Stay on Track: A Pilot Randomized Control Trial on the Feasibility of a Diet and Exercise Intervention in Patients with Breast Cancer Receiving Radiation Therapy.

BACKGROUND: Among patients with breast cancer undergoing radiation therapy (RT), post-treatment cardiovascular disease and worsened quality of life (QOL) are leading causes of morbidity and mortality. To overcome these negative RT effects, this prospective, randomized clinical trial pilots a 12-week Stay on Track exercise and diet intervention for overweight patients with non-metastatic breast cancer undergoing whole-breast RT. METHODS: The intervention group (n=22) participated in three personal exercise and dietary counseling sessions, and received three text reminders/week to adhere to recommendations. The control group (n=22) was administered a diet/exercise information binder. All patients received a Fitbit, and at baseline, 3, and 6 months, measurements of biomarkers, dual-energy X-ray absorptiometry scans, quality of life and physical activity surveys, and food frequency questionnaires were obtained. A satisfaction survey was administered at three months. RESULTS: Stay on Track was well received, with high rates of adherence and satisfaction. The intervention group showed an increase in self-reported physical activity and preserved QOL, a decrease in BMI and visceral fat, and higher ACS/AICR dietary adherence. The control participants had reduced QOL, anti-inflammatory markers, and increased metabolic syndrome markers. Both groups had decreased overall body mass. These changes were within group effects. When comparing the intervention and control groups over time, there were notable improvements in dietary adherence in the intervention group. CONCLUSIONS: Targeted lifestyle interventions during RT are feasible and could decrease cardiovascular comorbidities in patients with breast cancer. Larger-scale implementation with longer follow-up can better determine interventions that influence cardiometabolic health and QOL.

Noninvasive Autopsy-Validated Tumor Probability Maps Identify Glioma Invasion Beyond Contrast Enhancement.

BACKGROUND AND OBJECTIVES: This study identified a clinically significant subset of patients with glioma with tumor outside of contrast enhancement present at autopsy and subsequently developed a method for detecting nonenhancing tumor using radio-pathomic mapping. We tested the hypothesis that autopsy-based radio-pathomic tumor probability maps would be able to noninvasively identify areas of infiltrative tumor beyond traditional imaging signatures. METHODS: A total of 159 tissue samples from 65 subjects were aligned to MRI acquired nearest to death for this retrospective study. Demographic and survival characteristics for patients with and without tumor beyond the contrast-enhancing margin were computed. An ensemble algorithm was used to predict pixelwise tumor presence from pathological annotations using segmented cellularity (Cell), extracellular fluid, and cytoplasm density as input (6 train/3 test subjects). A second level of ensemble algorithms was used to predict voxelwise Cell, extracellular fluid, and cytoplasm on the full data set (43 train/22 test subjects) using 5-by-5 voxel tiles from T1, T1 + C, fluid-attenuated inversion recovery, and apparent diffusion coefficient as input. The models were then combined to generate noninvasive whole brain maps of tumor probability. RESULTS: Tumor outside of contrast was identified in 41.5% of patients, who showed worse survival outcomes (hazard ratio = 3.90, P < .001). Tumor probability maps reliably tracked nonenhancing tumor on a range of local and external unseen data, identifying tumor outside of contrast in 69% of presurgical cases that also showed reduced survival outcomes (hazard ratio = 1.67, P = .027). CONCLUSION: This study developed a multistage model for mapping gliomas using autopsy tissue samples as ground truth, which was able to identify regions of tumor beyond traditional imaging signatures.

Radio-pathomic maps of glioblastoma identify phenotypes of non-enhancing tumor infiltration associated with bevacizumab treatment response.

