Single pre-operative radiation therapy (SPORT-CK) trial for low-risk breast cancer: Early results of a phase 2 study.

BACKGROUND AND PURPOSE: Preoperative partial breast irradiation (PBI) is a novel technique that can be used in patients with early-stage breast cancer with the goal of limiting the irradiated breast volume, toxicity and number of fractions. The aim of this trial is to assess the toxicity, surgical, oncologic and cosmetic outcomes of preoperative PBI. MATERIALS AND METHODS: In this single-arm phase II trial, we enrolled women ≥ 60 years, with unifocal low-risk breast invasive ductal carcinoma (cT1N0, grade 1-2, ER+, Her2-). Patients were treated with a single fraction of 20 Gy of preoperative PBI using volumetric modulated arc therapy (VMAT). Patients then underwent breast-conserving surgery (BCS) +/- sentinel lymph node biopsy within 72 h of radiation. Primary outcomes were rate of surgical complications and early toxicity. Secondary outcomes were cosmesis at 12 months, chronic toxicity and ipsilateral breast tumor recurrence. RESULTS: Twenty-five patients were recruited with a median age of 67 years, and a median follow-up of 60 months. Sentinel biopsy was positive in 1 out of 24 patients (4 %). Two patients received adjuvant RT for close margins or positive lymph nodes. Within the first 90 days, none of the patients had surgical complications; almost all had grade 0 to 1 acute and late RTOG skin toxicity. The cosmetic outcome was rated between good and excellent in all cases by physicians and patients, except for one patient who self-rated her cosmesis as fair as of the third year. There were no recurrences. CONCLUSION: Preoperative single-fraction PBI is a safe and feasible treatment for elderly patients with low-risk early-stage breast cancer, with no surgical complications, very low rates of acute and late radiation toxicity, and excellent cosmetic outcomes. Randomized controlled trials are needed to compare preoperative to adjuvant PBI in this patient population.

Atypical fractures of the lower extremities in two patients with rheumatoid arthritis: clinical presentations of presumed methotrexate osteopathy.

We present two patients who developed multiple lower limb stress fractures. Potential causes, such as osteoporosis, malignancies and disturbances in calcium metabolism were investigated. This led the physicians to consider whether methotrexate (MTX) exposure posed a risk of atypical fractures.The association between MTX and lower limb fractures has been described in at least 80 cases in the literature. Stress fractures associated with MTX treatment are atypical of osteoporosis and located in the lower extremities, most often the tibia. The limited data suggest that discontinuation of MTX may improve symptoms and chances of fracture healing, while antiresorptive or osteoanabolic therapies have not proven clinically efficient. It seems evident, however, that the benefits of MTX treatment in rheumatological disease clearly outweigh the risk of MTX osteopathy and related fractures.

Survival in esophageal cancer with nonregional lymphadenopathy: a propensity score-matched analysis.

BACKGROUND: Survival among patients with esophageal cancer with stage IV nonregional lymphadenopathy treated with neoadjuvant therapy and surgical resection is not well described. This study aimed to compare the survival outcomes of patients with nonregional lymphadenopathy with a propensity-matched cohort of patients with locoregional disease. METHODS: This was a retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada. From January 2010 to December 2022, patients with radiologically suspicious nonregional retroperitoneal or supraclavicular lymphadenopathy were identified. Using 1:1 propensity score matching, a control group without nonregional disease was created. RESULTS: Of the 1235 patients identified, 39 met the inclusion criteria and were allocated to the study group of whom 35 of 39 (89%) had adenocarcinoma. Retroperitoneal and supraclavicular lymphadenopathy occurred in 26 of 39 patients (67%) and 13 of 39 patients (33%). Of the 39 patients, 34 (87%) received neoadjuvant chemotherapy, and 5 (13%) received chemoradiotherapy. After resection, ypN0 of nonregional lymph node stations occurred in 21 of 39 patients (54%). When comparing the study group with a matched non-stage IV control group, the median overall survival was similar in patients with retroperitoneal lymphadenopathy (21.0 months [95% CI, 8.0-21.0] vs 27.0 months [95% CI, 13.0-41.0]; P = .262) but not with supraclavicular disease (13.0 months; 95% CI, 8.0-18.0; P = .039). The median follow-up intervals were 40.1 months (95% CI, 1.0-83.0) for the study group and 70.0 (95% CI, 33.0-106.0) for the control groups. CONCLUSION: Compared with a matched cohort of patients with similar disease burden but not stage IV disease, retroperitoneal lymphadenopathy did not negatively affect survival outcomes. Multimodal curative intent therapy may be appropriate in select cases.

