Risk factors for breast cancer-related lymphedema in patients undergoing 3 years of prospective surveillance with intervention.

BACKGROUND: To evaluate risk factors (treatment-related, comorbidities, and lifestyle) for breast cancer-related lymphedema (BCRL) within the context of a Prospective Surveillance and Early Intervention (PSEI) model of care for subclinical BCRL. METHODS: The parent randomized clinical trial assigned patients newly diagnosed with breast cancer to PSEI with either bioimpedance spectroscopy (BIS) or tape measurement (TM). Surgical, systemic and radiation treatments, comorbidities, and lifestyle factors were recorded. Detection of subclinical BCRL (change from baseline of either BIS L-Dex ≥6.5 or tape volume ≥ 5% and < 10%) triggered an intervention with compression therapy. Volume change from baseline ≥10% indicated progression to chronic lymphedema and need for complex decongestive physiotherapy. In this secondary analysis, multinomial logistic regressions including main and interaction effects of the study group and risk factors were used to test for factor associations with outcomes (no lymphedema, subclinical lymphedema, progression to chronic lymphedema after intervention, progression to chronic lymphedema without intervention). Post hoc tests of significant interaction effects were conducted using Bonferroni-corrected alphas of .008; otherwise, an alpha of .05 was used for statistical significance. RESULTS: The sample (n = 918; TM = 457; BIS = 461) was female with a median age of 58.4 years. Factors associated with BCRL risk included axillary lymph node dissection (ALND) (p < .001), taxane-based chemotherapy (p < .001), regional nodal irradiation (RNI) (p ≤ .001), body mass index >30 (p = .002), and rurality (p = .037). Mastectomy, age, hypertension, diabetes, seroma, smoking, and air travel were not associated with BCRL risk. CONCLUSIONS: Within the context of 3 years of PSEI for subclinical lymphedema, variables of ALND, taxane-based chemotherapy, RNI, body mass index >30, and rurality increased risk.

A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial. METHODS: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM). RESULTS: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model. CONCLUSIONS: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature.

CONTEXT: The safety of vitamin D replacement in subjects with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency is not well established. OBJECTIVE: To evaluate the safety of vitamin D replacement in PHPT. DATA SOURCE: Data were searched from Medline, EMBASE, Cochrane CENTRAL and abstracts form annual scientific meetings of various international bone and mineral societies. STUDY SELECTION: Studies examining the effect of preoperative vitamin D replacement in patients with PHPT and coexisting vitamin D deficiency, irrespective of year and language of the publication were included in the present meta-analysis. DATA EXTRACTION: Data were extracted from text of the included publications or abstract of conferences. DATA SYNTHESIS: Ten studies enrolling 340 subjects with PHPT were analysed in this meta-analysis. After vitamin D replacement, there was significant increase in 25(OH) D levels by 55·3 nmol/l (95% CI 33·3-77·3), reduction in serum parathyroid hormone levels by 3·5 pmol/l (5·8 to -1·2) without change in serum calcium (-0·08 mmol/l, -0·2 to +0·03) and urinary calcium levels (0·72 mmol/24 h, P = 0·2) compared to baseline. CONCLUSION: Vitamin D replacement in subjects with PHPT and coexistent vitamin D deficiency increase 25 (OH) D and reduce serum PTH significantly without causing hypercalcaemia and hypercalciuria. The finding of the study needs to be confirmed by a large randomized trial in patient with PHPT and coexistent vitamin D deficiency.

Meta-Analysis of 5-Fraction Preoperative Radiotherapy for Soft Tissue Sarcoma.