BACKGROUND: Autopsy-based radio-pathomic maps of glioma pathology have shown substantial promise inidentifying areas of non-enhancing tumor presence, which may be able to differentiate subsets of patients that respond favorably to treatments such as bevacizumab that have shown mixed efficacy evidence. We tested the hypthesis that phenotypes of non-enhancing tumor fronts can distinguish between glioblastoma patients that will respond favorably to bevacizumab and will visually capture treatment response. METHODS: T1, T1C, FLAIR, and ADC images were used to generate radio-pathomic maps of tumor characteristics for 79 pre-treatment patients with a primary GBM or high-grade IDH1-mutant astrocytoma for this study. Novel phenotyping (hypercellular, hypocellular, hybrid, or well-circumscribed front) of the non-enhancing tumor front was performed on each case. Kaplan Meier analyses were then used to assess differences in survival and bevacizumab efficacy between phenotypes. Phenotype compartment segmentations generated longitudinally for a subset of 26 patients over the course of bevacizumab treatment, where a mixed effect model was used to detect longitudinal changes. RESULTS: Well-Circumscribed patients showed significant/trending increases in survival compared to Hypercellular Front (HR = 2.0, p = 0.05), Hypocellular Front (HR = 2.02, p = 0.03), and Hybrid Front tumors (HR = 1.75, p = 0.09). Only patients with hypocellular or hybrid fronts showed significant survival benefits from bevacizumab treatment (HR = 2.35, p = 0.02; and HR = 2.45, p = 0.03, respectively). Hypocellular volumes decreased by an average 50.52 mm3 per day of bevacizumab treatment (p = 0.002). CONCLUSION: Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Stat5 induces androgen receptor (AR) gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.

Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of AR gene transcription. Stat5 suppression inhibited AR gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, and truncated AR proteins. Pharmacological Stat5 inhibition by a specific small-molecule Stat5 inhibitor down-regulated Stat5-inducible genes as well as AR and AR-regulated genes and suppressed PC growth. This work introduces the concept of Stat5 as an inducer of AR gene transcription in PC. Pharmacological Stat5 inhibitors may represent a new strategy for suppressing AR and CRPC growth.

Environmental Enrichment during Abstinence Reduces Oxycodone Seeking and c-Fos Expression in a Subpopulation of Medial Prefrontal Cortex Neurons.

BACKGROUND: Several preclinical studies have demonstrated that environmental enrichment (EE) during abstinence reduces drug seeking for psychostimulant and opioid drugs. Drug seeking is dependent on activity within the dorsomedial prefrontal cortex, and enrichment has been able to reduce drug seeking-associated increases in c-Fos in this region. In this study, we tested the hypothesis that EE during abstinence from oxycodone self-administration would reduce drug seeking and c-Fos immunoreactivity within the prefrontal cortex in a cell-type specific manner. METHODS: Male rats self-administered oxycodone in two-hours sessions for three weeks, then underwent an initial drug seeking test under extinction conditions after one week of forced abstinence. Following this test, rats received either EE or remained individually housed in their home cage, then a second drug seeking test, with tissue collection immediately afterward. RESULTS: Compared to rats in standard housing, environmentally enriched rats had lower oxycodone seeking. In the prelimbic and infralimbic prefrontal cortices, the number of c-Fos+ cells was reduced, and this reduction was predominantly in inhibitory cells neurons, as evidenced by a reduction in the proportion of c-Fos+ cells in GAD+, but not CamKII+ cells. There was also a robust positive relationship between the number of c-Fos+ cells and persistence of oxycodone seeking in both the PrL and IL. CONCLUSIONS: These findings further support the effectiveness of enriched environments to reduce reactivity to drug-associated stimuli and contexts and provide a potential mechanism by which this occurs.

Radio-pathomic maps of glioblastoma identify phenotypes of non-enhancing tumor infiltration associated with bevacizumab treatment response.