Survival and perioperative outcomes of octo- and nonagenarians with resectable esophageal carcinoma.

The outcomes of different treatment modalities for patients aged 80 and above with locally advanced and resectable esophageal carcinoma are not well described. The aim of this study was to explore survival and perioperative outcomes among this specific group of patients. A retrospective, cohort analysis was performed on a prospectively maintained esophageal cancer database from the McGill regional upper gastroinestinal cancer network. Between 2010 and 2020, all patients ≥80 years with cT2-4a, Nany, M0 esophageal carcinoma were identified and stratified according to the treatment modality: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT); definitive CRT (dCRT); upfront surgery; palliative CT/RT; or best supportive care (BSC). Of the 162 patients identified, 79 were included in this study. The median age was 83 years (80-97), most were cT3 (73%), cN- (56%), and had adenocarcinoma (62%). Treatment included: nCT/nCRT (16/79, 20%); surgery alone (19/79, 24%); dCRT (12/29, 15%); palliative RT/CT (27/79, 34%); and BSC (5/79, 6%). Neoadjuvant treatment was completed in 10/16 (63%). Of the 35/79 who underwent surgery, major complications occurred in 13/35 (37%) and 90-day mortality in 3/35 (9%). Overall survival (OS) for the cohort at 1- and 3-years was 58% and 19%. Among patients treated with nCT/nCRT, this was 94% and 46% respectively. Curative intent treatment (nCT/nCRT/upfront surgery/dCRT) had significantly increased 1- and 3- year OS compared with non-curative treatment (76%/31% vs. 34%/3.3%). Multimodal standard of care treatment is feasible and safe in select octo/nonagenarians, and may be associated with improved OS. Age alone should not bias against treatment with curative intent.

Targeted Intraoperative Radiation Therapy during Breast-Conserving Surgery for Patients with Early Stage Breast Cancer: A Phase II Single Center Prospective Trial.

Purpose: Patients with early stage breast cancer (ESBC) are conventionally treated with breast-conserving surgery (BCS) followed by whole-breast external beam radiation therapy (EBRT). The emergence of targeted intraoperative radiation therapy (TARGIT) with Intrabeam has been used as a therapeutic alternative for patients with risk-adapted ESBC. Here we present our radiation therapy toxicities (RTT), postoperative complications (PC), and short-term outcomes of the prospective phase II trial at the McGill University Health Center. Methods and Materials: Patients aged ≥50 years with biopsy-proven hormone receptor-positive, grade 1 or 2, invasive ductal carcinoma of the breast, cT1N0, were eligible for the study. Enrolled patients underwent BCS followed by immediate TARGIT of 20 Gy in 1 fraction. Upon final pathology, patients with low-risk breast cancer (LRBC) received no further EBRT, and those with high-risk breast cancer (HRBC) received further 15 to 16 fractions of whole breast EBRT. HRBC criteria included pathologic tumor size >2 cm, grade 3, positive lympho-vascular invasion, multifocal disease, close margins (<2 mm), or positive nodal disease. Results: A total of 61 patients with ESBC were enrolled in the study; upon final pathology, 40 (65.6%) had LRBC, and 21 (34.4%) had HRBC. The median follow-up was 3.9 years. The most common HRBC criteria were close margins in 66.6% (n = 14) and lymphovascular invasion in 28.6% (n = 6). No grade 4 RTT were observed in either group. The most common PC were seroma and cellulitis for both groups. The rate of locoregional recurrence was 0% in both groups. The overall survival in LRBC was 97.5% and in HRBC 95.2% with no significant differences. Deaths were nonbreast cancer related. Conclusions: In patients with ESBC undergoing BCS, the use of TARGIT shows low rates of RTT and PC complications. Moreover, our short-term outcomes show no significant difference at 3.9 years median follow-up for locoregional recurrence or overall survival between groups of patients receiving TARGIT alone or TARGIT followed by EBRT. Of all patients, 34.4% required further EBRT, most commonly due to close margins.

The 16-year evolution of a military-civilian partnership: The University of Alabama at Birmingham experience.

