Abstract Objective Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition ...during radiochemotherapy. Methods We conducted a phase II study evaluating 3 × weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m2 ) co-administered with 1 × weekly intravenous cisplatin (40 mg/m2 ) and daily pelvic radiation (45 Gy) in women with stage IB2 –IVB cervical (n = 22) or stage II–IV vaginal (n = 3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-18 F fluoro-2-deoxy- d -glucose positron emission tomography (PET/CT) and clinical examination. Results 3-AP radiochemotherapy achieved clinical responses in 24 (96% 95% confidence interval: 80–99%) of 25 patients (median follow-up 20 months, range 2–35 months). 23 (96% 95% confidence interval: 80–99%) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. Conclusions The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
Background: Youth with T2D experience barriers to obtaining diabetes care. We evaluated whether healthcare utilization (HCU) was associated with glycemic outcomes in youth with T2D.
Methods: We ...evaluated annual HCU in 1,324 T2D PDC youth by diabetes duration up to 13 years post diagnosis. Medical record and self-reported HCU data were collected at enrollment and annually. Frequency of diabetes related inpatient admissions, Emergency Department (ED), urgent care, Diabetes Management (DM), Registered Dietician (RD) visits, and 911 calls were collected.
Results: After adjusting for age, gender, diabetes duration, and annual visits, those with ≥1 admission/year, regardless of admission reason, (16%) had a higher A1c vs. those without admission, 8.8 vs. 8.4% (p=0.002). Those with ≥2 DM office visits/year (75%) had lower A1c vs. those with 0-1 visits, 8.4 vs. 8.8% (p=0.001). BMI and A1c did not differ by number of RD visits (p=0.63 and 0.39 respectively); RD visits/year decreased over time.
Conclusions: In T2D youth, hospitalizations and <2 DM office visits/year are associated with higher A1c. Frequencies of ED and inpatient admissions for T2D are stable following the first year of T2D diagnosis. Only 24-38% of T2D youth had 4 DM visits/year while ∼50% have ≥3 visits a year, even with long T2D duration. Methods to improve follow-up care are needed to improve outcomes in youth with T2D.
Disclosure
G.J. Klingensmith: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Dexcom, Inc. P. Cheng: None. R.L. Gal: None. L.C. Beaulieu: None. C. Kollman: None. R.L. Adams: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. L.M. Looper: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.
Funding
Boehringer Ingelheim; Novo Nordisk; Takeda Pharmaceutical Company Limited
Recurrent gynecologic cancers are often difficult to manage without significant morbidity. We conducted a phase II study to assess the safety and the efficacy of ablative robotic stereotactic body ...radiosurgery (SBRT) in women with metastatic gynecologic cancers.
A total of 50 patients with recurrent gynecologic cancer who had single or multiple (≤4) metastases underwent robotic-armed Cyberknife SBRT (24Gy/3 daily doses). Toxicities were graded prospectively by common toxicity criteria for adverse events (version 4.0). SBRT target responses were recorded following RECIST criteria (version 1.0). Rates of clinical benefit for SBRT and non-radiosurgical disease relapse were calculated. Disease-free and overall survivals were estimated by the Kaplan-Meier method and the Cox proportional hazards model was used to control for prognostic variables.
SBRT was safely delivered, with 49 (98%) of 50 patients completing three prescribed fractions. The most frequent grade 2 or higher adverse events attributed to SBRT included fatigue (16%), nausea (8%), and diarrhea (4%). One (2%) grade four hyperbilirubinemia occurred. SBRT target response was 96% (48 of 50 patients). A 6-month clinical benefit was recorded in 34 68% (95% CI, 53.2, 80.1) patients. No SBRT targeted disease progressed. Non-radiosurgical disease relapse occurred in 31 (62%) patients. Median disease-free survival was 7.8 months (95% CI, 4.0, 11.6). Median overall survival was 20.2 months (95% CI, 10.9, 29.5).
