Effects on Lung Tissue After Breast Cancer Radiation: Comparing Photon and Proton Therapies.

Purpose: In breast cancer, improved treatment approaches that reduce injury to lung tissue and early diagnosis and intervention for lung toxicity are increasingly important in survivorship. The aims of this study are to (1) compare lung tissue radiographic changes in women treated with conventional photon radiation therapy and those treated with proton therapy (PT), (2) assess the volume of lung irradiated to 5 Gy (V5) and 20 Gy (V20) by treatment modality, and (3) quantify the effects of V5, V20, time, and smoking history on the severity of tissue radiographic changes. Patients and Methods: A prospective observational study of female breast cancer patients was conducted to monitor postradiation subclinical lung tissue radiographic changes. Repeated follow-up x-ray computed tomography scans were acquired through 2 years after treatment. In-house software was used to quantify an internally normalized measure of pulmonary tissue density change over time from the computed tomography scans, emphasizing the 6- and 12-month time points. Results: Compared with photon therapy, PT was associated with significantly lower lung V5 and V20. Lung V20 (but not V5) correlated significantly with increased subclinical lung tissue radiographic changes 6 months after treatment, and neither correlated with lung effects at 12 months. Significant lung tissue density changes were present in photon therapy patients at 6 and 12 months but not in PT patients. Significant lung tissue density change persisted at 12 months in ever-smokers but not in never-smokers. Conclusion: Patients treated with PT had significantly lower radiation exposure to the lungs and less statistically significant tissue density change, suggesting decreased injury and/or improved recovery compared to photon therapy. These findings motivate additional studies in larger, randomized, and more diverse cohorts to further investigate the contributions of treatment modality and smoking regarding the short- and long-term radiographic effects of radiation on lung tissue.

Association between trajectories of adherence to endocrine therapy and risk of treated breast cancer recurrence among US nonmetastatic breast cancer survivors.

BACKGROUND: Endocrine therapy is the mainstay treatment for breast cancer (BC) to reduce BC recurrence risk. During the first year of endocrine therapy use, nearly 30% of BC survivors are nonadherent, which may increase BC recurrence risk. This study is to examine the association between endocrine therapy adherence trajectories and BC recurrence risk in nonmetastatic BC survivors. METHODS: This retrospective cohort study included Medicare beneficiaries in the United States (US) with incident nonmetastatic BC followed by endocrine therapy initiation in 2010-2019 US Surveillance, Epidemiology, and End Results linked Medicare data. We calculated monthly fill-based proportion of days covered in the first year of endocrine therapy. We applied group-based trajectory models to identify distinct endocrine therapy adherence patterns. After the end of the first-year endocrine therapy trajectory measurement period, we estimated the risk of time to first treated BC recurrence within 4 years using Cox proportional hazards models. RESULTS: We identified 5 trajectories of adherence to endocrine therapy in BC Stages 0-I subgroup (n = 28,042) and in Stages II-III subgroup (n = 7781). A trajectory of discontinuation before 6 months accounted for 7.0% in Stages 0-I and 5.8% in Stages II-III subgroups, and this trajectory was associated with an increased treated BC recurrence risk compared to nearly perfect adherence (Stages 0-I: adjusted hazard [aHR] = 1.84, 95% CI = 1.46-2.33; Stages II-III: aHR = 1.38, 95% CI = 1.07-1.77). CONCLUSIONS: Nearly 7% of BC survivors who discontinued before completing 6 months of treatment was associated with an increased treated BC recurrence risk compared to those with nearly perfect adherence among Medicare nonmetastatic BC survivors.

Association between trajectories of prescription opioid use and risk of opioid use disorder and overdose among US nonmetastatic breast cancer survivors.

