Radiation Therapy Quality Assurance Analysis of Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Pancreas.

PURPOSE: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered. METHODS AND MATERIALS: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable deviations. Additionally, we performed a post hoc RT QA analysis in which contours and plans were reviewed by 3 radiation oncologists and assigned a score (1, 2, or 3) based on adequacy. A score of 1 indicated no deviation, 2 indicated minor deviation, and 3 indicated a major deviation that could be clinically significant. Clinical outcomes were compared by treatment modality and by case score. RESULTS: Forty patients were registered to receive RT (1 planned but not treated) at 27 centers (18 academic and 9 community). Twenty-three centers were appropriately credentialed for moving lung/liver targets and 4 for static head and neck only. Thirty-two of 39 patients (82.1%) were treated with SBRT and 7 (17.9%) with hypofractionated RT. Five cases (13%) required revision before treatment. On post hoc review, 23 patients (59.0%) were noted to have suboptimal contours or plan coverage, 12 (30.8%) were scored a 2, and 11 (28.2%) were scored a 3. There were no apparent differences in failure patterns or surgical outcomes based on treatment technique or post hoc case score. Details related to on-treatment imaging were not recorded. CONCLUSIONS: Despite rigorous QA, we encountered variability in simulation, contouring, plan coverage, and dose on trial. Although clinical outcomes did not appear to have been affected, findings from this analysis serve to inform subsequent PDAC SBRT trial designs and QA requirements.

Validation of the Polar Team Pro System for Sprint Speed With Ice Hockey Players.

ABSTRACT: Conners, RT, Whitehead, PN, Dodds, FT, Schott, KD, and Quick, MC. Validation of the polar team pro system for sprint speed with ice hockey players. J Strength Cond Res 36(12): 3468-3472, 2022-Commercially available player tracking sensors such as the Polar Team Pro system (PTPS) have been used to monitor athlete performance. Use during ice hockey practices and games has resulted in seemingly plausible and valid values for internal metrics (heart rate); however, external metrics (distance, speed, and acceleration) seem sporadic and counterintuitive. To determine the validity of the PTPS for measuring sprint speed with collegiate hockey players, 15 NCAA Division I male athletes (21.86 ± 1.04 years, 175.86 ± 6.78 cm, 80.58 ± 4.44 kg) participated in the study. Subjects wore a PTPS strap, at the level of the xiphoid process, and performed 2 sprints of 15.24 m (blue line to blue line) and 35.05 m (red line to the far blue line) in 3 conditions: indoor ice skating, indoor running, and outdoor running. Timing gates (TG) were used to determine sprint times, which allowed for manual calculation of speed. Speed values from the PTPS and TG were compared using paired-samples t -tests, and an alpha level of 0.05, 2-sided, was set a priori as a significance level. For indoor ice skating, PTPS significantly underestimated speeds at both distances ( p < 0.001). However, PTPS significantly overestimated speeds for indoor and outdoor sprints at both distances ( p ≤ 0.001). The PTPS is not accurate for measuring short-distance linear sprint speed or linear sprint speed during indoor ice skating. The inconsistency in speed values needs to be taken into consideration when using the system for science-based training because inaccurate speed values may negatively affect other external performance metrics provided by PTPS.

Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group.

PURPOSE: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR). METHODS AND MATERIALS: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D). RESULTS: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection. CONCLUSIONS: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.

Recombinant HA-based vaccine outperforms split and subunit vaccines in elicitation of influenza-specific CD4 T cells and CD4 T cell-dependent antibody responses in humans.

Although traditional egg-based inactivated influenza vaccines can protect against infection, there have been significant efforts to develop improved formats to overcome disadvantages of this platform. Here, we have assessed human CD4 T cell responses to a traditional egg-based influenza vaccine with recently available cell-derived vaccines and recombinant baculovirus-derived vaccines. Adults were administered either egg-derived Fluzone®, mammalian cell-derived Flucelvax® or recombinant HA (Flublok®). CD4 T cell responses to each HA protein were assessed by cytokine EliSpot and intracellular staining assays. The specificity and magnitude of antibody responses were quantified by ELISA and HAI assays. By all criteria, Flublok vaccine exhibited superior performance in eliciting both CD4 T cell responses and HA-specific antibody responses, whether measured by mean response magnitude or percent of responders. Although the mechanism(s) underlying this advantage is not yet clear, it is likely that both qualitative and quantitative features of the vaccines impact the response.