OBJECTIVES: Studies investigating preoperative 5-fraction radiation therapy (RT) for soft tissue sarcoma (STS) are limited. We performed a meta-analysis to determine the efficacy and safety of this treatment paradigm. METHODS: This study-level meta-analysis was conducted using Bayesian methods. Statistical estimation for risk of outcome rates was conducted by posterior mean and 95% highest posterior density (HPD) intervals. Studies with 2-year local control (LC) and description of major wound complications (MWC) per the CAN-NCIC-SR2 study were included and served as the primary endpoints. Secondary endpoints included rates of acute and late toxicity. A total of 10 studies were identified and 7 met the inclusion criteria. Subgroup analyses were performed for ≥30 Gy vs <30 Gy. RESULTS: A total of 209 patients from 7 studies were included. Five studies used ≥30 Gy (n=144), and 2 studies <30 Gy (n=64). Median follow-up was 29 months (range: 21 to 57 mo). Primary tumor location was lower extremity in 68% and upper extremity in 22%. Most tumors were intermediate or high grade (95%, 160/169), and 50% (79/158) were >10 cm. The two-year LC for the entire cohort was 96.9%, and the rate of MWC was 30.6%. There was a trend toward improved LC with ≥ 30 Gy (95% HPD: 0.95 to 0.99 vs 0.84 to 0.99). There was no difference in MWC (95% HPD: 0.18 to 0.42 vs 0.17 to 0.55) or late toxicity between the groups. CONCLUSIONS: Preoperative 5-fraction RT for STS demonstrates excellent 2-year LC with MWC and toxicity similar to standard fractionation preoperative RT. Multi-institutional trials with a universal RT protocol are warranted.

Five Fraction External Beam Partial Breast Irradiation: A User's Guide.

OBJECTIVE: Mature follow up from multiple randomized trials have demonstrated the safety and efficacy of external beam partial breast irradiation (PBI) for appropriately selected patients with early stage breast cancer. Despite this evidence, external beam PBI remains underutilized. In this user guide we outline patient selection, workflow, and address possible challenges to aid in implementation of evidence-based external beam PBI. MATERIALS AND METHODS: Review of the current guidelines for PBI suitability, surgical considerations, treatment technique, simulation, contouring, and treatment planning, citing the latest published literature to support PBI utilization. RESULTS: Prospective data supports the use of 30 Gy in 5 fractions delivered with intensity modulated radiation therapy on a daily or every other day basis for a significant proportion of early stage breast cancer patients. The surgical cavity must be clearly visualized on treatment planning scan, recommend 3-5 weeks post-operatively, and the recommended clinical target volume expansion on the surgical cavity is 0.5-1.0 cm. A planning target volume expansion, based on motion management and image guidance, of 0.5-1.0 cm should be used. Organ at risk dose constraints of heart V3Gy ≤10% and contralateral breast Dmax ≤1 Gy are often achievable. CONCLUSIONS: Five fraction external beam PBI is a highly effective treatment with very limited toxicity for patients with early stage breast cancer following breast conserving surgery. Commonly utilized intensity modulated treatment planning techniques with plan delivery on standard linear accelerators results significant normal tissue sparing and makes implementation feasible at most radiation oncology centers.

Cancer Diagnoses and Use of Radiation Therapy Among Persons Experiencing Homelessness.

PURPOSE: Persons experiencing homelessness (PEH) have low rates of cancer screening and worse cancer mortality compared with persons not experiencing homelessness. Data regarding cancer diagnosis and treatment in PEH are limited. We investigated cancer prevalence and use of radiation therapy (RT) in PEH. METHODS AND MATERIALS: Patients presenting between January 1, 2014, and September 27, 2021, at a large metropolitan hospital system were assessed for homelessness via intake screening or chart search. PEH data were cross-referenced with the institution's cancer database to identify PEH with cancer diagnoses. Demographic, clinical, and treatment variables were abstracted. RESULTS: Of a total of 9654 (9250 evaluable) PEH with a median age of 42 years, 81 patients (0.88%) had at least 1 cancer diagnosis and 5 had multiple diagnoses, for a total of 87 PEH with at least 1 cancer diagnosis. The median age at diagnosis was 60 years. In total, 43% were female and 51% were Black, and 43% presented with advanced or metastatic disease. Lung (17%), prostate (15%), leukemia/lymphoma (13%), and head/neck (9%) were the most common diagnoses. In total, 17% of patients underwent surgery alone, 13% received chemotherapy alone, 14% received RT alone, and 6% received hormone therapy alone. A total of 8% of patients underwent no treatment, and 43% underwent multimodality therapy. In total, 58% of treated patients never achieved disease-free status. Of the 31 patients who received RT, 87% received external beam RT. Most patients (70%) received hypofractionated regimens. For patients who had multifraction treatment, the treatment completion rate was 85%, significantly lower than the departmental completion rate of 98% (P < .00001). CONCLUSIONS: In a large cohort of PEH in a metropolitan setting, cancer diagnoses were uncommon and were frequently in advanced stages. Most patients underwent single-modality treatment or no treatment at all. Despite the use of hypofractionation, the RT completion rate was low, likely reflecting complex barriers to care. Further interventions to optimize cancer diagnosis and treatment in PEH are urgently needed.