Background: Autopsy-based radio-pathomic maps of glioma pathology have shown substantial promise inidentifying areas of non-enhancing tumor presence, which may be able to differentiate subsets of patients that respond favorably to treatments such as bevacizumab that have shown mixed efficacy evidence. We tested the hypthesis that phenotypes of non-enhancing tumor fronts can distinguish between glioblastoma patients that will respond favorably to bevacizumab and will visually capture treatment response. Methods: T1, T1C, FLAIR, and ADC images were used to generate radio-pathomic maps of tumor characteristics for 79 pre-treatment patients with a primary GBM or high-grade IDH1-mutant astrocytoma for this study. Novel phenotyping (hypercellular, hypocellular, hybrid, or well-circumscribed front) of the non-enhancing tumor front was performed on each case. Kaplan Meier analyses were then used to assess differences in survival and bevacizumab efficacy between phenotypes. Phenotype compartment segmentations generated longitudinally for a subset of 26 patients over the course of bevacizumab treatment, where a mixed effect model was used to detect longitudinal changes. Results: Well-Circumscribed patients showed significant/trending increases in survival compared to Hypercellular Front (HR = 2.0, p = 0.05), Hypocellular Front (HR = 2.02, p = 0.03), and Hybrid Front tumors (HR = 1.75, p = 0.09). Only patients with hypocellular or hybrid fronts showed significant survival benefits from bevacizumab treatment (HR = 2.35, p = 0.02; and HR = 2.45, p = 0.03, respectively). Hypocellular volumes decreased by an average 50.52 mm3 per day of bevacizumab treatment (p = 0.002). Conclusion: Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Topical Treatment of Cutaneous Squamous Cell Carcinoma in Situ and the Impact of Clinical Risk Factors and Positive Histologic Margins at the Time of Diagnosis.

BACKGROUND: Limited data exist for the efficacy of topical 5-fluorouracil (5-FU) and imiquimod for cutaneous squamous cell carcinoma (cSCC) in situ (cSCCis) with positive histologic margins at the time of diagnosis. OBJECTIVE: Identify the efficacy of topical 5-FU and imiquimod in the treatment of cSCCis with positive histologic margins at the time of diagnosis in relation to clinical risk factors. MATERIALS AND METHODS: Pathology records were screened at a single institution from 2014 to 2021 for cSCCis with positive histologic margins. Patients were included if they were treated with curative intent with topical 5-FU or imiquimod. Recurrences were evaluated in relation to multiple clinical risk factors. RESULTS: Of 215 patients treated with 5-FU or imiquimod after biopsy-proven cSCCis, 19 patients had recurrent cSCCis and 1 patient had upstaging to invasive cSCC. Recurrence was more likely in larger lesions at the time of initial biopsy ( p = .033) and in patients treated with topical imiquimod compared with topical 5-FU ( p < .01). CONCLUSION: Topical 5-FU is an appropriate therapy for cSCCis in the correct clinical scenario. Extra consideration should be taken for use of 5-FU in larger diameter cSCCis lesions. Although limited by sample size, our study does not support the use of imiquimod for cSCCis.

Can I Leave? Perspectives on Parental Leave and Parenthood in Medical Training Among Program Directors and Trainees in Oncologic Specialties.

Purpose: Peak fertility commonly occurs during medical training, and delaying parenthood can complicate pregnancies. Trainee parental leave policies are varied and lack transparency. Research on the impacts of parenthood on trainee education is limited. Methods: A Qualtrics-based survey was distributed via e-mail/social media to program directors (PDs) within oncologic specialties with a request to forward a parallel survey to trainees. Questions assessed awareness of parental leave policies, supportiveness of parenthood, and impacts on trainee education. Statistical analyses included descriptive frequencies and bivariable comparisons by key groups. Results: A total of 195 PDs and 286 trainees responded. Twelve percent and 29% of PDs were unsure of maternity/paternity leave options, respectively. PDs felt they were more supportive of trainee parenthood than trainees perceived they were. Thirty-nine percent of nonparent trainees (NPTs) would have children already if not in medicine, and >80% of women trainees were concerned about declining fertility. Perceived impacts of parenthood on trainee overall education and academic productivity were more negative for women trainees when rated by PDs and NPTs; however, men/women parents self-reported equal impacts. Leave burden was perceived as higher for women trainees. Conclusions: A significant portion of PDs lack awareness of parental leave policies, highlighting needs for increased transparency. Trainees' perception of PD support for parenthood is less than PD self-reported support. Alongside significant rates of delayed parenthood and fertility concerns, this poses a problem for trainees seeking to start a family, particularly women who are perceived more negatively. Further work is needed to create a supportive culture for trainee parenthood.