PURPOSE: To examine the association between prescription opioid use trajectories and risk of opioid use disorder (OUD) or overdose among nonmetastatic breast cancer survivors by treatment type. METHODS: This retrospective cohort study included female nonmetastatic breast cancer survivors with at least 1 opioid prescription fill in 2010-2019 Surveillance, Epidemiology and End Results linked Medicare data. Opioid mean daily morphine milligram equivalents (MME) calculated within 1.5 years after initiating active breast cancer therapy. Group-based trajectory models identified distinct opioid use trajectory patterns. Risk of time to first OUD/overdose event within 1 year after the trajectory period was calculated for distinct trajectory groups using Cox proportional hazards models. Analyses were stratified by treatment type. RESULTS: Four opioid use trajectories were identified for each treatment group. For 38,030 survivors with systemic endocrine therapy, 3 trajectories were associated with increased OUD/overdose risk compared with early discontinuation: minimal dose (< 5 MME; adjusted hazard ratio [aHR] = 1.73 [95% CI 1.43-2.09]), very low dose (5-25 MME; 2.67 [2.05-3.48]), and moderate dose (51-90 MME; 6.20 [4.69-8.19]). For 9477 survivors with adjuvant chemotherapy, low-dose opioid use was associated with higher OUD/overdose risk (aHR = 7.33 [95% CI 2.52-21.31]) compared with early discontinuation. For 3513 survivors with neoadjuvant chemotherapy, the differences in OUD/OD risks across the 4 trajectories were not significant. CONCLUSIONS: Among Medicare nonmetastatic breast cancer survivors receiving systemic endocrine therapy or adjuvant chemotherapy, compared with early discontinuation, low-dose or moderate-dose opioid use were associated with six- to sevenfold higher OUD/overdose risk. Breast cancer survivors at high-risk of OUD/overdose may benefit from targeted interventions (e.g., pain clinic referral).

Sex differences in brain transcriptomes of juvenile Cynomolgus macaques.

Background: Behavioral, social, and physical characteristics are posited to distinguish the sexes, yet research on transcription-level sexual differences in the brain is limited. Here, we investigated sexually divergent brain transcriptomics in prepubertal cynomolgus macaques, a commonly used surrogate species to humans. Methods: A transcriptomic profile using RNA sequencing was generated for the temporal lobe, ventral midbrain, and cerebellum of 3 female and 3 male cynomolgus macaques previously treated with an Adeno-associated virus vector mix. Statistical analyses to determine differentially expressed protein-coding genes in all three lobes were conducted using DeSeq2 with a false discovery rate corrected P value of .05. Results: We identified target genes in the temporal lobe, ventral midbrain, and cerebellum with functions in translation, immunity, behavior, and neurological disorders that exhibited statistically significant sexually divergent expression. Conclusions: We provide potential mechanistic insights to the epidemiological differences observed between the sexes with regards to mental health and infectious diseases, such as COVID19. Our results provide pre-pubertal information on sexual differences in non-human primate brain transcriptomics and may provide insight to health disparities between the biological sexes in humans.

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice.

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

Economic Burden of Sanfilippo Syndrome in the United States.

Introduction: Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available. Objectives: To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward. Design and Setting: A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward. Main Outcome Measures: Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death. Results: From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome. Conclusion: Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.

Trends, characteristics, race, and ethnicity associated with nonadherence to antidepressants among breast cancer survivors with depression.