Early outcomes of ultra-hypofractionated preoperative radiation therapy for soft tissue sarcoma followed by immediate surgical resection.

BACKGROUND: There is increasing interest in shorter courses of radiation therapy (RT) in the management of soft tissue sarcoma (STS). We report our institutional experience for patients undergoing ultra-hypofractionated preoperative RT followed by immediate resection. METHODS: An IRB approved review of patients treated with preoperative 5 fraction, once daily RT followed by immediate resection (within 7 days) for STS of the extremity or trunk was conducted. The primary endpoints are major wound complications and local control (LC). Secondary endpoints include grade ≥ 2 toxicity, metastasis free survival (MFS), and overall survival (OS). RESULTS: Twenty-two patients with a median age of 67 years (range 30-87) and median follow-up of 24.5 months (IQR 17.0-35.7) met eligibility criteria; 18/22 patients (81.8 %) had ≥ 1 year follow-up. Primary tumor location was lower extremity in 15 patients (68.2 %), upper extremity in 5 (22.7 %), and trunk in 2 (9.1 %). All patients received 30 Gy in 5 fractions. The median time to resection following RT was 1 day (range 0-5). The median time from biopsy to resection was 34 days (range 20-69). Local control was 100 %; in patients with localized disease, 2-year MFS and OS were 71.3 % and 76.9 %, respectively. Major wound complications occurred in 9 patients (40.9 %), with wound complications requiring reoperation occurring in 8 patients (36.4 %). Other acute and late grade ≥ 2 toxicities were seen in 0 and 4 patients (18.2 %), respectively. CONCLUSION: Ultra-hypofractionated preoperative RT followed by immediate resection permits expedited completion of oncologic therapy with early results demonstrating excellent local control and acceptable toxicity. Prospective data with long-term follow-up is needed.

A Reanalysis of Experimental Brain Strain Data: Implication for Finite Element Head Model Validation.

Relative motion between the brain and skull and brain deformation are biomechanics aspects associated with many types of traumatic brain injury (TBI). Thus far, there is only one experimental endeavor (Hardy et al., 2007) reported brain strain under loading conditions commensurate with levels that were capable of producing injury. Most of the existing finite element (FE) head models are validated against brain-skull relative motion and then used for TBI prediction based on strain metrics. However, the suitability of using a model validated against brain-skull relative motion for strain prediction remains to be determined. To partially address the deficiency of experimental brain deformation data, this study revisits the only existing dynamic experimental brain strain data and updates the original calculations, which reflect incremental strain changes. The brain strain is recomputed by imposing the measured motion of neutral density target (NDT) to the NDT triad model. The revised brain strain and the brain-skull relative motion data are then used to test the hypothesis that an FE head model validated against brainskull relative motion does not guarantee its accuracy in terms of brain strain prediction. To this end, responses of brain strain and brain-skull relative motion of a previously developed FE head model (Kleiven, 2007) are compared with available experimental data. CORrelation and Analysis (CORA) and Normalized Integral Square Error (NISE) are employed to evaluate model validation performance for both brain strain and brain-skull relative motion. Correlation analyses (Pearson coefficient) are conducted between average cluster peak strain and average cluster peak brain-skull relative motion, and also between brain strain validation scores and brain-skull relative motion validation scores. The results show no significant correlations, neither between experimentally acquired peaks nor between computationally determined validation scores. These findings indicate that a head model validated against brain-skull relative motion may not be sufficient to assure its strain prediction accuracy. It is suggested that a FE head model with intended use for strain prediction should be validated against the experimental brain deformation data and not just the brain-skull relative motion.