The rates of second lung cancers and the survival of surgically-resected second primary lung cancers in patients undergoing resection of an initial primary lung cancer.

BACKGROUND: The Lung Cancer Screening Trial demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS), likely due to finding early-stage NSCLC. The purpose of our investigation is to evaluate whether long-term surveillance strategies (4+ years after surgical resection of the initial lung cancer(1LC)) would be beneficial in NSCLC patients by assessing the rates of second lung cancers(2LC) and the OS/LCSS in patients undergoing definitive surgery in 1LC as compared to 2LC (>48 months after 1LC) populations. METHODS: SEER13/18 database was reviewed for patients during 1998-2013. Log-rank tests were used to determine the OS/LCSS differences between the 1LC and 2LC in the entire surgical group(EG) and in those having an early-stage resectable tumors (ESR, tumors <4 cm, node negative). Joinpoint analysis was used to determine rates of second cancers 4-10 year after 1LC using SEER-9 during years 1985-2014. RESULTS: The rate of 2LCs was significantly less than all other second cancers until 2001 when the incidence of 2LCs increased sharply and became significantly greater than all other second cancers in females starting in year 2005 and in men starting in year 2010. OS/LCSS, adjusted for propensity score by using inverse probability weighting, demonstrated similar OS, but worse LCSS for 2LCs in the EG, but similar OS/LCSSs in the ESR group. CONCLUSION: Because the rate of 2LCs are increasing and because the OS/LCSS of the 1LC and 2LC are similar in early-stage lesions, we feel that continued surveillance of patients in order to find early-stage disease may be beneficial.

Shoulder Strength and Range of Motion Between Collegiate Pitchers and Position Players in Baseball.

Baseball is a sport that places excessive strain on the shoulder complex caused from repetitive overhead throws. In the sport of baseball, shoulder strength and range of motion (ROM) are paramount for success on the field. The purpose of this study was to determine strength and ROM differences between collegiate baseball pitchers and position players. It was hypothesized that pitchers would have higher strength and ROM values, due to the volume of throwing a pitcher performs. A total of nine collegiate baseball pitchers and position players (n = 18) volunteered for the study (age = 20.94 ± 1.21 years, height = 183.42 ± 4.74 cm, and mass = 89.56 ± 10.76 kg). Shoulder strength was measured using a Humac Norm isokinetic dynamometer at 180ºsec-1 and 300ºsec-1 and ROM was measured using a goniometer. All participants completed a five-minute warm-up at 50 rpm on an upper body ergometer. Following the warm-up, passive internal and external ROM were measured for the throwing (dominant) arm. No statistical differences were found in external ROM (p = 0.319), internal ROM (p = 0.258), external peak torque @180ºsec-1 (p = 0.467), internal peak torque @180ºsec-1 (p = 0.156), external peak torque @300ºsec-1 (p = 0.225), or internal peak torque @300ºsec-1 (p = 0.137). The findings indicate similar isokinetic strength and flexibility in the throwing shoulder of collegiate athletes who perform repeated overhead throwing motions. Thus, in this study the player's baseball position (pitchers vs. position player) did not influence throwing shoulder strength and ROM characteristics.

Open access image repositories: high-quality data to enable machine learning research.

Originally motivated by the need for research reproducibility and data reuse, large-scale, open access information repositories have become key resources for training and testing of advanced machine learning applications in biomedical and clinical research. To be of value, such repositories must provide large, high-quality data sets, where quality is defined as minimising variance due to data collection protocols and data misrepresentations. Curation is the key to quality. We have constructed a large public access image repository, The Cancer Imaging Archive, dedicated to the promotion of open science to advance the global effort to diagnose and treat cancer. Drawing on this experience and our experience in applying machine learning techniques to the analysis of radiology and pathology image data, we will review the requirements placed on such information repositories by state-of-the-art machine learning applications and how these requirements can be met.

Use of the Dermatology Life Quality Index work/study domain to estimate overall work productivity loss among patients with psoriasis: an analysis based on real-world data.

Psoriasis is a chronic autoimmune disease that is associated with substantial economic burden related to work productivity loss (WPL). WPL is commonly measured using the Work Productivity and Activity Impairment (WPAI) questionnaire. However, WPAI does not measure outcomes among unemployed patients, and may therefore underestimate the burden of psoriasis. This study evaluated the relationship between the Dermatology Life Quality Index (DLQI) questionnaire work/study domain and WPL using the WPAI, as DLQI assesses the impact of psoriasis on the ability to work/study regardless of employment status, but does not estimate WPL. Data were drawn from the Adelphi Psoriasis Disease Specific Programme survey. A positive linear relationship was observed between DLQI work/study scores and WPAI results, showing that higher DLQI scores were associated with greater percent WPL. These findings suggest that the DLQI work/study domain can be used to estimate overall WPL among patients with psoriasis, including those who cannot work because of their disease.

Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.

An optimized, clinically relevant mouse model of cisplatin-induced ototoxicity.

Cisplatin-induced ototoxicity results in significant, permanent hearing loss in pediatric and adult cancer survivors. Elucidating the mechanisms underlying cisplatin-induced hearing loss as well as the development of therapies to reduce and/or reverse cisplatin ototoxicity have been impeded by suboptimal animal models. Clinically, cisplatin is most commonly administered in multi-dose, multi-cycle protocols. However, many animal studies are conducted using single injections of high-dose cisplatin, which is not reflective of clinical cisplatin administration protocols. Significant limitations of both high-dose, single-injection protocols and previous multi-dose protocols in rodent models include high mortality rates and relatively small changes in hearing sensitivity. These limitations restrict assessment of both long-term changes in hearing sensitivity and effects of potential protective therapies. Here, we present a detailed method for an optimized mouse model of cisplatin ototoxicity that utilizes a multi-cycle administration protocol that better approximates the type and degree of hearing loss observed clinically. This protocol results in significant hearing loss with very low mortality. This mouse model of cisplatin ototoxicity provides a platform for examining mechanisms of cisplatin-induced hearing loss as well as developing therapies to protect the hearing of cancer patients receiving cisplatin therapy.

Mobile technology use and skills among individuals with fragile X syndrome: implications for healthcare decision making.

BACKGROUND: Little is known about how individuals with fragile X syndrome (FXS) and their families use technology in daily life and what skills individuals with FXS can perform when using mobile technologies. METHODS: Using a mixed-methods design, including an online survey of parents (n = 198) and a skills assessment of individuals with FXS (n = 6), we examined the experiences and abilities of individuals with FXS for engaging with mobile technology. RESULTS: Parents reported that individuals with FXS often used technology in their daily lives, with variations based on age of child, sex, autism status, depression, and overall ability. Parents frequently sought and shared FXS-related information online. Assessment data revealed that individuals with FXS demonstrated proficiency in interacting with technology. CONCLUSIONS: Mobile technology is a tool that can be used in FXS to build skills and increase independence rather than simply for recreational purposes. Implications for using mobile technology to enhance healthcare decision making are discussed.

Effect of Standard Radiotherapy With Cisplatin vs Accelerated Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma: A Randomized Clinical Trial.

IMPORTANCE: The Canadian Cancer Trials Group study HN.6 is the largest randomized clinical trial to date comparing the concurrent administration of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies with radiotherapy (RT) to standard chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). OBJECTIVE: To compare progression-free survival (PFS) in patients with LA-SCCHN treated with standard-fractionation RT plus high-dose cisplatin vs accelerated-fractionation RT plus the anti-EGFR antibody panitumumab. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 3 clinical trial in 17 Canadian centers. A total of 320 patients were randomized between December 2008 and November 2011. INTERVENTIONS: Patients with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive standard-fractionation RT (70 Gy/35 over 7 weeks) plus cisplatin at 100 mg/m2 intravenous for 3 doses (arm A) vs accelerated-fractionation RT (70 Gy/35 over 6 weeks) plus panitumumab at 9 mg/kg intravenous for 3 doses (arm B). MAIN OUTCOMES AND MEASURES: Primary end point was PFS. Due to an observed declining event rate, the protocol was amended to a time-based analysis. Secondary end points included overall survival, local and regional PFS, distant metastasis-free survival, quality of life, adverse events, and safety. RESULTS: Of 320 patients randomized (268 [84%] male; median age, 56 years), 156 received arm A and 159 arm B. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI, 65%-79%) in arm A and 76% (95% CI, 68%-82%) in arm B (hazard ratio [HR], 0.95; 95% CI, 0.60-1.50; P = .83). The upper bound of the HR 95% CI exceeded the prespecified noninferiority margin. Two-year overall survival was 85% (95% CI, 78%-90%) in arm A and 88% (95% CI, 82%-92%) in arm B (HR, 0.89; 95% CI, 0.54-1.48; P = .66). Incidence of any grade 3 to 5 nonhematologic adverse event was 88% in arm A and 92% in arm B (P = .25). CONCLUSIONS AND RELEVANCE: With a median follow-up of 46 months, the PFS of panitumumab plus accelerated-fractionation RT was not superior to cisplatin plus standard-fractionation RT in LA-SCCHN and noninferiority was not proven. Despite having negative results, HN.6 has contributed important data regarding disease control and toxic effects of these treatment strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00820248.

