Infertility and risk of postmenopausal breast cancer in the women's health initiative.

PURPOSE: Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25 years of follow-up). METHODS: At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy. RESULTS: We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%). CONCLUSION: These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

Distinct sets of molecular characteristics define tumor-rejecting neoantigens.

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid.

Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to IPE (p = 0.004). We also noted that the methylation signal was significantly higher in IPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and indeterminate pleural effusion groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.

Preoperative quality of life at time of gynecologic surgery: considerations for postoperative management.

BACKGROUND: Patients presenting for gynecologic surgery are a heterogeneous group. Preoperative quality of life may be a useful tool to guide postoperative management. OBJECTIVE: This study aimed to examine the key drivers of preoperative quality of life to improve counseling and postoperative management. STUDY DESIGN: This study analyzed preoperative survey results from 154 participants using the following surveys: National Institutes of Health Toolbox Global Health v1.2, Gastrointestinal: Gas and Bloating v1.1 13a, Gastrointestinal: Diarrhea v1.0 6a, and Sexual Function and Satisfaction Brief Profile (Female) v2.0, Perceived Stress Scale, the Vaginal Assessment Scale, and the Vulvar Assessment Scale. Survey results in the form of T-scores were compared in patients with endometrial cancer and patients with benign gynecologic conditions using the Kruskal-Wallis test. The multivariate analysis was performed using linear regression to adjust the comparisons for age, body mass index, and comorbidity. RESULTS: Of the 154 patients, preoperative diagnosis was benign in 66% (n=102) and endometrial cancer in 34% (n=52). Patients with endometrial cancer were more likely to be older, non-White, in lower income brackets, have higher body mass index, and be postmenopausal (P<.05). Although preoperative global health scores were similar between benign and malignant cases (P>.05), when adjusted for age, the differences in global health quality of life between patients with benign gynecologic conditions and those with endometrial cancer became significant, because the endometrial cancer group was older than the benign group (P<.05). However, when adjusting for age, body mass index, and comorbidities (hypertension and diabetes), the differences were no longer significant (P>.05). Sexual interest was decreased in the patients with endometrial cancer both in the unadjusted and adjusted model; and vulvar complaints became significantly different between the groups when controlling for body mass index, age, and comorbidities (P<.05). CONCLUSION: Despite substantial differences in preoperative diagnosis, preoperative quality of life is highly influenced by age, body mass index, and comorbidities. Therefore, these factors should be explored in surgical outcomes and postoperative management trials.

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma.

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. It is the only known neuroendocrine tumor (NET) with a virus etiology. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens into normal human fibroblasts by performing RNA sequencing. Our findings suggested that the WNT signaling pathway plays a critical role in the development of MCC. To test this model, we bioinformatically evaluated various perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor potential in multiple cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium effectively targets multiple MCC vulnerabilities. Specifically, pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical WNT signaling pathways but also inhibits cancer cell growth by activating the p53-mediated apoptosis pathway, disrupting mitochondrial function, and inducing endoplasmic reticulum (ER) stress. Pyrvinium also effectively inhibits tumor growth in an MCC mouse xenograft model. These findings offer new avenues for the development of therapeutic strategies for neuroendocrine cancer and highlight the utility of pyrvinium as a potential treatment for MCC.

Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid.

Background: Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology malignant pleural effusion diagnosis is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. Results: This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), PPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to PPE (p = 0.004). We also noted that the methylation signal was significantly higher in PPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and paramalignant groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. Conclusions: The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.

Restoring Balance: a physical activity intervention for Native American cancer survivors and their familial support persons.