Complex Neck Loading and Injury Tolerance in Lateral Bending With Head Rotation From Human Cadaver Tests.

Advancements in automated vehicles may position the occupant in postures different from the current standard posture. It may affect human tolerance responses. The objective of this study was to determine the lateral bending tolerance of the head-cervical spine with initial head rotation posture using loads at the occipital condyles and lower neck and describe injuries. Using a custom loading device, head-cervical spine complexes from human cadavers were prepared with load cells at the ends. Lateral bending loads were applied to prerotated specimens at 1.5 m/s. At the occipital condyles, peak axial and antero-posterior and medial-lateral shear forces were: 316-954 N, 176-254 N, and 327-508 N, and coronal, sagittal, and axial moments were: 27-38 N·m, 21-38 N·m, and 9.7-19.8 N·m, respectively. At the lower neck, peak axial and shear forces were: 677-1004 N, 115-227 N, and 178-350 N, and coronal, sagittal, and axial moments were: 30-39 N·m, 7.6-21.3 N·m, and 5.7-13.4 N·m, respectively. Ipsilateral atlas lateral mass fractures occurred in four out of five specimens with varying joint diastasis and capsular ligament involvements. Acknowledging that the study used a small sample size, initial tolerances at the occipital condyles and lower neck were estimated using survival analysis. Injury patterns with posture variations are discussed.

Associations of prior concussion severity with brain microstructure using mean apparent propagator magnetic resonance imaging.

Magnetic resonance imaging (MRI) diffusion studies have shown chronic microstructural tissue abnormalities in athletes with history of concussion, but with inconsistent findings. Concussions with post-traumatic amnesia (PTA) and/or loss of consciousness (LOC) have been connected to greater physiological injury. The novel mean apparent propagator (MAP) MRI is expected to be more sensitive to such tissue injury than the conventional diffusion tensor imaging. This study examined effects of prior concussion severity on microstructure with MAP-MRI. Collegiate-aged athletes (N = 111, 38 females; ≥6 months since most recent concussion, if present) completed semistructured interviews to determine the presence of prior concussion and associated injury characteristics, including PTA and LOC. MAP-MRI metrics (mean non-Gaussian diffusion [NG Mean], return-to-origin probability [RTOP], and mean square displacement [MSD]) were calculated from multi-shell diffusion data, then evaluated for associations with concussion severity through group comparisons in a primary model (athletes with/without prior concussion) and two secondary models (athletes with/without prior concussion with PTA and/or LOC, and athletes with/without prior concussion with LOC only). Bayesian multilevel modeling estimated models in regions of interest (ROI) in white matter and subcortical gray matter, separately. In gray matter, the primary model showed decreased NG Mean and RTOP in the bilateral pallidum and decreased NG Mean in the left putamen with prior concussion. In white matter, lower NG Mean with prior concussion was present in all ROI across all models and was further decreased with LOC. However, only prior concussion with LOC was associated with decreased RTOP and increased MSD across ROI. Exploratory analyses conducted separately in male and female athletes indicate associations in the primary model may differ by sex. Results suggest microstructural measures in gray matter are associated with a general history of concussion, while a severity-dependent association of prior concussion may exist in white matter.

Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy.

PURPOSE/OBJECTIVES: Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. MATERIALS/METHODS: Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. RESULTS: 121 patients were included with a median age of 62 years (37-86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving <18 months and ≥18 months regarding the presence of lung only metastases (36% vs. 16%, p = 0.04), number of organs with metastases (≥2 vs. 1, p = 0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p = 0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p = 0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19-9 (p < 0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p = 0.03). In those patients that normalized their CA 19-9, median overall survival was 16 months. CONCLUSIONS: In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions.

Preliminary Data of Neck Muscle Morphology With Head-Supported Mass in Male and Female Volunteers.