BACKGROUND: Breast cancer is the most diagnosed cancer in the United States, and half of breast cancer survivors experience major depressive disorders (hereafter depression). Healthcare Effectiveness Data and Information Set (HEDIS) quality measures evaluating depression treatment practices recommend uninterrupted antidepressant treatment for 3 months in the acute phase and 3 months in the continuation phase for the general population. However, little is known about the extent of and trends in antidepressant nonadherence among breast cancer survivors with depression, which may impact adherence to breast cancer treatment, potentially leading to breast cancer recurrence and other adverse outcomes. OBJECTIVE: To examine the trends and characteristics associated with antidepressant nonadherence among breast cancer survivors with depression in the United States. METHODS: We conducted cross-sectional analyses of Surveillance, Epidemiology, and End Results linked with Medicare data (2010-2019) for women with breast cancer and depression who newly initiated antidepressant use. Using HEDIS measures of nonadherence (ie, antidepressant prescription coverage ≤84 days of the 114-day acute phase or ≤180 days of the 231-day continuation phase), we calculated the annual crude prevalence of antidepressant nonadherence and examined trends using unadjusted logistic regression. Multivariable logistic regression identified characteristics associated with antidepressant nonadherence. RESULTS: Among 9,452 eligible breast cancer survivors with depression (aged ≥65 years = 84% and White race = 82%), the crude prevalence of antidepressant nonadherence decreased from 2010 to 2019 for both the acute (49% to 40%; Ptrend<0.001) and continuation (67% to 57%; Ptrend<0.001) phases. Factors significantly associated with higher odds of antidepressant nonadherence in both the acute and continuation phases included Black race (odds ratios [ORs] [95% CI] for the acute/continuation phases: 2.0 [1.7-2.4]/2.0 [1.7-2.3]) and Hispanic ethnicity (1.5 [1.1-1.9]/2.2 [1.6-2.9]) compared with White race; receiving the first antidepressant from an oncologist vs a psychiatrist (1.4 [1.1-1.8]/1.6 [1.2-2.0]); and using antidepressants not recommended for older adults by the Beers criteria (2.2 [1.6-2.9]/2.0 [1.4-2.7]). Factors associated with lower odds of antidepressant nonadherence in both phases included receiving lymph node dissection (0.7 [0.5-0.9]/0.7 [0.5-0.9]), receiving endocrine therapy (0.9 [0.8-0.9]/0.8 [0.7-0.9]), having a higher National Cancer Institute comorbid index (0.8 [0.7-0.8]/0.9 [0.8-0.9]), having a follow-up visit with a psychiatrist (0.9 [0.8-0.9]/0.9 [0.8-0.9]), and switching to different antidepressants (0.7 [0.6-0.8]/0.7 [0.7-0.8]). CONCLUSIONS: Despite antidepressant nonadherence prevalence decreasing from 2010 to 2019, over half of breast cancer survivors with depression and Medicare were nonadherent in the continuation phase. Patients with identified nonadherence risk factors may benefit from close monitoring and targeted interventions. DISCLOSURES: Wei-Hsuan Lo-Ciganic reported grants from the National Institute on Drug Abuse (R01DA044985 and R01DA050676), the National Institute on Aging (R21AG060308), the National Institute of Mental Health (R01MH121907), Merck Sharp & Dohme, Bristol Myers Squibb, the Richard King Mellon Foundation at the University of Pittsburgh, the Clinical and Translational Science Institute of the University of Florida, the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation, and the US Department of Veterans Affairs outside the submitted work; in addition, Wei-Hsuan Lo-Ciganic has a patent pending for U1195.70174US00. Haesuk Park reported grants from Bristol Myers Squibb/Pfizer Alliance American Thrombosis Investigator Initiated Research Program (ARISTA-USA) outside the submitted work. Juan M. Hincapie-Castillo reported grants from Merck outside the submitted work. Debbie Wilson reported grants from the National Institute on Drug Abuse, the National Institute on Aging, Merck Sharp & Dohme, and Bristol Myers Squibb outside the submitted work; and serving as an editorial board member for the Journal of Pharmacy Technology. Ching-Yuan Chang's contributions to this manuscript were made while at the University of Florida College of Pharmacy. Ching-Yuan Chang is currently employed by Vertex Pharmaceuticals, Inc. Vertex did not fund or have any involvement in this study or publication. Vakaramoko Diaby is currently employed by Otsuka, Inc. Otsuka did not fund or have any involvement in this study or publication. No other disclosures were reported.

Comparative effectiveness of pegfilgrastim biosimilars vs originator for prevention of febrile neutropenia: A retrospective cohort study.