Six-Year Results From a Phase I/II Trial for Hypofractionated Accelerated Partial Breast Irradiation Using a 2-Day Dose Schedule.

BACKGROUND: To report 6-year outcomes from a phase I/II trial using balloon-based brachytherapy to deliver APBI in 2 days. METHODS: A total of 45 patients with early-stage breast cancer received adjuvant APBI in 2 days with high-dose rate (HDR) brachytherapy totaling 2800 cGy in 4 fractions (700 cGy BID) using a balloon-based applicator as part of a prospective phase I/II clinical trial. All patients had negative margins and skin spacing ≥8 mm. We evaluated toxicities (CTCAE v3) as well as ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis, disease-free survival, cause-specific survival, and overall survival. RESULTS: Median age and tumor size were 66 years old (48 to 83) and 0.8 cm (0.2 to 2.3 cm), respectively. Four percent of patients were N1 (n=2) and 73% were estrogen receptor (ER) positive (n=32). Median follow-up was 6.2 years (2.4 to 8.0 y). Nearly all toxicities at 6 years were grade 1 to 2 except 1 instance of grade 3 telangiectasia (2%). Eleven percent (n=5) of patients had chronic asymptomatic fat necrosis whereas asymptomatic seromas were noted on mammogram in 13% of cases (n=6). Cosmesis at last follow-up was good or excellent in 91% of cases (n=40) and fair in 9% (n=4). Two of the previously reported rib fractures healed with conservative measures. There were no IBTR or RNF (6 y IBTR/RNF rate 0%); however, 2 patients experienced distant metastasis (4% at 6 y). The 6-year actuarial disease-free survival, cause-specific survival, and overall survival were 96%, 100%, and 93%, respectively. CONCLUSIONS: Hypofractionated 2-day APBI using brachytherapy resulted in excellent clinical outcomes with acceptable chronic toxicities.

Four-year results using balloon-based brachytherapy to deliver accelerated partial breast irradiation with a 2-day dose fractionation schedule.

PURPOSE: We present 4-year results from a Phase I/II trial using balloon-based brachytherapy to deliver accelerated partial breast irradiation in 2 days. MATERIALS/METHODS: Forty-five patients received breast-conserving surgery followed by adjuvant radiation therapy using a balloon-based brachytherapy applicator delivering 2800 cGy in four fractions over 2 days. Outcomes analyzed include toxicities scored using the NCI Common Toxicity Criteria v3.0 scale, ipsilateral breast tumor recurrence, regional nodal failure, distant metastasis, disease-free survival, cause-specific survival, and overall survival. RESULTS: Median age was 66 years (range, 48-83 years) and median tumor size was 0.6 cm (range, 0.2-2.3 cm). Five percent of patients were node positive (n=2), whereas 73% was estrogen receptor positive (n=33). Median followup was 3.7 years (2.4-7.0 years) with greater than 2 years of followup for all patients. Only Grades 1 and 2 chronic toxicities were noted with fat necrosis (18%) and asymptomatic seromas (42%) being the most common toxicities. Seven percent of patients developed ipsilateral rib fractures (n=3), although this was not statistically associated with maximum rib dose (p=0.31). Ninety-eight percent of patients had a good or excellent radiation-related cosmetic outcome at the time of last followup. There were no ipsilateral breast tumor recurrences or regional nodal failures; however, 2 patients developed distant metastases. Four-year actuarial disease-free survival, cause-specific survival, and overall survival were 96%, 100%, and 93%, respectively. CONCLUSIONS: Treatment of early-stage breast cancer patients with breast-conserving therapy using a 2-day radiation dose schedule resulted in acceptable chronic toxicity and similar clinical outcomes as standard 5-day fractionation.

Mechanisms of traumatic rupture of the aorta and associated peri-isthmic motion and deformation.