INTRODUCTION: This study quantified parameters related to muscle morphology using a group of upright seated female and male volunteers with a head-supported mass. MATERIALS AND METHODS: Upright magnetic resonance images (MRIs) were obtained from 23 healthy volunteers after approval from the U.S. DoD. They were asymptomatic for neck pain, with no history of injury. The volunteers were scanned using an upright MRI scanner with a head-supported mass (army combat helmet). T1 and T2 sagittal and axial images were obtained. Measurements were performed by an engineer and a neurosurgeon. The cross-sectional areas of the sternocleidomastoid and multifidus muscles were measured at the inferior endplate in the sub-axial column, and the centroid angle and centroid radius were quantified. Differences in the morphology by gender and spinal level were analyzed using a repeated measures analysis of variance model, adjusted for multiple corrections. RESULTS: For females and males, the cross-sectional area of the sternocleidomastoid muscle ranged from 2.3 to 3.6 cm2 and from 3.4 to 5.4 cm2, the centroid radius ranged from 4.1 to 5.1 cm and from 4.7 to 5.7 cm, and the centroid angle ranged from 75° to 131° and from 4.8° to 131.2°, respectively. For the multifidus muscle, the area ranged from 1.7 to 3.9 cm2 and from 2.4 to 4.2 cm2, the radius ranged from 3.1 to 3.4 cm and from 3.3 to 3.8 cm, the angle ranged from 15° to 24.4° and 16.2° to 24.4°, respectively. Results from all levels for both muscles and male and female spines are given. CONCLUSIONS: The cross-sectional area, angulation, and centroid radii data for flexor and extensor muscles of the cervical spine serve as a dataset that may be used to better define morphologies in computational models and obtain segmental motions and loads under external mechanical forces. These data can be used in computational models for injury prevention, mitigation, and readiness.

Subaxial Cervical Spine Motion With Different Sizes of Head-supported Mass Under Accelerative Forces.

INTRODUCTION: The evolution of military helmet devices has increased the amount of head-supported mass (HSM) worn by warfighters. HSM has important implications for spine biomechanics, and yet, there is a paucity of studies that investigated the effects of differing HSM and accelerative profiles on spine biomechanics. The aim of this study is to investigate the segmental motions in the subaxial cervical spine with different sizes of HSM under Gx accelerative loading. METHODS: A three-dimensional finite element model of the male head-neck spinal column was used. Three different size military helmets were modeled and incorporated into head-neck model. The models were exercised under Gx accelerative loading by inputting low and high pulses to the cervical vertebra used in the experimental studies. Segmental motions were obtained and normalized with respect to the non-HSM case to quantify the effect of HSM. RESULTS: Segmental motions increased with an increase in velocity at all segments of the spine. Increasing helmet size resulted in larger motion increases. Angulations ranged from 0.9° to 9.3° at 1.8 m/s and from 1.3° to 10.3° at 2.6 m/s without a helmet. Helmet increased motion between 5% to 74% at 1.8 m/s. At 2.6 m/s, the helmet increased segmental motion anywhere from 10% to 105% in the subaxial cervical spine. The greatest motion was seen at the C5-C6 level, followed by the C6-C7 level. CONCLUSIONS: The subaxial cervical spine experiences motion increases at all levels at both velocity profiles with increasing HSM. Larger helmet and greater impact velocity increased motion at all levels, with C5-C6 demonstrating the largest range of motion. HSM should be minimized to reduce the risk of cervical spine injury to the warfighter.

Upper cervical spine bone mineral content variations in elderly females.

The purpose of the study was to determine the bone mineral densities (BMDs) of the C1 and C2 vertebrae and discuss their implications for autonomous vehicle environments and vulnerable road users. Using quantitated computed tomography (QCT), the BMDs were obtained at eight regions for the C1 vertebra and seven regions for the C2 vertebra. The spine surgeon author outlined the boundaries of each region, and nine elderly female human cadaver specimens were used. The regions were based on potential stabilization locations for fracture fixation. In the C1 vertebra, the BMD was greatest at the anterior tubercle, followed by the posterior tubercle, the posterior arch, and the lateral and anterior lateral masses. In the C2 vertebra, the distal odontoid had the greatest BMD, followed by the spinous process, the C2-lateral mass, the odontoid-body interface, and the anterior inferior aspect of the body. Use of these data in female-specific finite element models may lead to a better understanding of load paths, injuries, mechanisms, and tolerance.