BACKGROUND: Real-world evidence on the comparative effectiveness of pegfilgrastim biosimilars compared with the originator product is limited. OBJECTIVE: To compare the risk of febrile neutropenia (FN) among users of pegfilgrastim biosimilars (pegfilgrastim-jmdb and pegfilgrastim-cbqv) and the originator product. METHODS: A retrospective cohort study was conducted using 2019 IBM MarketScan databases to assess comparative effectiveness of pegfilgrastim originator and biosimilars for prevention of FN among patients receiving myelosuppressive chemotherapy. Patients with cancer, including breast, lung, colorectal, esophageal and gastric, pancreatic, prostate, ovarian, and non-Hodgkin lymphomas, initiating myelosuppressive chemotherapy courses were selected. We further selected patients who used pegfilgrastim originator and biosimilars within 3 days of chemotherapy completion. FN-associated hospitalizations were measured by International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes. After 1:1 propensity score matching, we used equivalence (with a margin of 6%) hypothesis tests to compare FN-related hospitalization risk in the first cycle and across all cycles between biosimilars and originator users. RESULTS: A total of 2,045 patients were included, of which 445 (21.8%) used pegfilgrastim-jmdb, 636 (31.1%) used pegfilgrastim-cbqv, and 964 (47.1%) used pegfilgrastim originator. After matching, 13 out of 445 originator users and 17 out of 445 pegfilgrastim-jmdb users developed FN after the first chemotherapy cycle (risk difference was 0.9%; P < 0.001 for equivalence test indicating statistical equivalence). After matching, 14 out of 633 originator users and 16 out of 633 pegfilgrastim-cbqv users developed FN (risk difference was 0.32%; P < 0.001 for equivalence test indicating statistical equivalence). Results across all cycles (including the first cycle) were consistent with that in the first cycle. CONCLUSIONS: In this real-world study of patients with cancer receiving myelosuppressive chemotherapy, there was no difference in FN risk between patients receiving pegfilgrastim originator and biosimilars in the first cycle and across all cycles. These results add further to the current evidence on pegfilgrastim biosimilars and support wider adoption of pegfilgrastim biosimilars among payers, providers, and patients. Future studies assessing the tolerability, side effects, and other safety issues of pegfilgrastim biosimilars are needed.

Disease correction in mucopolysaccharidosis type IIIB mice by intraparenchymal or cisternal delivery of a capsid modified AAV8 codon-optimized NAGLU vector.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood-brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.

Patient out-of-pocket and payer costs for pegfilgrastim originator vs biosimilars as primary prophylaxis of febrile neutropenia in the first cycle among a commercially insured population.

BACKGROUND: It is unknown whether using pegfilgrastim biosimilars is cost saving in a real-world setting. OBJECTIVE: To compare medical costs including pegfilgrastim drug costs and febrile neutropenia (FN) treatment and management costs between pegfilgrastim biosimilars (pegfilgrastim-jmdb, pegfilgrastim-cbqv) and originator users for primary prophylaxis of febrile neutropenia. METHODS: A retrospective cohort study using 2019 IBM MarketScan Commercial and Medicare Supplemental databases was conducted in adult patients with cancer initiating myelosuppressive chemotherapy courses. At least 2 diagnoses of the same cancer (at least 7 days apart) were required within 30 days of the chemotherapy initiation date. Pegfilgrastim (excluding on-body injector) costs included drug costs only (excluding administration fees). FN-related costs included all FN-related health care utilizations that were defined as having neutropenia, fever, or infection diagnosis. Per-patient per-cycle (PPPC) out-of-pocket (OOP) costs, health plan costs, and total costs were compared between originator (excluding on-body injector) and biosimilars users in the first cycle. A generalized linear model and a 2-part model were used. RESULTS: A total of 1,930 patients were included, of whom 884 (45.8%) used pegfilgrastim originator, 427 (22.1%) used pegfilgrastim-jmdb, and 619 (32.1%) used pegfilgrastim-cbqv. Adjusted PPPC OOP pegfilgrastim costs in the first cycle were significantly lower for the biosimilars vs the originator ($182 for pegfilgrastim-jmdb and $159 for pegfilgrastim-cbqv vs $299 for originator, P < 0.0001 for both comparisons). However, there was no difference in health plan costs ($5,783 for pegfilgrastim-jmdb and $5,845 for pegfilgrastim-cbqv vs $5,618 for originator) and total costs. In addition, no difference was observed for adjusted PPPC FN treatment and management OOP costs, health plan costs, and total costs in the first cycle. FN treatment OOP costs were $192 for originator, $197 for pegfilgrastim-jmdb (P = 0.958), and $240 for pegfilgrastim-cbqv (P = 0.680). FN treatment health plan costs were $2,804 for originator, $2,970 for pegfilgrastim-jmdb (P = 0.692), and $2,745 for pegfilgrastim-cbqv (P = 0.879). CONCLUSIONS: In a commercially insured population, using pegfilgrastim biosimilars in the first cycle for primary prophylaxis of FN led to cost savings for patients but not payers. No difference in FN-related costs was observed.

Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death.

Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.

Trends in Use of Granulocyte Colony-Stimulating Factor Following Introduction of Biosimilars Among Adults With Cancer and Commercial or Medicare Insurance From 2014 to 2019.

Importance: The introduction of biosimilars and novel delivery devices between 2014 and 2019 may have changed the utilization of granulocyte colony-stimulating factors (G-CSF). Objective: To assess utilization trends of G-CSFs for primary prophylaxis of febrile neutropenia (FN) among patients with cancer receiving myelosuppressive chemotherapy with commercial or Medicare insurance. Design, Setting, and Participants: This cross-sectional study assessed G-CSF utilization trends overall and stratified by regimen febrile neutropenia risk level. Associations between patient characteristics and G-CSF use were evaluated. Patients with cancer, including breast, lung, colorectal, esophageal and gastric, pancreatic, prostate, ovarian, and non-Hodgkin lymphomas, initiating myelosuppressive chemotherapy courses were included from the 2014 to 2019 commercial insurance and 2014 to 2018 Medicare fee-for-service claims databases. Data were analyzed from March to June 2021. Exposures: Year of chemotherapy initiation. Main Outcomes and Measures: The main outcomes were use and trends of G-CSFs for primary prophylaxis, from completion to 3 days after in the first chemotherapy cycle. Results: In total, 86 731 chemotherapy courses (mean [SD] age, 57.7 [11.5] years; 57 838 [66.7%] women and 28 893 [33.3%] men) were identified from 82 410 patients in the commercial insurance database and 32 398 chemotherapy courses (mean [SD] age, 71.8 [8.3] years; 18 468 [57.0%] women and 13 930 [43.0%] men) were identified from 30 279 patients in the Medicare database. Among the commercially insured population, 39 639 patients (45.7%) received G-CSFs, and 12 562 patients (38.8%) received G-CSFs among Medicare insured patients. Overall G-CSF use increased significantly throughout the study period in both populations, from 45.1% (95% CI, 44.4%-45.7%) of patients in 2014 to 47.5% (95% CI, 46.5%-48.5%) of patients in 2019 (P = .001) in the commercially insured population and from 36.0% (95% CI, 34.2%-38.0%) of patients in 2014 to 39.1% (95% CI, 38.1%-40.1%) of patients in 2018 (P < .001) in the Medicare population. The greatest increases in G-CSF use were observed among patients with high FN risk, from 75.0% (95% CI, 74.1%-76.0%) of patients to 83.2% (95% CI, 82.0%-84.2%) of patients (P < .001) among the commercially insured population and 75.3% (95% CI, 71.8%-78.6%) of patients to 86.2% (95% CI, 84.7%-87.6%) of patients (P < .001) among the Medicare population. Use of G-CSFs decreased in the commercially insured population among patients with intermediate FN risk (from 27.5% [95% CI, 26.4%-28.5%] of patients to 20.4% [95% CI, 19.1%-21.7%] of patients; P < .001) or low FN risk (from 19.3% [95% CI, 18.3%-20.4%] of patients to 16.3% [95% CI, 14.7%-18.0%] of patients; P < .001) and remained stable in the Medicare population (intermediate risk: from 26.4% [95% CI, 23.8%-29.2%] of patients to 28.4% [95% CI, 27.0%-29.8%] of patients; P = .35; low risk: from 19.6% [95% CI, 17.0%-22.4%] of patients to 20.9% [95% CI, 19.6%-22.3%] of patients; P = .58). Factors associated with increased odds of G-CSF use included older age (commercial insurance: adjusted odds ratio [aOR], 1.50 [95% CI, 1.41-1.59]; Medicare: aOR, 1.36 [95% CI, 1.08-1.71]), receiving a regimen with high FN risk (commercial insurance: aOR, 16.01 [95% CI, 15.17-16.90]; Medicare: aOR, 17.17 [95% CI, 15.76-18.71]), and history of neutropenia (commercial insurance: 3.90 (3.67-4.15); Medicare: 3.82 (3.50-4.18). Conclusions and Relevance: This cross-sectional study found that utilization of G-CSFs increased among patients with cancer with high FN risk in both a commercially and Medicare-insured population, but 14% to 17% of patients still did not receive preventive treatment.

