Citations

Abstract The multi-target stool DNA (mt-sDNA) test screens for colorectal cancer by analyzing DNA methylation/mutation and hemoglobin markers to algorithmically derive a qualitative result. A new panel of highly discriminant candidate methylated DNA markers (MDM) was recently developed. Performance of the novel MDM panel, with hemoglobin, was evaluated in a simulated screening population using archived stool samples weighted to early-stage colorectal cancer and prospectively collected advanced precancerous lesions (APL). Marker selection study (MSS) and separate preliminary independent verification studies (VS) were conducted utilizing samples from multi-center, case–control studies. Sample processing included targeted MDM capture, bisulfite conversion, and MDM quantitation. Fecal hemoglobin was quantified using ELISA. Samples were stratified into 75%/25% training-testing sets; model outcomes were cross-validated 1,000 times. All laboratory operators were blinded. The MSS included 232 cases (120 colorectal cancer/112 APLs) and 490 controls. The VS featured 210 cases (112 colorectal cancer/98 APLs) and 567 controls; APLs were 86.7% adenomas and 13.3% sessile serrated lesions (SSL). Average age was 65.5 (cases) and 63.2 (controls) years. Mean sensitivity in the VS from cross-validation was 95.2% for colorectal cancer and 57.2% for APLs, with specificities of 89.8% (no CRC/APLs) and 92.4% (no neoplasia). Subgroup analyses showed colorectal cancer sensitivities of 93.4% (stage I) and 94.2% (stage II). APL sensitivity was 82.9% for high-grade dysplasia, 73.4% for villous lesions, 49.8% for tubular lesions, and 30.2% for SSLs. These data support high sensitivity and specificity for a next-generation mt-sDNA test panel. Further evaluation of assay performance will be characterized in a prospective, multi-center clinical validation study (NCT04144738). Prevention Relevance: This study highlights performance of the next-generation mt-sDNA test, which exhibits high sensitivity and specificity for detecting colorectal cancer and APLs. This noninvasive option has potential to increase screening participation and clinical outcomes. A multi-center, clinical validation trial is underway. See related commentary by Bresalier, p. 93

Abstract Introduction . Dispersion in an accelerator quantifies the deviation of the proton trajectory when there is a momentum deviation. We present for the first time a safe method of measuring dispersion in the clinic, using a scintillator detector and the momentum deviations within a spill. This is an important accelerator quantity as we found that this is the reason behind the large dose fluctuation in our absolute dosimetry measurement. Methods . Dispersions are measured for nine energies in a Hitachi ProBeat system at three locations (isocenter and at two profile monitors) and at two gantry angles (0 and 90 degrees) by first measuring the spot position and momentum drift within a spill. The spot position drift is measured by the XRV-4000 at the isocenter, and by the two profile monitors located at 0.57 and 2.27 m from the isocenter. The momentum drift is calculated from the intra-spill range drift which is measured using the Ranger accessory. The dispersion at isocenter and its gradient are calculated using the weighted least square regression on the measured dispersions at the three locations. A constraint is formulated on the dispersion and its gradient to ensure minimal intra-spill spot position deviation around the isocenter. Results . The measured intra-spill range and spot positional drift at isocenter are less than 0.25 mm and 0.7 mm respectively. The momentum spread calculated from the range drift are less than 0.08%. The dispersion at the isocenter ranged from 0.50 to 4.30 m and the zero-crossing happens upstream of isocenter for all energies. 2 of the 9 energies (168.0 and 187.5 MeV) violated the constraint and has an intra-spill spot positional deviation greater than 1.0 within 5 cm from the isocenter. Conclusion . This measurement is recommended as part of commissioning and annual quality assurance for accelerator monitoring and to ensure intra-spill spot deviations remain low.