BACKGROUND: At the University of Alabama at Birmingham (UAB), a multi-tiered military-civilian partnership (MCP) has evolved since 2006. We aimed to outline this model to facilitate potential replication nationally. METHODS: We performed a comprehensive review of the partnership between UAB, the United States Air Force Special Operations Command, and the Department of Defense (DoD) reviewing key documents and conducting interviews with providers. As a purely descriptive study, this project did not involve any patient data acquisition or analysis and therefore was exempt from institutional review board approval per institutional policy. RESULTS: At the time of this review, six core programs existed targeting training, clinical proficiency, and research. Training: (1) The Special Operations Center for Medical Integration and Development trains up to 144 combat medics yearly. (2) UAB trains one integrated military Surgery resident yearly with two additional civilian-sponsored military residents in Emergency Medicine. (3) UAB's Surgical Critical Care Fellowship had one National Guard member with two incoming Active-Duty, one Reservist and one prior service member in August 2022. Clinical Proficiency: (4) UAB hosts four permanently assigned United States Air Force Special Operations Command Special Operations Surgical Teams composed of general surgeons, anesthesiologists, certified registered nurse anesthetists, surgical technologists, emergency physicians, critical care registered nurses, and respiratory therapists totaling 24 permanently assigned active-duty health care professionals. (5) In addition, two fellowship-trained Air Force Trauma Critical Care Surgeons, one Active-Duty and one Reservist, are permanently assigned to UAB. These clinicians participate fully and independently in the routine care of patients alongside their civilian counterparts. Research: (6) UAB's Division of Trauma and Acute Care Surgery is currently conducting nine DoD-funded research projects totaling $6,482,790, and four research projects with military relevance funded by other agencies totaling $15,357,191. CONCLUSION: The collaboration between UAB and various elements within the DoD illustrates a comprehensive approach to MCP. Replicating appropriate components of this model nationally may aid in the development of a truly integrated trauma system best prepared for the challenges of the future. LEVEL OF EVIDENCE: Economic and Value-based Evaluations; Level IV.

Comorbidities, biomarkers and cause specific mortality in patients with irritable bowel syndrome: A phenome-wide association study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional digestive disorders. Our understanding about its comorbidities, biomarkers, or long-term risks is still incomplete. OBJECTIVE: To characterize comorbidities and biomarkers for IBS and establish the effect of IBS on overall- and cause specific mortality. METHODS: We analyzed data from the population-based cohort of the UK Biobank (UKB) with 493,974 participants, including self-reported physician-diagnosed (n = 20,603) and ICD-10 diagnosed (n = 7656) IBS patients, with a mean follow-up of 11 years. We performed a phenome-wide association study (PheWAS) and competing risk analysis to characterize common clinical features in IBS patients. RESULTS: In PheWAS analyses, 260 PheCodes were significantly overrepresented in self-reported physician-diagnosed IBS patients, 633 in patients with ICD-10 diagnosed IBS (ICD-10-IBS), with 221 (40%) overlapping. In addition to gastrointestinal diseases, psychiatric, musculoskeletal, and endocrine/metabolic disorders represented the most strongly associated PheCodes in IBS patients. Self-reported physician-diagnosed IBS was not associated with increased overall mortality and the risk of death from cancer was decreased (hazard ratio [HR] = 0.78 [95% CI = 0.7-0.9]). Lastly, we evaluated changes in serum metabolites in IBS patients and identified glycoprotein acetyls (GlycA) as a potential biomarker in IBS. One standard deviation increase in GlycA raised the risk of self-reported IBS/ICD-10 coded by 9%-20% (odds ratio [OR] = 1.09 [95% CI = 1.1-1.1]/OR = 1.20 [95% CI = 1.1-1.3]) and the risk of overall mortality in ICD-10-IBS patients by 28% (HR = 1.28 [95% CI = 1.1-1.5]). CONCLUSION: Our large-scale association study determined IBS patients having an increased risk of several different comorbidities and that GlycA was increased in IBS patients.

A Scalable Radiomics- and Natural Language Processing-Based Machine Learning Pipeline to Distinguish Between Painful and Painless Thoracic Spinal Bone Metastases: Retrospective Algorithm Development and Validation Study.

