Effect of internal mammary vessels radiation dose on outcomes of free flap breast reconstruction.

To assess the impact of internal mammary (IM) vessels radiation dose on autologous free-flap based breast reconstruction outcomes. We retrospectively evaluated the medical records of breast cancer patients who underwent mastectomy and free-flap breast reconstruction after postoperative radiation therapy (RT) to the breast/chest wall with (n = 9) or without (n = 11) electively including the IM lymph nodes. Twenty patients were included. Median age at diagnosis was 50 years (range, 33-63). The median time interval between the start of RT and reconstructive surgery was 16 months (range, 6-45). The maximal IM vessels dose was not associated with the risk of all complications (P = 0.44) or fat necrosis (P = 0.31). The mean IM vessels dose was not significant for the risk of all complications (P = 0.13) but was significant for fat necrosis (P = 0.04). A high mean IM vessels dose was related to the occurrence of fat necrosis.

Hypofractionation for breast cancer: lessons learned from our neighbors to the north and across the pond.

Adjuvant whole breast irradiation was established within the standard of care for breast-conserving therapy in the early 1980s, following the results of major randomized trials comparing mastectomy vs breast-conserving surgery and radiation. Since that time, techniques and treatment strategies have evolved, but one major thread that carries forward is the need to balance cost, efficacy, complications, and convenience. Fortunately, data from randomized trials conducted in Canada and Great Britain provide a solid framework for the consideration of hypofractionated radiation in the treatment of breast cancer. In this review we discuss the rationale and underlying radiobiologic concepts for hypofractionation, and review the clinical trials and American Society for Radiation Oncology (ASTRO) guidelines supporting this approach. We also review the practical considerations for treatment planning, including dosimetric criteria and how to approach treatment of the node-positive patient. In the current era of healthcare reform and cost awareness, thoughtful utilization of hypofractionation may offer considerable savings to individual patients and the healthcare system--without compromising clinical outcomes or quality of life.

The Use of Hyperbaric Oxygen Therapy in the Management of Severe Radiation-Induced Hemorrhagic Gastritis in a Pediatric Patient.

Radiation-induced hemorrhagic gastritis is a serious and rare complication of radiation therapy. Optimal therapies in the pediatric population are not well established. We report a 2-year-old female diagnosed with rhabdomyosarcoma who developed hemorrhagic gastritis following chemotherapy and radiation therapy. The patient presented with acute onset anemia, hematemesis, and melena. Endoscopies revealed circumferential ulceration at the pylorus with spontaneous oozing that failed to respond effectively with multimodal medical and endoscopic therapies. Following hemodynamic stabilization, the patient was treated with hyperbaric oxygen therapy with excellent clinical response of the bleeding. Further research on the benefit of hyperbaric oxygen therapy is warranted to determine if this treatment can reduce the incidence of gastrointestinal complications in patients who have received radiation therapy.

Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease.

OBJECTIVE: To investigate the spectrum and prevalence of cognitive deficits among children with type 3 (chronic neuronopathic) Gaucher disease (GD). STUDY DESIGN: A case review study identified 32 children (male/female; 17:15) with type 3 GD who had received enzyme replacement therapy (ERT) or a bone marrow transplant. The diagnosis of GD was established by enzymatic assay and DNA testing. Subjects were assessed with standard neuropsychological testing, and data from the most recent evaluation were included. RESULTS: Neuropsychometric assessments demonstrated a wide spectrum of full-scale IQ scores ranging from 39 to 124 (mean 75). About 60% of subjects had intellectual skills below average. There were significant discrepancies between verbal and performance IQ, with a range between -6 and 38 points (P = .02). This gap was more prominent in older subjects, with better performance in the verbal areas. No correlation was observed between intelligence measures and genotype or the extent of systemic involvement. The dosage, age at initiation, and the length of ERT had no significant effect on IQ scores. CONCLUSIONS: In type 3 GD, cognitive deficits, characterized by visual-spatial dysfunction, are common but underappreciated and appear resistant to ERT.

Multivalent Binding and Biomimetic Cell Rolling Improves the Sensitivity and Specificity of Circulating Tumor Cell Capture.

Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in patients with cancer undergoing radiotherapy treatment.Experimental Design: Patients with histologically confirmed primary carcinoma undergoing radiotherapy, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to five time points, including before radiotherapy, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of radiotherapy. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR.Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45-/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before radiotherapy to 32 CTCs/mL at completion of radiotherapy (P = 0.001). CTCs declined throughout radiotherapy in patients with complete clinical and/or radiographic response, in contrast with an elevation in CTCs at mid or post-radiotherapy in the two patients with known pathologic residual disease.Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared with multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment. Clin Cancer Res; 24(11); 2539-47. ©2018 AACR.

Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy.

Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer.

BACKGROUND AND PURPOSE: To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. MATERIAL AND METHODS: Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. RESULTS: 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. CONCLUSIONS: Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity.

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy.

Immunotherapy holds tremendous promise for improving cancer treatment. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the 'abscopal effect'. Unfortunately, response rates for this strategy remain low. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties. We showed that AC-NPs deliver tumour-specific proteins to antigen-presenting cells (APCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment using the B16F10 melanoma model, generating up to a 20% cure rate compared with 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+T/Treg and CD8+T/Treg ratios (Treg, regulatory T cells). Our work presents a novel strategy to improve cancer immunotherapy with nanotechnology.