AbstractBackgroundAbsolute dosimetry measurement is an integral part of Treatment Planning System (TPS) commissioning and it involves measuring the integrated absorbed dose to water for all energies in a pencil beam scanning delivery system. During the commissioning of Singapore's first proton therapy center, a uniform scanned field with an Advanced Markus chamber method was employed for this measurement, and a large dose fluctuation of at least 5% was observed for 10% of the energy layers during repeated measurements.PurposeThis study aims to understand the root cause of this fluctuation by relating the actual delivered spot information in the log file with the charge measurement by the ion chambers.MethodsA dedicated pencil beam dose algorithm was developed, taking into account the log file parameters, to calculate the dose for a single energy layer in a homogeneous water phantom. Three energies, 70.2, 182.7, and 228.7 MeV were used in this study, with the 182.7 MeV energy exhibiting large dose fluctuation. The dose fluctuation was investigated as a function of detector's sizes (pinpoint 3D, Advanced Markus, PTW 34070, and PTW 34089) and water depth (2 , 6, and 20 cm). Twelve ion chambers measurements were performed for each chamber and depth. The comparison of the theoretically predicted integrated dose and the charge measurement served as a validation of the algorithm.ResultsAbout 5.9% and 9.6% dose fluctuation were observed in Advanced Markus and pinpoint 3D measurements at 2 cm depth for 182.7 MeV, while fluctuation of 1.6% and 1.1% were observed in Advanced Markus with 228.7 and 70.2 MeV at similar depth. Fluctuation of less than 0.1% was observed for PTW34070 and PTW 34089 for all energies. The fluctuation was found to diminish with larger spot size at 20 cm depth to 1.3% for 182.7 MeV. The theoretical and measured charge comparison showed a high linear correlation of for all datasets, indicating the fluctuation originated from the delivered spot characteristics. The cause of fluctuation was identified to be due to the spill change occurring close to the detector, and since the spot positional deviation profiles were different between two spills, this resulted in local hot spots between columns of spots. The actual position of spill change varies randomly during measurement, which led to a random occurrence of hot spot within the detector's sensitive volume and a fluctuating dose measurement.ConclusionThis is the first report of a dose fluctuation greater than 5% in absolute dosimetry measurement with a uniform scanned field and the cause of the fluctuation has been conclusively determined. It is important to choose the MU and scanning pattern carefully to avoid spill change happening when the spot delivery is near the detector.

Abstract Background and Aims The FDA-approved multitarget stool-DNA [mt-sDNA] test is a successful colorectal cancer [CRC] screening tool in average-risk individuals but is not indicated for patients with inflammatory bowel disease [IBD]. We determined the performance of the mt-sDNA assay without the haemoglobin component [mt-sDNAHgb-] in patients with IBD, while measuring sensitivity for colorectal cancer and advanced colorectal neoplasia [ACRN]. Methods This was a multi-centre, proof-of-concept investigation in persons aged 18–84 years with a diagnosis of IBD, or primary sclerosing cholangitis [PSC] with IBD. Enrolment occurred between March 2013 and May 2016. Stool was tested with the mt-sDNA molecular markers only, minus the immunochemical haemoglobin component. Results The analysis set contained 355 samples. The median age was 52 [range 39–62] years, 45.6% were female and 93% were White. Two-thirds [63%] had ulcerative colitis [UC] and 10.1% had PSC/IBD. Colonoscopy revealed cancer in 8.5% [N = 30], advanced precancerous lesions [APLs] in 9.3% [N = 33] and non-advanced precancerous lesions in 7.6% [N = 27], and three-quarters [74.7%, N = 265] had negative findings. mt-sDNAHgb- sensitivity was 73.3% for any stage cancers, and 76.2% for ACRN. Sensitivity was highest for IBD-associated high-grade dysplasia at 100% and 84.6% for IBD-associated low-grade dysplasia ≥1 cm. The test showed higher sensitivity and lower specificity in UC than in Crohn’s disease. Increasing inflammation score was associated with a significant decrease in mt-sDNAHgb- test score [ = 0.028] amongst neoplasia-negative individuals, but not in patients with ACRN. Conclusions These data highlight the potential of multitarget stool-DNA marker testing as an important addition to colorectal cancer surveillance by complementing colonoscopic evaluations in IBD patients.

