A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol.

BACKGROUND: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control. METHODS/DESIGN: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015. DISCUSSION: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options

Durability of high-frequency 10-kHz spinal cord stimulation for patients with painful diabetic neuropathy refractory to conventional treatments: 12-month results from a randomized controlled trial

No abstract available

A randomized controlled trial of high frequency (10 kHz) spinal cord stimulation in painful diabetic neuropathy

Importance: Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments. Objective: To determine whether 10-kHz spinal cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN). Design, Setting, and Participants: The prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A1c (HbA1c) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated. Interventions: Implanted medical device delivering 10-kHz SCS. Main Outcomes and Measures: The prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months. Results: Of 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001). Conclusions and Relevance: Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can safely and effectively treat patients with refractory PDN. Trial Registration: ClincalTrials.gov Identifier: NCT0322842

Trends in hospitalizations and epidemiological characteristics of adults Moyamoya disorder in the United States

There has been an increasing prevalence of Moyamoya disorder (MMD) reported from recent US literature. There is a paucity of data available regarding trends of prevalence and epidemiological factors in the United States. To goal of this study was to test the hypotheses that racial-, sex-specific MMD hospitalizations and epidemiological factors have been increasing in the United States over the last decade. In this retrospective observational study, using the National Inpatient Sample (NIS) database from 2005 to 2016, MMD-related hospitalizations in patients aged ≥18 years were identified. Trends of epidemiological factors were analyzed over time using the linear regression model with the significance of differences in trend over time assessed using the Wald test. Sex- and race-specific burden of MMD were calculated using the annual US Census data. Joinpoint regression model was used to evaluate trends of hospitalizations over time. A total of 24,484 adult hospitalizations were identified from January 2005 to September 2015 after excluding <18 years. Among them, approximately ~90% were aged ≤60 years, and 73.5% were females. The most common vascular and non-vascular presentations were ischemic stroke (17.3%) and seizures (21%), respectively. The trend of antithrombotic therapy has increased, while extracranial-intracranial bypass has remained stagnant. The actual average hospitalizations of MMD was 10.4 cases/ million population/year (range 4.1–17.9) and varied significantly by sex (females 14.7 [range 6.2–23.6] and males 5.9 [range 1.8–11.9]) over the 2005 to 2016 study period. The burden of hospitalizations also differed by race (African Americans 40.6 [range 32.8–63.7], Asians 24.8 [15.4–34.8], Non-Hispanic Whites 8.1 [range 6.4–11.5], and Hispanics 8.4 [2.8–12.8]) over the 2010 to 2016 study period. Joinpoint regression analysis showed an increasing overall MMD trend across the study period (+11.7%; P < 0.001), which was higher in males (+14.5% vs. +10.7%; P < 0.001). The Hispanic group had significantly increased hospitalizations over the years (+20.2%; P < 0.001). Although overall more prevalent in females, MMD-related hospitalizations are increasing more rapidly in males. Among the racial subpopulations, African Americans had the highest MMD-related hospitalizations, even higher than Asian Americans. MMD-related hospitalizations have increased quicker in Hispanics than in any other racial group. •Moyamoya disorder (MMD) is an increasingly recognized cause for stroke in the US. reka•African Americans have the highest MMD-related hospitalization rate among all racial groups.•Although overall higher in females, the rate of MMD-related hospitalizations are rising faster in males.•MMD presents more often as ischemic rather than hemorrhagic stroke in the Western population.•The use of antithrombotics has increased over the years; EC-IC bypass procedure performance rates have remained static

Role of obesity in less radiographic correction and worse health-related quality-of-life outcomes following minimally invasive deformity surgery

OBJECTIVE Minimally invasive surgery (MIS) for adult spinal deformity (ASD) can offer deformity correction with less tissue manipulation and damage. However, the impact of obesity on clinical outcomes and radiographic correction following MIS for ASD is poorly understood. The goal of this study was to determine the role, if any, that obesity has on radiographic correction and health-related quality-of-life measures in MIS for ASD. METHODS Data were collected from a multicenter database of MIS for ASD. This was a retrospective review of a prospectively collected database. Patient inclusion criteria were age ≥ 18 years and coronal Cobb angle ≥ 20°, pelvic incidence–lumbar lordosis mismatch ≥ 10°, or sagittal vertical axis (SVA) > 5 cm. A group of patients with body mass index (BMI) < 30 kg/m 2 was the control cohort; BMI ≥ 30 kg/m 2 was used to define obesity. Obesity cohorts were categorized into BMI 30–34.99 and BMI ≥ 35. All patients had at least 1 year of follow-up. Preoperative and postoperative health-related quality-of-life measures and radiographic parameters, as well as complications, were compared via statistical analysis. RESULTS A total of 106 patients were available for analysis (69 control, 17 in the BMI 30–34.99 group, and 20 in the BMI ≥ 35 group). The average BMI was 25.24 kg/m 2 for the control group versus 32.46 kg/m 2 (p < 0.001) and 39.5 kg/m 2 (p < 0.001) for the obese groups. Preoperatively, the BMI 30–34.99 group had significantly more prior spine surgery (70.6% vs 42%, p = 0.04) and worse preoperative numeric rating scale leg scores (7.71 vs 5.08, p = 0.001). Postoperatively, the BMI 30–34.99 cohort had worse Oswestry Disability Index scores (33.86 vs 23.55, p = 0.028), greater improvement in numeric rating scale leg scores (−4.88 vs −2.71, p = 0.012), and worse SVA (51.34 vs 26.98, p = 0.042) at 1 year postoperatively. Preoperatively, the BMI ≥ 35 cohort had significantly worse frailty (4.5 vs 3.27, p = 0.001), Oswestry Disability Index scores (52.9 vs 44.83, p = 0.017), and T1 pelvic angle (26.82 vs 20.71, p = 0.038). Postoperatively, after controlling for differences in frailty, the BMI ≥ 35 cohort had significantly less improvement in their Scoliosis Research Society–22 outcomes questionnaire scores (0.603 vs 1.05, p = 0.025), higher SVA (64.71 vs 25.33, p = 0.015) and T1 pelvic angle (22.76 vs 15.48, p = 0.029), and less change in maximum Cobb angle (−3.93 vs −10.71, p = 0.034) at 1 year. The BMI 30–34.99 cohort had significantly more infections (11.8% vs 0%, p = 0.004). The BMI ≥ 35 cohort had significantly more implant complications (30% vs 11.8%, p = 0.014) and revision surgery within 90 days (5% vs 1.4%, p = 0.034). CONCLUSIONS Obese patients who undergo MIS for ASD have less correction of their deformity, worse quality-of-life outcomes, more implant complications and infections, and an increased rate of revision surgery compared with their nonobese counterparts, although both groups benefit from surgery. Appropriate counseling should be provided to obese patients