2·08–10·8, p<0·0001). However, the number of urological procedures was lower in the radiotherapy than in the surgery group (adjusted hazard ratio 0·66, 95% CI 0·63–0·69; p<0·0001) Interpretation Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy. Funding Ajmera Family Chair in Urologic Oncology.
Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) ...currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT.
Nanoelectronic devices based on nanomaterials such as nanowires, carbon nanotubes, graphene, and other 2D nanomaterials offer extremely large surface-to-volume ratios, high carrier mobility, low ...power consumption, and high compatibility for integration with modern electronic technologies. These distinct advantages promise great potential for nanoelectronic devices as next generation chemical and biological sensors. Currently, majority of existing nanoelectronic sensors are direct current (DC) sensors, which rely ubiquitously on detection of conductance change associated with molecular adsorption. However, despite the simplicity of the conventional DC sensing technology, it also has severe limitations such as the Debye screening effect in ionic solutions, and the speed-sensitivity trade-off for the detection of charge-neutral molecules. Hence, the development of nanoelectronic sensors calls for new sensing platform technologies that can truly showcase the advantages of electronic sensors. In this Account, we will summarize recent efforts from our group on the development of a new electronic sensing paradigm, the nanoelectronic heterodyne sensors. Unlike conventional charge-detection based sensors, the heterodyne sensor explores the frequency mixing response between molecular dipoles and a nanoscale transistor. As an example, we first discuss the capability of heterodyne sensing in gas sensing applications by using graphene devices. Rapid (down to 0.1 s) and sensitive (down to 1 ppb) detection of a wide range of vapor analytes is achieved, representing orders of magnitude improvement over state-of-the-art nanoelectronic sensors. Furthermore, the heterodyne sensing technique enables electrical probing and tuning of the noncovalent physisorption of polar molecules on graphene surface for the first time. These results provide insight into small molecule-nanomaterial interaction dynamics and signify the ability to electrically tailor interactions, which can lead to rational designs of complex chemical processes for catalysis and drug discovery. Finally, we discuss the application of heterodyne sensing in solution for chemical and biological sensors by using carbon nanotube devices. The fundamental ionic screening effect can be mitigated by operating carbon nanotube field effect transistor as a heterodyne biosensor. Electrical detection of streptavidin binding to biotin in 100 mM buffer solution can be achieved at a frequency beyond 1 MHz. The results should promise a new biosensing platform for point-of-care detection, where biosensors functioning directly in physiologically relevant condition are desired.
Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses ...rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer.
We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0–2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.
Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0–40·7). 39 (41%; 95% CI 30·7–51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two 2% patients) and hyponatraemia (in three 3% patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related.
Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population.
Merck Sharp & Dohme.
Abstract Context Non–muscle-invasive bladder cancer (NMIBC) commonly recurs, requiring invasive and costly transurethral resection of bladder tumor (TURBT). A meta-analysis of seven trials published ...in 2004 demonstrated that intravesical chemotherapy (IVC) following TURBT reduces recurrences. Despite European Association of Urology endorsement, adoption of this practice has been modest. Objective To investigate whether immediate postoperative IVC prolongs the recurrence-free interval (RFI) and early recurrences (ERs) in light of new trial data and to explore the quality of evidence supporting its use. Evidence acquisition A systematic literature review of random controlled trials (RCTs) published before March 2013 was performed using the Medline, Embase, and Cochrane databases. Trials examining NMIBC recurrence for adults receiving IVC immediately following TURBT were included. RFI was estimated by hazard ratio (HR), and ER was estimated by absolute risk reduction (ARR) of recurrences within 1 yr of TURBT. Both outcomes were synthesized using random-effects models. Risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool, and quality of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Evidence synthesis Thirteen studies with 2548 patients were included. IVC prolonged RFI by 38% (HR: 0.62; 95% confidence interval CI, 0.50–0.77; p < 0.001; I2 : 69%), and ERs were 12% less likely in the intervention population (ARR: 0.12; 95% CI, −0.18 to −0.06; p < 0.001, I2 : 0%). The number needed to treat to prevent one ER was 9 (95% CI, 6–17 patients). There was high risk of bias present in 12 of 13 publications. Quality of evidence for RFI was very low and low for ERs. Conclusions Our updated meta-analysis supports that IVC prolongs RFI and reduces ERs of NMIBC when administered immediately after TURBT. However, contemporary methodology suggests low evidence quality for examined outcomes. Thus RCTs with careful randomization and blinding are still warranted to clarify the usefulness of immediate postoperative IVC in this population.
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