This study investigated the mechanisms of traumatic rupture of the aorta (TRA). Eight unembalmed human cadavers were tested using various dynamic blunt loading modes. Impacts were conducted using a 32-kg impactor with a 152-mm face, and high-speed seatbelt pretensioners. High-speed biplane x-ray was used to visualize aortic motion within the mediastinum, and to measure deformation of the aorta. An axillary thoracotomy approach was used to access the peri-isthmic region to place radiopaque markers on the aorta. The cadavers were inverted for testing. Clinically relevant TRA was observed in seven of the tests. Peak average longitudinal Lagrange strain was 0.644, with the average peak for all tests being 0.208 +/- 0.216. Peak intraluminal pressure of 165 kPa was recorded. Longitudinal stretch of the aorta was found to be a principal component of injury causation. Stretch of the aorta was generated by thoracic deformation, which is required for injury to occur. The presence of atherosclerosis was demonstrated to promote injury. The isthmus of the aorta moved dorsocranially during frontal impact and submarining loading modes. The aortic isthmus moved medially and anteriorly during impact to the left side. The results of this study provide a better understanding of the mechanisms associated with TRA, and can be used for the validation of finite element models developed for the examination and prediction of TRA.

A study of the response of the human cadaver head to impact.

High-speed biplane x-ray and neutral density targets were used to examine brain displacement and deformation during impact. Relative motion, maximum principal strain, maximum shear strain, and intracranial pressure were measured in thirty-five impacts using eight human cadaver head and neck specimens. The effect of a helmet was evaluated. During impact, local brain tissue tends to keep its position and shape with respect to the inertial frame, resulting in relative motion between the brain and skull and deformation of the brain. The local brain motions tend to follow looping patterns. Similar patterns are observed for impact in different planes, with some degree of posterior-anterior and right-left symmetry. Peak coup pressure and pressure rate increase with increasing linear acceleration, but coup pressure pulse duration decreases. Peak average maximum principal strain and maximum shear are on the order of 0.09 for CFC 60 Hz data for these tests. Peak average maximum principal strain and maximum shear decrease with increasing linear acceleration, coup pressure, and coup pressure rate. Linear and angular acceleration of the head are reduced with use of a helmet, but strain increases. These results can be used for the validation of finite element models of the human head.

Study of potential mechanisms of traumatic rupture of the aorta using insitu experiments.

Traumatic rupture of the aorta (TRA) is an important transportation-related injury. This study investigated TRA mechanisms using in situ human cadaver experiments. Four quasi-static tests and one dynamic test were performed. The quasi-static experiments were conducted by perturbing the mediastinal structures of the cadavers. The mechanisms investigated included anterior, superior, and lateral displacement of the heart and aortic arch. The resulting injuries ranged from partial tears to complete transections. All injuries occurred within the peri-isthmic region. Intimal tears were associated with the primary injuries. The average failure load and stretch were 148 N and 30 percent for the quasi-static tests. This study illustrates that TRA can result from appropriate application of nominal levels of longitudinal load and tension. The results demonstrate that intraluminal pressure and whole-body acceleration are not required for TRA to occur. The results suggest that the role of the ligamentum arteriosum is likely limited, and that TRA can occur in the absence of pulmonary artery injury. Tethering of the descending thoracic aorta by the parietal pleura is a principal aspect of this injury.

Dynamic biaxial tissue properties of the human cadaver aorta.

This study focuses on the biaxial mechanical properties of planar aorta tissue at strain rates likely to be experienced during automotive crashes. It also examines the structural response of the whole aorta to longitudinal tension. Twenty-six tissue-level tests were conducted using twelve thoracic aortas harvested from human cadavers. Cruciate samples were excised from the ascending, peri-isthmic, and descending regions. The samples were subjected to equibiaxial stretch at two nominal speed levels using a new biaxial tissue-testing device. Inertia-compensated loads were measured to facilitate calculation of true stress. High-speed videography and regional correlation analysis were used to track ink dots marked on the center of each sample to obtain strain. In a series of component-level tests, the response of the intact thoracic aorta to longitudinal stretch was obtained using seven aorta specimens. The aorta fails within the peri-isthmic region. The aorta fails in the transverse direction, and the intima fails before the media or adventitia. The aorta tissue exhibits nonlinear behavior. The aorta as complete structure can transect completely from 92 N axial load and 0.221 axial strain. Complete transection can be accompanied by intimal tears. These results have application to finite element modeling and the better understanding of traumatic rupture of the aorta.