Linking canonical microcircuits and neuronal activity: Dynamic causal modelling of laminar recordings.

Neural models describe brain activity at different scales, ranging from single cells to whole brain networks. Here, we attempt to reconcile models operating at the microscopic (compartmental) and mesoscopic (neural mass) scales to analyse data from microelectrode recordings of intralaminar neural activity. Although these two classes of models operate at different scales, it is relatively straightforward to create neural mass models of ensemble activity that are equipped with priors obtained after fitting data generated by detailed microscopic models. This provides generative (forward) models of measured neuronal responses that retain construct validity in relation to compartmental models. We illustrate our approach using cross spectral responses obtained from V1 during a visual perception paradigm that involved optogenetic manipulation of the basal forebrain. We find that the resulting neural mass model can distinguish between activity in distinct cortical layers - both with and without optogenetic activation - and that cholinergic input appears to enhance (disinhibit) superficial layer activity relative to deep layers. This is particularly interesting from the perspective of predictive coding, where neuromodulators are thought to boost prediction errors that ascend the cortical hierarchy.

Localized high-grade gastroenteropancreatic neuroendocrine tumors: Defining prognostic and therapeutic factors for a disease of increasing clinical significance.

BACKGROUND: Due to the limited sample size in the existing series, the natural history and management of high-grade gastroenteropancreatic neuroendocrine tumors (GEP-NET) is poorly understood. In order to better understand high-grade GEP-NET, a large cohort study was undertaken. OBJECTIVE: To determine the prognostic factors associated with high-grade GEP-NET. METHODS: Patients diagnosed with non-metastatic high-grade GEP-NET from 1988 to 2010 were identified in SEER. RESULTS: Incidence of high-grade GEP-NETs increased from 0.03 to 0.19/100,000 over the study period. The median age was 65 years, and the majority of the patients were white and females. The most common primary site was colorectal, and the most frequent T classification was T3. Surgical resection was performed in 89% of patients that varied by site (p < 0.0001). Nodal involvement was frequent and varied by site (p = 0.0002). The 5-year disease-specific survival was 63.3% and was the greatest for small bowel (p = 0.0003). Survival was associated with age, node status and surgery (p < 0.05). On multivariate analysis, the node status, surgery, and site continued to be associated with survival (p < 0.05); however, age (p = 0.08) no longer influenced the patient's survival. CONCLUSION: High-grade GEP-NETs are neoplasms with exponentially increasing in incidence. Tumor location and nodal status are predictors of survival. Surgery is associated with a survival advantage and could be considered for localized disease.

Radiotherapy quality assurance report from children's oncology group AHOD0031.

PURPOSE: A phase 3 trial assessing response-based therapy in intermediate-risk Hodgkin lymphoma mandated real-time central review of involved field radiation therapy (IFRT) and imaging records by a centralized review center to maximize protocol compliance. We report the impact of centralized radiation therapy review on protocol compliance. METHODS AND MATERIALS: Review of simulation films, port films, and dosimetry records was required before and after treatment. Records were reviewed by study-affiliated or review center-affiliated radiation oncologists. A deviation of 6% to 10% from protocol-specified dose was scored as "minor"; a deviation of >10% was "major." A volume deviation was scored as "minor" if margins were less than specified or "major" if fields transected disease-bearing areas. Interventional review and final compliance review scores were assigned to each radiation therapy case and compared. RESULTS: Of 1712 patients enrolled, 1173 underwent IFRT at 256 institutions in 7 countries. An interventional review was performed in 88% of patients and a final review in 98%. Overall, minor and major deviations were found in 12% and 6% of patients, respectively. Among the cases for which ≥1 pre-IFRT modification was requested by the Quality Assurance Review Center and subsequently made by the treating institution, 100% were made compliant on final review. By contrast, among the cases for which ≥1 modification was requested but not made by the treating institution, 10% were deemed compliant on final review. CONCLUSIONS: In a large trial with complex treatment pathways and heterogeneous radiation therapy fields, central review was performed in a large percentage of cases before IFRT and identified frequent potential deviations in a timely manner. When suggested modifications were performed by the institutions, deviations were almost eliminated.