BACKGROUND: The identification of objective pain biomarkers can contribute to an improved understanding of pain, as well as its prognosis and better management. Hence, it has the potential to improve the quality of life of patients with cancer. Artificial intelligence can aid in the extraction of objective pain biomarkers for patients with cancer with bone metastases (BMs). OBJECTIVE: This study aimed to develop and evaluate a scalable natural language processing (NLP)- and radiomics-based machine learning pipeline to differentiate between painless and painful BM lesions in simulation computed tomography (CT) images using imaging features (biomarkers) extracted from lesion center point-based regions of interest (ROIs). METHODS: Patients treated at our comprehensive cancer center who received palliative radiotherapy for thoracic spine BM between January 2016 and September 2019 were included in this retrospective study. Physician-reported pain scores were extracted automatically from radiation oncology consultation notes using an NLP pipeline. BM center points were manually pinpointed on CT images by radiation oncologists. Nested ROIs with various diameters were automatically delineated around these expert-identified BM center points, and radiomics features were extracted from each ROI. Synthetic Minority Oversampling Technique resampling, the Least Absolute Shrinkage And Selection Operator feature selection method, and various machine learning classifiers were evaluated using precision, recall, F1-score, and area under the receiver operating characteristic curve. RESULTS: Radiation therapy consultation notes and simulation CT images of 176 patients (mean age 66, SD 14 years; 95 males) with thoracic spine BM were included in this study. After BM center point identification, 107 radiomics features were extracted from each spherical ROI using pyradiomics. Data were divided into 70% and 30% training and hold-out test sets, respectively. In the test set, the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of our best performing model (neural network classifier on an ensemble ROI) were 0.82 (132/163), 0.59 (16/27), 0.85 (116/136), and 0.83, respectively. CONCLUSIONS: Our NLP- and radiomics-based machine learning pipeline was successful in differentiating between painful and painless BM lesions. It is intrinsically scalable by using NLP to extract pain scores from clinical notes and by requiring only center points to identify BM lesions in CT images.

Radiomics-based machine learning models to distinguish between metastatic and healthy bone using lesion-center-based geometric regions of interest.

Radiomics-based machine learning classifiers have shown potential for detecting bone metastases (BM) and for evaluating BM response to radiotherapy (RT). However, current radiomics models require large datasets of images with expert-segmented 3D regions of interest (ROIs). Full ROI segmentation is time consuming and oncologists often outline just RT treatment fields in clinical practice. This presents a challenge for real-world radiomics research. As such, a method that simplifies BM identification but does not compromise the power of radiomics is needed. The objective of this study was to investigate the feasibility of radiomics models for BM detection using lesion-center-based geometric ROIs. The planning-CT images of 170 patients with non-metastatic lung cancer and 189 patients with spinal BM were used. The point locations of 631 BM and 674 healthy bone (HB) regions were identified by experts. ROIs with various geometric shapes were centered and automatically delineated on the identified locations, and 107 radiomics features were extracted. Various feature selection methods and machine learning classifiers were evaluated. Our point-based radiomics pipeline was successful in differentiating BM from HB. Lesion-center-based segmentation approach greatly simplifies the process of preparing images for use in radiomics studies and avoids the bottleneck of full ROI segmentation.

Generation of human parallel chimeric antigen receptor (pCAR) T cells to achieve synergistic T cell co-stimulation.

Dual co-stimulation may be harnessed using parallel chimeric antigen receptors (pCARs) in which two distinct co-stimulatory units are adjacently localized on the plasma membrane. This protocol summarizes construct design, human T cell isolation, retroviral transduction, tissue culture expansion, and preclinical testing of pCAR T cells, exemplified by receptors that co-target avb6 integrin and ErbB dimers. For complete details on the use and execution of this protocol, please refer to Muliaditan et al. (2021).

Extreme weekly locoregional hypofractionated radiation in elderly women with non-metastatic breast cancer.

BACKGROUND AND PURPOSE: Breast cancer locoregional (LR) radiation in the elderly requires careful consideration between the benefits of aggressive treatment and its potential toll on these patients. Extreme weekly LR hypofractionated radiation (HFRT), delivering >5 Gy per fraction, may be better suited in such a population. It represents a good compromise between RT omission and exhaustive daily radiation. This study aims to report the local and LR control rate as well as the acute and long-term side effects of the elderly patients treated with HFRT in our institution, and to compare these results to those from the literature. MATERIALS AND METHODS: We conducted a retrospective study by reviewing medical records of elderly patients with breast cancer treated with adjuvant once-weekly LR HFRT between 2011 and 2020. Fifty patients presenting with primary non-metastatic node-positive breast tumors were included. Treatment outcomes including local/LR control and overall survival were reported. Early and late toxicity profiles were also assessed. RESULTS: After a median follow-up of 4.8 years, only one local recurrence in the chest wall occurred and there was no regional recurrence. The distant metastatic rate was 6%. The long-term recurrence-free survival rate was 80% at 5 years. The cause specific survival rate was 90% at 5 years. The overall survival rate was 69.4% and 55.5% at 3 and 5 years, respectively. There were 44 (88%) patients with Grade 1 or 2 early toxicity. There was no Grade 3 or higher acute toxicity registered. Late toxicity was mainly Grade 1 or 2 subcutaneous fibrosis, lymphoedema, and neuropathy except for one patient with Grade 3 fibrosis. CONCLUSION: Extreme LR HFRT is well tolerated with good outcomes and is a good alternative for elderly and frail patients. Our results confirm the efficacy and safety of such a regimen. Further randomized trials assessing both oncologic outcome and toxicity profile are justified.

TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties.

BACKGROUND/PURPOSE: TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. EXPERIMENTAL DESIGN/METHODS: To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. RESULTS: TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. CONCLUSIONS: Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.

CAR T-Cells Targeting the Integrin αvß6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies.

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvß6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvß6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors.

The role of the interleukin (IL)-6/IL-6 receptor axis in cancer.

Interleukin-6 (IL-6) is a pleiotropic cytokine that activates a classic signalling pathway upon binding to its membrane-bound receptor (IL-6R). Alternatively, IL-6 may 'trans-signal' in a manner that is facilitated by its binding to a soluble derivative of the IL-6 receptor (sIL-6R). Resultant signal transduction is, respectively, driven by the association of IL-6/IL-6R or IL-6/sIL-6R complex with the membrane-associated signal transducer, gp130 (Glycoprotein 130). Distinct JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) and other signalling pathways are activated as a consequence. Of translational relevance, overexpression of IL-6 has been documented in several neoplastic disorders, including but not limited to colorectal, ovarian and breast cancer and several haematological malignancies. This review attempts to summarise our current understanding of the role of IL-6 in cancer development. In short, these studies have shown important roles for IL-6 signalling in tumour cell growth and survival, angiogenesis, immunomodulation of the tumour microenvironment, stromal cell activation, and ultimate disease progression. Given this background, we also consider the potential for therapeutic targeting of this system in cancer.

Recent advances in austere combat surgery: Use of aortic balloon occlusion as well as blood challenges by special operations medical forces in recent combat operations.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) for control of noncompressible torso hemorrhage is a technology that is increasingly being utilized in the combat casualty setting. Its use in the resource restricted environment holds potential to improve hemorrhage control, decrease blood product utilization, decrease morbidity, and improve combat mortality. The objective of this report is to present the single largest series of REBOA use on severely injured combat casualties. METHODS: Over an 18-month period, austere surgical teams comprised of coalition partners provided initial damage control resuscitation (DCR) and surgical stabilization for over 2,300 combat casualties prior to transferring patients to the next level of trauma care. RESULTS: Twenty patients presented with injuries from explosion and gunshot wounds with mean initial heart rate of 129 bpm and mean initial systolic blood pressure of 71 mm Hg. Femoral cutdowns were used in six patients. Aortic occlusion was achieved with REBOA catheter placement in Zone 1 (n = 17) and Zone 3 (n = 2). Systolic blood pressure increased an average of 56 mm Hg with aortic occlusion. There were no access related site complications. All patients survived transport to the next level of care. The majority of blood products transfused in this cohort were whole blood, largely supported by emergent blood drives. CONCLUSION: This series demonstrates the potential for REBOA as a lifesaving technique for the patient who presents with hemodynamic instability and noncompressible torso hemorrhage. Resuscitative endovascular balloon occlusion of the aorta allows austere surgical teams to rapidly stabilize severely injured combat casualties, expand capability, and provide enhanced DCR while minimizing personnel, resources, and blood product utilization. The use of "whole blood only" strategy for DCR shows potential to be superior to traditional component therapy, and when combined with "proactive" REBOA utilization, provides significant improvements in hemodynamics and hemorrhage control. LEVEL OF EVIDENCE: Case series, level V.

Readability of the Most Commonly Accessed Online Patient Education Materials Pertaining to Pathology of the Hand.