Glucocerebrosidase mutations are not found in association with LRRK2 G2019S in subjects with parkinsonism.

Alteration G2019S in the leucine-rich repeat kinase 2 gene (LRRK2) has been identified in several populations of patients with parkinsonism, including Ashkenazi Jewish subjects with Parkinson disease. Mutations in glucocerebrosidase (GBA), the enzyme deficient in Gaucher disease, are also identified at an increased frequency among Parkinson probands, including those of Ashkenazi Jewish ancestry. A Taqman Assay-by-Design SNP genotyping strategy was utilized to establish whether G2019S was found in association with GBA mutations. Among 37 subjects with parkinsonism who were heterozygous for a GBA mutation, none carried G2019S. Furthermore, G2019S was not found in 18 patients with Gaucher disease who developed parkinsonian manifestations and 11 other Gaucher probands with parkinsonism in a first degree relative. Among 45 patients with Gaucher disease without a history of parkinsonism, one G2019S carrier was found. These findings suggest that GBA and LRRK2 mutations are discrete risk factors for parkinsonism in both Ashkenazi Jewish and non-Jewish subjects.

Toward a better understanding of task demands, workload, and performance during physician-computer interactions.

OBJECTIVE: To assess the relationship between (1) task demands and workload, (2) task demands and performance, and (3) workload and performance, all during physician-computer interactions in a simulated environment. METHODS: Two experiments were performed in 2 different electronic medical record (EMR) environments: WebCIS (n = 12) and Epic (n = 17). Each participant was instructed to complete a set of prespecified tasks on 3 routine clinical EMR-based scenarios: urinary tract infection (UTI), pneumonia (PN), and heart failure (HF). Task demands were quantified using behavioral responses (click and time analysis). At the end of each scenario, subjective workload was measured using the NASA-Task-Load Index (NASA-TLX). Physiological workload was measured using pupillary dilation and electroencephalography (EEG) data collected throughout the scenarios. Performance was quantified based on the maximum severity of omission errors. RESULTS: Data analysis indicated that the PN and HF scenarios were significantly more demanding than the UTI scenario for participants using WebCIS (P < .01), and that the PN scenario was significantly more demanding than the UTI and HF scenarios for participants using Epic (P < .01). In both experiments, the regression analysis indicated a significant relationship only between task demands and performance (P < .01). DISCUSSION: Results suggest that task demands as experienced by participants are related to participants' performance. Future work may support the notion that task demands could be used as a quality metric that is likely representative of performance, and perhaps patient outcomes. CONCLUSION: The present study is a reasonable next step in a systematic assessment of how task demands and workload are related to performance in EMR-evolving environments.

Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications.

PURPOSE: Data are limited on the clinical significance of brachial plexopathy in patients with apical non-small cell lung cancers (NSCLC) treated with definitive radiation therapy. We report the rates of radiation-induced brachial plexopathy (RIBP) and tumor-related brachial plexopathy (TRBP) and associated dosimetric parameters in apical NSCLC patients. METHODS AND MATERIALS: Charts of NSCLC patients with primary upper lobe or superiorly located nodal disease who received ≥50 Gy of definitive conventionally fractionated radiation or chemoradiation were retrospectively reviewed for evidence of brachial plexopathy and categorized as RIBP, TRBP, or trauma-related. Dosimetric data were gathered on ipsilateral brachial plexuses (IBP) contoured according to Radiation Therapy Oncology Group atlas guidelines. RESULTS: Eighty patients were identified with a median follow-up and survival time of 17.2 and 17.7 months, respectively. The median prescribed dose was 66.6 Gy (range, 50.4-84.0), and 71% of patients received concurrent chemotherapy. RIBP occurred in 5 patients with an estimated 3-year rate of 12% when accounting for competing risk of death. Seven patients developed TRBP (estimated 3-year rate of 13%), comprising 24% of patients who developed locoregional failures. Grade 3 brachial plexopathy was more common in patients who experienced TRBP than RIBP (57% vs 20%). No patient who received ≤78 Gy to the IBP developed RIBP. On multivariable competing risk analysis, IBP V76 receiving ≥1 cc, and primary tumor failure had the highest hazard ratios for developing RIBP and TRBP, respectively. CONCLUSIONS: RIBP is a relatively uncommon complication in patients with apical NSCLC tumors receiving definitive doses of radiation, while patients who develop primary tumor failures are at high risk for developing morbid TRBP. These findings suggest that the importance of primary tumor control with adequate doses of radiation outweigh the risk of RIBP in this population of patients.

Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease.

BACKGROUND: An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD). METHODS: The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity. FINDINGS: The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R. INTERPRETATION: These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin.

Perinatal lethal Gaucher disease: a distinct phenotype along the neuronopathic continuum.

Gaucher disease, the inherited deficiency of glucocerebrosidase, is characterized by significant genetic and phenotypic heterogeneity. At the extreme end of the phenotypic continuum is the perinatal lethal variant, typically presenting in utero or during the neonatal period as hydrops and/orcongenital ichthyosis, with severe and progressive neurological involvement. Insights from the null-allele Gaucher mouse model contributed to the identification of this distinct phenotype, which has unique epidermal involvement. While multiple mutations are encountered, many affected infants are homozygous for recombinant alleles. The diagnosis is often missed due to the early lethality and the failure to recognize the association between lysosomal disorders and hydrops fetalis. The incidence of severe perinatal Gaucher disease may prove more common than currently appreciated with greater physician awareness of the disorder.