Regional variations in C1-C2 bone density on quantitated computed tomography and clinical implications.

Background: Our elderly population is growing and the number of spine fractures in the elderly is also growing. The elderly population in general may be considered as poor surgical candidates experience a high rate of fractures at C1 and C2 compared with the general population. Nonoperative management of upper cervical fractures is not benign as there is a high nonunion rate for both C1 and C2 fractures in the elderly, and orthosis compliance is often suboptimal, or complicated by skin breakdown. The optimal technique for upper cervical stabilization in the elderly may be different than in younger populations as the bone quality is inferior in the elderly. The objective of this basic science study is to determine whether the bone mineral density (BMD) of C1 and C2 vary by region, and if this is a gender difference in this elderly age group. Methods: Twenty cadaveric spines from 45 to 83 years of age were used to obtain BMD using quantitated computed tomography (QCT). BMD was measured using a QCT. For C1, 8 regions were determined: anterior tubercle, bilateral anterior and medial lateral masses, bilateral posterior arches, and posterior tubercle. For C2, 7 regional BMDs were determined: top of odontoid, base of odontoid-body interface, mid body, bilateral lateral masses, anterior inferior body near the discs space, and the C2 spinous process. Results: The BMD was greatest at the C1 anterior tubercle (564.4±175.8 mg/cm3) and C1 posterior ring (420.8±110.2 mg/cm3), and least at the anterior and medial lateral masses (262.8±59.5 mg/cm3, 316.9±72.6 mg/cm3). At C2 QCT BMD was greatest at the top of the dens (400.6±107.9 mg/cm3) decreasing down through the odontoid-C2 body junction (267.8±103.5 mg/cm3) and least in the mid C2 body 249.1±68.8 mg/cm3). The posterior arch of C1 and the spinous process of C2 had higher BMD's 420.8±110.2 mg/cm3 and 284.1±93.0 mg/cm3, respectively. A high correlation was observed between the BMD at the interface of the dens-vertebral body with the vertebral body with a Pearson correlation coefficient of 0.86. The BMD of the top of dens was significantly higher (p<.05) than all the regions in C2. Conclusions: Regional and segmental BMD variations at C1 and C2 have clinical implications for surgical constructs in the elderly population. Given the higher BMDs of the C1 and C2 spinous process and posterior arches, consideration should be given to incorporate these areas using various C1-C2 wiring techniques. In the elderly, lateral masses particularly at C1 with lower BMD may result in potential screw loosening and nonunion in this age group. Old-school wiring techniques have a track record of efficacy and safety with less blood loss, reduced operative time, reduced X-ray exposure, and should be considered in the elderly as a primary stabilization technique or a belt-over suspenders approach based on regional variations in BMD in the elderly.

Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.

BACKGROUND: Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. METHODS: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. RESULTS: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. CONCLUSION: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03219476.

Severity of Prior Coronavirus Disease 2019 is Associated With Postoperative Outcomes After Major Inpatient Surgery.