Five-Year Breast Surgeon Experience in LYMPHA at Time of ALND for Treatment of Clinical T1-4N1-3M0 Breast Cancer.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a source of postoperative morbidity for breast cancer survivors. Lymphatic microsurgical preventive healing approach (LYMPHA) is a technique used to prevent BCRL at the time of axillary lymph node dissection (ALND). We report the 5-year experience of a breast surgeon trained in LYMPHA and investigate the outcomes of patients who underwent LYMPHA following ALND for treatment of cT1-4N1-3M0 breast cancer. METHODS: A retrospective review of patients with cT1-4N1-3M0 breast cancer was performed in patients who underwent ALND with and without LYMPHA. Diagnosis of BCRL was made by certified lymphedema therapists. Descriptive statistics and lymphedema surveillance data were analyzed using results of Fisher's exact or Wilcoxon rank-sum tests. Logistic regression and propensity matching were performed to assess the reduction of BCRL occurrence following LYMPHA. RESULTS: In a 5-year period, 132 patients met inclusion criteria with 76 patients undergoing LYMPHA at the time of ALND and 56 patients undergoing ALND alone. Patients who underwent LYMPHA at the time of ALND were significantly less likely to develop BCRL than those who underwent ALND alone (p = 0.045). Risk factors associated with BCRL development were increased patient age (p = 0.007), body mass index (BMI) (p = 0.003), and, in patients undergoing LYMPHA, number of positive nodes (p = 0.026). CONCLUSIONS: LYMPHA may be successfully employed by breast surgeons trained in lymphatic-venous anastomosis at the time of ALND. While research efforts should continue to focus on prevention and surveillance of BCRL, LYMPHA remains an option to reduce BCRL and improve patient quality of life.

The beta-glucuronidase intracisternal A particle insertion model results in similar overall MPSVII phenotype as the single base deletion model when on the same C57BL/6J mouse background.

Two unique gene mutations in the enzyme beta-glucuronidase (GUSB) that result in the lysosomal storage disease Mucopolysaccharidosis (MPS) type VII had previously been reported to have differing disease phenotype severities when compared on differing mouse strains. The MPSVII mouse has proven to be a highly efficacious model to study mucopolysaccharidoses and for evaluating potential gene or stem cell therapies for lysosomal storage diseases. We examined the single base pair deletion (MPSVII) and the intracisternal A particle element insertion (MPSVII2J) in GUSB compared with control animals by skeletal measures, electroretinography, auditory-evoked brainstem response and life span on a C57BL/6J background strain. In all measures, both mutations result in either a trend toward or significant changes from the background strain control. In all measures, there is no significant phenotypic difference between the two mutations. The 2J variant is a more easily genotyped and equally affected phenotype, which holds promise for further studies of chimerism and stem cell therapy approaches.

Reflections of Healthcare Experiences of African Americans With Sickle Cell Disease or Cancer: A Qualitative Study.