BACKGROUND: The American Medical Association (AMA) and National Institutes of Health (NIH) recommend that patient education materials be written at no higher than a sixth-grade reading level. METHODS: We examined 100 online educational materials for the 10 hand conditions most commonly treated by hand surgeons, as reported by the American Society for Surgery of the Hand. The listed conditions were carpal tunnel syndrome, basal joint arthritis of the thumb, de Quervain syndrome, Dupuytren's contracture, ganglion cysts, hand fractures, trigger finger, extensor tendon injuries, flexor tendon injuries, and mallet finger. Following a Google search for each condition, we analyzed the 10 most visited websites for each disorder utilizing the Flesch-Kincaid formula. RESULTS: The average grade reading level of the 100 websites studied was 9.49 with a reading ease of 53.03 ("fairly difficult high school"). Only 29% of the websites were at or below the national average of an eighth-grade reading level. Carpal tunnel syndrome had the highest average grade reading level at 10.32 (standard deviation: 1.52), whereas hand fractures had the lowest at 8.14 (2.03). Every hand condition in this study had an average readability at or above the ninth-grade reading level. CONCLUSIONS: The most frequently accessed materials for common maladies of the hand exceed both the readability limits recommended by the AMA and NIH, and the average reading ability of most US adults. Therefore, the most commonly accessed websites pertaining to hand pathology may not be comprehended by the audience for which it is intended.

A simplified, validated protocol for measuring fibular reduction on ankle CT.

BACKGROUND: Inadequate ankle syndesmotic reduction is a common and important cause of poor outcome after surgery. It is not clear what magnitude or planes of displacement impact most. Many computerised tomography (CT) measurement techniques rely on landmarks that are difficult to reproduce, and none measure all types of mal-positioning in a single protocol. The purpose of this study was to design and validate a protocol for measuring the distal tibio-fibular relationship. METHODS: We devised a method for measuring fibular diastasis, antero-posterior translation (APT) and fibular length on CT images. CTs of sixteen un-injured ankles were examined using our protocol and that of an established alternative method for comparison. The measurements were recorded by two independent observers and repeated for inter- and intra-observer agreement scores. RESULTS: Our method showed inter- and intra-observer agreement of r=0.994 and r=0.999, demonstrating strong agreement. This compared to r=0.218 and r=0.820 respectively for the comparative protocol. CONCLUSION: This ankle CT measurement protocol is accurate, reproducible and simple to use. Its aim is to be a useful tool for clinicians to quantify post-operative mal-positioning of the distal fibula in comparison to the un-injured ankle. We believe that routine, bilateral, post-operative CT imaging will lead to improvements in the understanding and outcomes of the treatment of complex ankle fractures. To our knowledge no other validated measurement of fibular length on CT images exists in the literature.

A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer.

Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug. G114-particles (∼950 nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic 'Trojan Horse' therapy for targeted delivery of therapeutic agents to sites of metastatic PCa.

Contrasting analytical and data-driven frameworks for radiogenomic modeling of normal tissue toxicities in prostate cancer.

BACKGROUND AND PURPOSE: We explore analytical and data-driven approaches to investigate the integration of genetic variations (single nucleotide polymorphisms [SNPs] and copy number variations [CNVs]) with dosimetric and clinical variables in modeling radiation-induced rectal bleeding (RB) and erectile dysfunction (ED) in prostate cancer patients. MATERIALS AND METHODS: Sixty-two patients who underwent curative hypofractionated radiotherapy (66 Gy in 22 fractions) between 2002 and 2010 were retrospectively genotyped for CNV and SNP rs5489 in the xrcc1 DNA repair gene. Fifty-four patients had full dosimetric profiles. Two parallel modeling approaches were compared to assess the risk of severe RB (Grade⩾3) and ED (Grade⩾1); Maximum likelihood estimated generalized Lyman-Kutcher-Burman (LKB) and logistic regression. Statistical resampling based on cross-validation was used to evaluate model predictive power and generalizability to unseen data. RESULTS: Integration of biological variables xrcc1 CNV and SNP improved the fit of the RB and ED analytical and data-driven models. Cross-validation of the generalized LKB models yielded increases in classification performance of 27.4% for RB and 14.6% for ED when xrcc1 CNV and SNP were included, respectively. Biological variables added to logistic regression modeling improved classification performance over standard dosimetric models by 33.5% for RB and 21.2% for ED models. CONCLUSION: As a proof-of-concept, we demonstrated that the combination of genetic and dosimetric variables can provide significant improvement in NTCP prediction using analytical and data-driven approaches. The improvement in prediction performance was more pronounced in the data driven approaches. Moreover, we have shown that CNVs, in addition to SNPs, may be useful structural genetic variants in predicting radiation toxicities.