Introduction/Purpose: Exercise interventions among Native American cancer survivors are lacking, despite major cancer health disparities in survivorship. The purpose of this study was to evaluate a 12-week randomized controlled trial (RCT) of culturally tailored exercise on cancer risk biomarkers and quality of life among Native American cancer survivors and family members. Methods: Participants were randomized to immediate start versus 6-week waitlist control at two rural and two urban sites. Participants enrolled in a small feasibility pilot study (only cancer survivors evaluated, n=18; cohort 1) or larger efficacy pilot study where cancer survivors (n=38; cohort 2) and familial supporters (n=25; cohort 3) were evaluated concurrently. Resistance, aerobic, flexibility, and balance exercises were tailored by cultural experts representing ten tribes. Exercises was supervised on-site one day per week and continued in home-based settings two to five days per week. Fat mass, blood pressure, hemoglobin A1c, 6-min walk, sit-to-stand test, and quality of life (Patient-Reported Outcomes Measurement Information System Global Health short form and isolation subscale) were measured. Mixed effects models evaluated differences between RCT arms from baseline to 6 weeks, and 12-week intervention effects in combined arms. Results: There were no consistent differences at 6 weeks between randomized groups. Upon combining RCT arms, 6-min walk and sit-to-stand tests improved in all three cohorts by 12 weeks (both survivors and familial support persons, p<0.001); social isolation was reduced in all three cohorts (p≤0.05). Familial support persons additionally improved blood pressure and HbA1c (p≤0.05). Conclusion: Exercise improved cardiorespiratory fitness and physical function among Native American cancer survivors and familial supporters. A longer intervention may influence other important health outcomes among Native American survivors. Additional improvements demonstrated among Native American family members may have a meaningful impact on cancer prevention in this underserved population with shared heritable and environmental risks.

Oxylipins as Biomarkers for Aromatase Inhibitor-Induced Arthralgia (AIA) in Breast Cancer Patients.

Aromatase inhibitor-induced arthralgia (AIA) presents a major problem for patients with breast cancer but is poorly understood. This prospective study explored the inflammatory metabolomic changes in the development of AIA. This single-arm, prospective clinical trial enrolled 28 postmenopausal women with early-stage (0-3) ER+ breast cancer starting adjuvant anastrozole. Patients completed the Breast Cancer Prevention Trial (BCPT) Symptom Checklist and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) at 0, 3, and 6 months. The plasma levels of four polyunsaturated fatty acids (PUFAs) and 48 oxylipins were quantified at each timepoint. The subscores for WOMAC-pain and stiffness as well as BCPT-total, hot flash, and musculoskeletal pain significantly increased from baseline to 6 months (all p < 0.05). PUFA and oxylipin levels were stable over time. The baseline levels of 8-HETE were positively associated with worsening BCPT-total, BCPT-hot flash, BCPT-musculoskeletal pain, WOMAC-pain, and WOMAC- stiffness at 6 months (all p < 0.05). Both 9-HOTrE and 13(S)-HOTrE were related to worsening hot flash, and 5-HETE was related to worsening stiffness (all p < 0.05). This is the first study to prospectively characterize oxylipin and PUFA levels in patients with breast cancer starting adjuvant anastrozole. The oxylipin 8-HETE should be investigated further as a potential biomarker for AIA.

EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons.

Dendritic spines are the postsynaptic compartment of a neuronal synapse and are critical for synaptic connectivity and plasticity. A developmental precursor to dendritic spines, dendritic filopodia (DF), facilitate synapse formation by sampling the environment for suitable axon partners during neurodevelopment and learning. Despite the significance of the actin cytoskeleton in driving these dynamic protrusions, the actin elongation factors involved are not well characterized. We identified the Ena/VASP protein EVL as uniquely required for the morphogenesis and dynamics of DF. Using a combination of genetic and optogenetic manipulations, we demonstrated that EVL promotes protrusive motility through membrane-direct actin polymerization at DF tips. EVL forms a complex at nascent protrusions and DF tips with MIM/MTSS1, an I-BAR protein important for the initiation of DF. We proposed a model in which EVL cooperates with MIM to coalesce and elongate branched actin filaments, establishing the dynamic lamellipodia-like architecture of DF.

Protein biomarkers in cervicovaginal lavages for detection of endometrial cancer.