Abstract Background For gravely ill patients who have no treatment options and who are ineligible for clinical trials, the US Food and Drug Administration (FDA) established the Expanded Access Program (EAP). Motivated by efforts to weaken FDA regulation and sold as providing greater access to experimental drugs, the federal Right to Try Act (RTT) was passed in 2017. It reduces FDA oversight by not requiring physicians to report safety data and foregoes approval of protocols by local institutional review boards. Methods This study explored the views of 17 neuro-oncologists from 15 different academic medical centers with varying experience with EAP and RTT using convenience sampling. We conducted semi-structured interviews and qualitative analysis to identify emerging themes. Results Most oncologists were confused between the two pathways, had little familiarity with RTT, and had little knowledge about experimental medicine available through either pathway. Oncologists reported a preference of enrolling patients in clinical trials over off-trial preapproval pathways with scant data. As a result, oncologists revealed concerns over properly evaluating risks for their patients. Conclusion Our findings suggest that neuro-oncologists need better resources and clearer mechanisms at their institutions to help navigate EAP and RTT in order to counsel patients interested in experimental medicine.

Introduction: Direct to consumer stem cell and regenerative interventions (SCRIs) for various medical conditions have increased in popularity due to unmet medical needs and the promise of SCRIs to meet those needs. These interventions may have varying levels of safety and efficacy data and many lack sufficient scientific data to be marketed. The direct to consumer SCRI industry has received significant attention due to potential physical, economic, and emotional harms to patients. Patients may seek the counsel of their primary care providers when considering stem cell therapy for their condition. Methods: Here we describe strategies primary care providers can utilize when counseling patients. Results: Although we recommend constructing these discussions around individual patients’ needs, one can utilize a general approach consisting of 4 parts. First, providers should recognize what information the patient is seeking and what is their understanding of stem cell and regenerative medicine. Next, providers should convey evidence-based information at the level of patients understanding so that they are aware of the risks, benefits, and descriptions of possible procedures. Throughout the conversations, attempts should be made to guide patients to a trusted resource that can provide additional information. Finally, providers should make an effort to address misinformation in a way that is nonjudgmental and patient-centered to make the patient feel safe and comfortable. Conclusion: Effectively communicating risk information by primary care providers to patients is important given the harms reported from direct-to-consumer SCRIs. Correcting misinformation remains a priority when discussing SCRI’s. Providers should strive to offer patients with additional resources such as the opportunity for consultation with a specialist or a consultation service dedicated to informing patients about regenerative medicine.

Objectives Penile urethral stricture disease not associated with hypospadias is rare, and there is a wide range of commonly used surgical repair techniques for this disease. We sought to compile a multi‐institutional database of patients who had surgical correction of strictures in the penile urethra not limited to the meatus, and who had no history of hypospadias, for analysis using the Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology classification system. Methods A retrospective database from 13 institutions was compiled of patients who had undergone surgical correction of Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology urethral stricture segments S2b/S2c and excluding E5, with a minimum follow‐up time of 4 months. Failure was defined as cystoscopically confirmed recurrence of a stricture measuring less than 16‐Fr. Results We analyzed 222 patients with a median age of 57 years and a follow‐up of 49 months. The overall surgical success rate was 80.2%. On multivariate analysis, the two variables identified that were predictive of surgical success were stricture length ≤2 cm as well as use of a buccal mucosa graft as compared to use of a fasciocutaneous flap, which had success rates of 83% and 52%, respectively ( P = 0.0004). No statistically significant differences were found based on incisional approach or surgical technique, nor were outcomes different based on etiology or preoperative patient demographics. Conclusions Surgical repair of penile urethral strictures of non‐hypospadiac origin have a favorable overall success rate, at 80.2%. Regardless of incisional approach or surgical technique, all operations appear to have similar outcomes other than repairs using fasciocutaneous flap, which were statistically less successful than those using buccal mucosa graft.