OBJECTIVE: To determine how the severity of prior history (Hx) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection influences postoperative outcomes after major elective inpatient surgery. BACKGROUND: Surgical guidelines instituted early in the coronavirus disease 2019 (COVID-19) pandemic recommended a delay in surgery of up to 8 weeks after an acute SARS-CoV-2 infection. This was based on the observation of elevated surgical risk after recovery from COVID-19 early in the pandemic. As the pandemic shifts to an endemic phase, it is unclear whether this association remains, especially for those recovering from asymptomatic or mildly symptomatic COVID-19. METHODS: Utilizing the National COVID Cohort Collaborative, we assessed postoperative outcomes for adults with and without a Hx of COVID-19 who underwent major elective inpatient surgery between January 2020 and February 2023. COVID-19 severity and time from infection to surgery were each used as independent variables in multivariable logistic regression models. RESULTS: This study included 387,030 patients, of whom 37,354 (9.7%) were diagnosed with preoperative COVID-19. Hx of COVID-19 was found to be an independent risk factor for adverse postoperative outcomes even after a 12-week delay for patients with moderate and severe SARS-CoV-2 infection. Patients with mild COVID-19 did not have an increased risk of adverse postoperative outcomes at any time point. Vaccination decreased the odds of respiratory failure. CONCLUSIONS: Impact of COVID-19 on postoperative outcomes is dependent on the severity of illness, with only moderate and severe disease leading to a higher risk of adverse outcomes. Existing perioperative policies should be updated to include consideration of COVID-19 disease severity and vaccination status.

Determinants of spinal cord stress and strain in degenerative cervical myelopathy: a patient-specific finite element study.

Degenerative cervical myelopathy (DCM) is the commonest cause of spinal cord dysfunction in older adults and is characterized by chronic cervical spinal cord compression. Spinal cord stress and strain during neck motion are also known contributors to the pathophysiology of DCM, yet these factors are not routinely assessed for surgical planning. The aim of this study was to measure spinal cord stress/strain in DCM using patient-specific 3D finite element models (FEMs) and determine whether spinal cord compression is the primary determinant of spinal cord stress/strain. Three-dimensional patient-specific FEMs were created for six DCM patients (mild [n = 2], moderate [n = 2] and severe [n = 2]). Flexion and extension of the cervical spine were simulated with a pure moment load of 2 Nm. Segmental spinal cord von Mises stress and maximum principal strain were measured. Measures of spinal cord compression and segmental range of motion (ROM) were included in a regression analysis to determine associations with spinal cord stress and strain. Segmental ROM in flexion-extension and axial rotation was independently associated with spinal cord stress (p < 0.001) and strain (p < 0.001), respectively. This relationship was not seen for lateral bending. Segmental ROM had a stronger association with spinal stress and strain as compared to spinal cord compression. Compared to the severity of spinal cord compression, segmental ROM is a stronger determinant spinal cord stress and strain. Surgical procedures that address segmental ROM in addition to cord compression may best optimize spinal cord biomechanics in DCM.

Severity of Prior COVID-19 Infection is Associated with Postoperative Outcomes Following Major Inpatient Surgery.

Objective: To determine the association between severity of prior history of SARS-CoV-2 infection and postoperative outcomes following major elective inpatient surgery. Summary Background Data: Surgical guidelines instituted early in the COVID-19 pandemic recommended delay in surgery up to 8 weeks following an acute SARS-CoV-2 infection. Given that surgical delay can lead to worse medical outcomes, it is unclear if continuation of such stringent policies is necessary and beneficial for all patients, especially those recovering from asymptomatic or mildly symptomatic COVID-19. Methods: Utilizing the National Covid Cohort Collaborative (N3C), we assessed postoperative outcomes for adults with and without a history of COVID-19 who underwent major elective inpatient surgery between January 2020 and February 2023. COVID-19 severity and time from SARS-CoV-2 infection to surgery were each used as independent variables in multivariable logistic regression models. Results: This study included 387,030 patients, of which 37,354 (9.7%) had a diagnosis of preoperative COVID-19. History of COVID-19 was found to be an independent risk factor for adverse postoperative outcomes even after a 12-week delay for patients with moderate and severe SARS-CoV-2 infection. Patients with mild COVID-19 did not have an increased risk of adverse postoperative outcomes at any time point. Vaccination decreased the odds of mortality and other complications. Conclusions: Impact of COVID-19 on postoperative outcomes is dependent on severity of illness, with only moderate and severe disease leading to higher risk of adverse outcomes. Existing wait time policies should be updated to include consideration of COVID-19 disease severity and vaccination status.