BACKGROUND: Rates of endometrial cancer (EC) are increasing. For a definitive diagnosis, women undergo various time-consuming and painful medical procedures, such as endometrial biopsy with or without hysteroscopy, and dilation and curettage, which may create a barrier to early detection and treatment, particularly for women with inadequate healthcare access. Thus, there is a need to develop robust EC diagnostics based on non- or minimally-invasive sampling. The objective of this study was to quantify a broad range of immuno-oncology proteins in cervicovaginal lavage (CVL) samples and investigate these proteins as predictive diagnostic biomarkers for EC. METHODS: One hundred ninety-two women undergoing hysterectomy for benign or malignant indications were enrolled in this cross-sectional study. Classification of women to four disease groups: benign conditions (n = 108), endometrial hyperplasia (n = 18), low-grade endometrioid carcinoma (n = 53) and other EC subtypes (n = 13) was based on histopathology of biopsy samples collected after the surgery. CVL samples were collected in the operating room during the standard-of-care hysterectomy procedure. Concentrations of 72 proteins in CVL samples were evaluated using multiplex immunoassays. Global protein profiles were assessed using principal component and hierarchical clustering analyses. The relationships between protein levels and disease groups and disease severity were determined using Spearman correlation, univariate and multivariate receiver operating characteristics, and logistic regression analyses. RESULTS: Women with EC and benign conditions exhibited distinctive cervicovaginal protein profiles. Several proteins in CVL samples (e.g., an immune checkpoint protein, TIM-3, growth factors, VEGF, TGF-α, and an anti-inflammatory cytokine, IL-10) discriminated EC from benign conditions, particularly, when tested in combinations with CA19-9, CA125, eotaxin, G-CSF, IL-6, MCP-1, MDC, MCP-3 and TRAIL (sensitivity of 86.1% and specificity of 87.9%). Furthermore, specific biomarkers (e.g., TIM-3, VEGF, TGF-α, TRAIL, MCP-3, IL-15, PD-L2, SCF) associated with histopathological tumor characteristics, including histological type and grade, tumor size, presence and depth of myometrial invasion or mismatch repair protein status, implying their potential utility for disease prognosis or monitoring therapies. CONCLUSIONS: This proof-of-principle study demonstrated that cervicovaginal sampling coupled with multiplex immunoassay technology can offer a minimally to non-invasive method for EC detection.

Immunometabolic profiling of cervicovaginal lavages identifies key signatures associated with adenomyosis.

Adenomyosis is a burdensome gynecologic condition that is associated with pelvic pain, dysmenorrhea, and abnormal uterine bleeding, leading to a negative impact on quality of life; and yet is often left undiagnosed. We recruited 108 women undergoing hysterectomy for benign gynecologic conditions and collected non-invasive cervicovaginal lavage samples for immunometabolic profiling. Patients were grouped according to adenomyosis status. We investigated the levels of 72 soluble immune proteins and >900 metabolites using multiplex immunoassays and an untargeted global metabolomics platform. There were statistically significant alterations in the levels of several immune proteins and a large quantity of metabolites, particularly cytokines related to type II immunity and amino acids, respectively. Enrichment analysis revealed that pyrimidine metabolism, carnitine synthesis, and histidine/histamine metabolism were significantly upregulated pathways in adenomyosis. This study demonstrates utility of non-invasive sampling combined with immunometabolic profiling for adenomyosis detection and a greater pathophysiological understanding of this enigmatic condition.

Visceral adipose tissue and cardiometabolic risk factors in young Hispanic and non-Hispanic girls.