SBRT safely controlled metastatic gynecologic cancer targets. Given an observed high rate of non-radiosurgical disease relapse, a phase I trial assessing co-administration of SBRT and cytotoxic chemotherapy is underway.
Case Comprehensive Cancer Center.
Very young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We ...conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population.
A total of 80 children aged 2.0-5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy.
There were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70-180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204).
Use of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.
Background. Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza ...severity in adults. IFITM3 has not been evaluated in pediatric influenza. Methods. The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA. Results. In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the Δ21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified. Conclusions. rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.
The purpose of this study was to collect 1 year of real-world data from individuals with type 1 diabetes (T1D) initiating the Medtronic 670G hybrid closed-loop insulin delivery system as part of ...usual care. We sought to expand current knowledge to understand how use of the system impacts patient-reported outcomes, in addition to clinical outcomes, for children and adults with T1D.
Questionnaires were completed by the participant (and/or parent) before initiation of the 670G system (baseline) and at 6 weeks, 6 months, and 12 months from enrollment. Clinical data were obtained at routine clinical visits.
Of 132 participants who initiated Auto Mode, 80 completed the 12-month questionnaires while persisting with the system. Nearly all reported receiving adequate training on the 670G. Participant and parent-reported fear of hypoglycemia decreased by 6 and 11 points, respectively, from baseline to 12 months. More than half reported issues with sleep interruption at night due to alarms and 40% did not like frequent exits from Auto Mode. For the subset who had complete continuous glucose monitor data (
= 27), mean percent time in target range (70-180 mg/dL) was 66% at baseline, and 74% and 68% at 6 and 12 months, respectively.
With this study, we have captured real-time feedback from patients with T1D who initiated the 670G system and continued to use it over 12 months regarding their experience with the system. This has helped to illuminate both benefits and burdens associated with the first commercially available hybrid closed-loop system.
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Background: Ablative radiation dose delivered by a robotic SBRT platform has shown progression-free survival benefit in two limited case series among patients with recurrent ...gynecological malignancies. The therapeutic impact of SBRT on disease progression (PD) was evaluated in the recurrent setting in this phase II trial. Methods: Fifty patients with recurrent and measurable gynecologic malignancy were treated with SBRT. The cohort included patients with recurrent ovarian (n =25), endometrial (n =14), cervical (n =9), or vulvar (n =2) cancer, 1 prior chemotherapy or radiation regimen, and GOG performance status 0, 1, 2. Patients underwent image-guided SBRT in 3 daily doses of 800 cGy = 2400 cGy. SBRT planning target volumes were determined by both the radiation and gynecologic oncologist using non-contrasted CT and
18
F-FDG PET/CT overlays. The primary endpoints were 6-month clinical benefit rate (# complete response + # partial response + # stable disease without PD by RECIST v1.0 / 50), and less than 30-day posttherapy toxicity. Results: Between July 2009 and September 2011, 50 patients were enrolled and have a median posttherapy follow-up of 9 months. At 3 months, 50% (n=25) had complete response, 46% (n=23) had partial response, and 4% (n=2) had stable disease in SBRT-targeted lesions. Twenty-six patients (52%) have had non-SBRT target PD and 18 (36%) have died of PD. Of the 50 patients, 33 had a PD-free interval of at least 6 months, for an overall clinical benefit rate of 66%. Less than 30-day posttherapy SBRT-related toxicities were grade 2 fatigue (n =9 18%), grade 2 nausea (n =36%, grade 3 nephropathy (n =24%), and grade 4 hyperbilirubinemia (n =12%). Conclusions: This is the first phase II clinical trial of SBRT showing a clinically relevant benefit of ablative radiation in the setting of recurrent gynecological disease. Despite excellent control of targeted lesions with minimal toxicity, non-SBRT target PD rates are high, spurring interest for future SBRT-chemotherapy clinical trials.
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