BACKGROUND: The experiences of African American adult patients before, during, and after acute care utilization are not well characterized for individuals with sickle cell disease (SCD) or cancer. OBJECTIVE: To describe the experiences of African Americans with SCD or cancer before, during, and after hospitalization for pain control. METHODS: We conducted a qualitative study among African American participants with SCD (n = 15; 11 male; mean age, 32.7 ± 10.9 years; mean pain intensity, 7.8 ± 2.6) or cancer (n = 15; 7 male; mean age, 53.7 ± 15.2 years; mean pain intensity, 4.9 ± 3.7). Participants completed demographic questions and pain intensity using PAINReportIt and responded to a 7-item open-ended interview, which was recorded and transcribed verbatim. We used content analysis to identify themes in the participants' responses. RESULTS: Themes identified included reason for admission, hospital experiences, and discharge expectations. Pain was the primary reason for admission for participants with SCD (n = 15) and for most participants with cancer (n = 10). Participants of both groups indicated that they experienced delayed treatment and a lack of communication. Participants with SCD also reported accusations of drug-seeking behavior, perceived mistreatment, and feeling of not being heard or believed. Participants from both groups verbalized concerns about well-being after discharge and hopeful expectations. CONCLUSIONS: Race-concordant participants with SCD but not with cancer communicated perceived bias from healthcare providers. IMPLICATIONS FOR PRACTICE: Practice change interventions are needed to improve patient-provider interactions, reduce implicit bias, and increase mutual trust, as well as facilitate more effective pain control, especially for those who with SCD.

The Value of Integrating Fluorescent Imaging and Immunohistochemistry for Future Anatomical Studies in Aesthetic Surgery: Lessons From the Cerebrospinal Fluid Circulatory System of Human Nerves and Brain.

BACKGROUND: During their work on the cerebrospinal fluid (CSF) circulatory system of human nerves and brain, the authors applied imaging and tissue techniques that complemented basic anatomical dissection. OBJECTIVES: The authors sought to show how integrating fluorescent imaging and basic immunohistochemistry (IHC) with facial anatomy can address current problems in aesthetic surgery. METHODS: The authors developed an algorithm and a set of principles from their work on the CSF circulatory system and applied these to 3 problems in aesthetic surgery: the functional anatomy of the vermilion-cutaneous junction; chemosis; and the functional anatomy of periosteal fixation. RESULTS: Integrating fluorescent imaging and IHC with anatomical dissection characterizes structural and functional anatomy. Fluorescent imaging helps to identify and locate easily missed structures. IHC defines cell type and function. The vermilion-cutaneous junction is defined by a major lymphatic vessel. Lymphatic flow from the medial limbus to the lateral canthus suggests the etiology of chemosis. Periosteal sites of fixation prevent shear where dural CSF vessels drain directly to subcutaneous lymphatics. CONCLUSIONS: Integrating anatomical dissection with fluorescent imaging and basic IHC characterizes structural and functional anatomy and helps to better understand many problems encountered in aesthetic surgery.

Repurposing Tranexamic Acid as an Anticancer Agent.

Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-N-acetylglucosaminidase. It is characterized by severe and complex central nervous system degeneration. Effective therapies will likely target early onset disease and overcome the blood-brain barrier. Modifications of adeno-associated viral (AAV) vector capsids that enhance transduction efficiency have been described in the retina. Herein, we describe for the first time, a transduction assessment of two intracranially administered adeno-associated virus serotype 8 variants, in which specific surface-exposed tyrosine (Y) and threonine (T) residues were substituted with phenylalanine (F) and valine (V) residues, respectively. A double-mutant (Y444 + 733F) and a triple-mutant (Y444 + 733F + T494V) AAV8 were evaluated for their efficacy for the potential treatment of MPS IIIB in a neonatal setting. We evaluated biodistribution and transduction profiles of both variants compared to the unmodified parental AAV8, and assessed whether the method of vector administration would modulate their utility. Vectors were administered through four intracranial routes: six sites (IC6), thalamic (T), intracerebroventricular, and ventral tegmental area into neonatal mice. Overall, we conclude that the IC6 method resulted in the widest biodistribution within the brain. Noteworthy, we demonstrate that GFP intensity was significantly more robust with AAV8 (double Y-F + T-V) compared to AAV8 (double Y-F). This provides proof of concept for the enhanced utility of IC6 administration of the capsid modified AAV8 (double Y-F + T-V) as a valid therapeutic approach for the treatment of MPS IIIB, with further implications for other monogenic diseases.