Background: Risk factors for cardiometabolic diseases (e.g., type 2 diabetes, cardiovascular disease) can begin developing in childhood. Elevated body mass index (BMI) is associated with greater likelihood of developing such diseases; however, this relationship varies by race and ethnicity. Notably, Hispanics tend to have high rates of obesity and are disproportionately affected by type 2 diabetes. We aimed to determine if visceral adiposes tissue (VAT) is associated with cardiometabolic risk factors (i.e., triglycerides, cholesterol, insulin resistance, C-reactive protein, and blood pressure), independent of BMI percentile, in a sample of primarily Hispanic adolescent girls. Methods and results: A total of 337 girls (73% Hispanic) took part in the cross-sectional study. Hispanic girls generally had greater BMI percentile, VAT, and cardiometabolic risk factors compared to non-Hispanic girls. Multiple linear regression was used to assess the relationships between Dual-energy X-ray Absorptiometry (DXA)-derived VAT and cardiometabolic outcomes, controlling for BMI percentile (<85th percentile or ≥85th percentile), age, ethnicity (Hispanic/non-Hispanic), and Tanner stage. Significant interactions between VAT and BMI percentile were identified for almost all cardiometabolic outcomes. Upon stratification, the association between VAT and cardiometabolic outcomes was strongest in girls ≥85th BMI percentile, as compared to girls <85th percentile. However, VAT was only significantly associated with higher triglycerides (girls ≥85th percentile) and higher insulin resistance (both BMI percentiles) after stratification. Conclusion: VAT was associated with increased triglycerides and insulin resistance in girls with overweight or obesity. These findings warrant further investigation between VAT and cardiometabolic health in Hispanic adolescents who tend to accumulate more adipose tissue during adolescence.

Association of low serum albumin with venous thrombosis in pediatric patients.

OBJECTIVES: The incidence of venous thromboembolism (VTE) in children is increasing, attributed in part to increased utilization of central venous catheters (CVCs). Children with protein losing disorders (PLDs) and low serum albumin may have an increased incidence of thrombosis. We sought to determine the prevalence of PLDs and hypoalbuminemia at the time of diagnosis of VTE in pediatric patients and its relationship to central venous catheters. METHODS: We performed a single institution retrospective study of 65 consecutive hospitalized pediatric patients with an acute VTE. Data collected included clinical diagnoses, type of thrombosis, presence or absence of a CVC, and serum albumin level, if available. RESULTS: Of 65 patients with acute VTE, 51 % (33/65) had catheter-related thrombosis (CRT), including 71 % (19/27) of patients <12 years of age and 37 % (14/38) of patients aged 12 to 23 (P = 0.008). Eleven VTEs occurred in patients with a diagnosis of a PLD; of these, ten (91 %) were CRT and one (9 %) was a non-CRT (P = 0.003). Serum albumin levels obtained within four days of diagnosis of VTE were available for 38 patients. An albumin level below the lower limit of the age-adjusted normal reference range was documented in 27/38 (71 %) patients with VTE compared to 1011/3028 (33 %) of all pediatric patients admitted to the hospital during a two-year period (P < 0.0001). Albumin levels were low in 19/22 (86 %) patients with CRT compared with 8/16 (50 %) patients with non-CRT (P = 0.019). CONCLUSION: Low serum albumin levels are highly prevalent among pediatric patients with VTE, especially in those patients with CRT.

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens. There is variable GILT protein expression in malignant melanocytes in melanoma specimens. High GILT mRNA expression in melanoma specimens is associated with improved overall survival, before the advent of immune checkpoint inhibitors (ICI). However, the association of GILT in metastatic melanoma with survival in patients treated with ICI and the cell type expressing GILT associated with survival have not been determined. Using RNA sequencing datasets, high GILT mRNA expression in metastatic melanoma specimens was associated with improved progression-free and overall survival in patients treated with ICI. A clinical dataset of metastatic melanoma specimens was generated and annotated with clinical information. Positive GILT immunohistochemical staining in antigen presenting cells and melanoma cells was observed in 100% and 65% of metastatic melanoma specimens, respectively. In the subset of patients treated with ICI in the clinical dataset, high GILT protein expression within melanoma cells was associated with improved overall survival. The association of GILT mRNA and protein expression with survival was independent of cancer stage. These studies support that high GILT mRNA expression in bulk tumor samples and high GILT protein expression in melanoma cells is associated with improved survival in ICI-treated patients. These findings support further investigation of GILT as a biomarker to predict the response to ICI.

Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation.

Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.

Diet Quality Following Food Pantry Visit Differs by Ethnicity.

Food insecurity is associated with poor diet quality and increased diet-related disease risk. Food pantry clients (n=194) completed one 24-hour dietary recall and the Healthy Eating Index-2015 was used to evaluate diet quality. Differences in diet quality relative to participants' last food pantry visit and self-reported ethnicity were evaluated using two-way ANOVA. Food pantry visits within 1-4 days compared to ≥5 days were associated with higher diet quality in non-Hispanics (p=0.01) but diet quality remained the same in Hispanics. Interventions to improve diet quality in food pantry users must consider potential ethnic differences when program planning.

Ambient UVR and Environmental Arsenic Exposure in Relation to Cutaneous Melanoma in Iowa.

Intermittent sun exposure is the major environmental risk factor for cutaneous melanoma (CM). Cumulative sun exposure and other environmental agents, such as environmental arsenic exposure, have not shown consistent associations. Ambient ultraviolet radiation (UVR) was used to measure individual total sun exposure as this is thought to be less prone to misclassification and recall bias. Data were analyzed from 1096 CM cases and 1033 controls in the Iowa Study of Skin Cancer and Its Causes, a population-based, case-control study. Self-reported residential histories were linked to satellite-derived ambient UVR, spatially derived environmental soil arsenic concentration, and drinking water arsenic concentrations. In men and women, ambient UVR during childhood and adolescence was not associated with CM but was positively associated during adulthood. Lifetime ambient UVR was positively associated with CM in men (OR for highest vs. lowest quartile: 6.09, 95% confidence interval (CI) 2.21-16.8), but this association was not as strong among women (OR for highest vs. lowest quartile: 2.15, 95% CI 0.84-5.54). No association was detected for environmental soil or drinking water arsenic concentrations and CM. Our findings suggest that lifetime and adulthood sun exposures may be important risk factors for CM.

Feasibility Trial to Evaluate Tendon Stiffness Obtained from Shear Wave Elastography Imaging as a Biomarker of Aromatase Inhibitor-Induced Arthralgias.

Aromatase inhibitor-induced arthralgia (AIA) comprises significant, activity-limiting musculoskeletal symptoms, including joint pain, myalgia, and joint stiffness. We conducted a prospective feasibility study in postmenopausal women diagnosed with early-stage (0-3) hormone receptor positive (HR+) breast cancer who were candidates for treatment with adjuvant AI therapy (n = 16). Tendons of the hands and wrists and the median nerve were imaged using gray-scale and power Doppler ultrasound (US) and US SWE. Arthralgia symptoms were evaluated using the Breast Cancer Prevention Trial (BCPT) Symptom Checklist musculoskeletal subscale (MS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness subscales. At baseline, there were significant differences in the SW velocities of tendons between dominant and nondominant hands. Increased velocity in 2 of 6 tendons and the median nerve was associated with greater pain at baseline, whereas slower velocity of the extensor digitorum tendon (suggesting decreased stiffness) was associated with a higher WOMAC stiffness score. Increased SW velocity (suggestive of increased stiffness) at baseline in the abductor pollicis longus tendon was associated with a worsening of all three pain and stiffness measures by 6 months. Future studies should evaluate SWE scores related to AIA outcomes in a larger sample size.

Liquid biopsy, using a novel DNA methylation signature, distinguishes pancreatic adenocarcinoma from benign pancreatic disease.

We tested the ability of a novel DNA methylation biomarker set to distinguish metastatic pancreatic cancer cases from benign pancreatic cyst patients and to monitor tumor dynamics using quantitative DNA methylation analysis of cell-free DNA (cfDNA) from blood samples. The biomarkers were able to distinguish malignant cases from benign disease with high sensitivity and specificity (AUC = 0.999). Furthermore, the biomarkers detected a consistent decline in tumor-derived cfDNA in samples from patients undergoing chemotherapy. The study indicates that our liquid biopsy assay could be useful for management of pancreatic cancer patients.