Patient and provider factors associated with the noninitiation of tamoxifen for young women at high-risk for the development of breast cancer.

We sought to identify factors associated with disparities in tamoxifen utilization among young patients at high-risk for developing breast cancer. We identified 67 premenopausal, high-risk women age 35-45, without surgical prophylaxis, who did not initiate tamoxifen. Factors associated with noninitiation were examined. About 37% of patients had no documented provider-based discussion regarding initiation. Type of high-risk diagnosis was the only factor associated with a provider-based discussion (P = .03). For patients offered tamoxifen, primary reasons for noninitiation were perceived minimal benefit (66.7%), fertility concerns (16.7%), and concerns about side effects (7.1%). Implementation of comprehensive educational strategies regarding the benefits of tamoxifen should be facilitated to improve initiation among young high-risk patients.

CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients.

BACKGROUND: Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear. METHODS: We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant. RESULTS: The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers. CONCLUSIONS: Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.

Subclinical inflammation phenotypes and long-term outcomes after pediatric kidney transplantation.

The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.

Decreasing deceased donor transplant rates among children (≤6 years) under the new kidney allocation system.

The Kidney Allocation System (KAS) was implemented in December 2014 with unknown impact on the pediatric waitlist. To understand the effect of KAS on pediatric registrants, deceased donor kidney transplant (DDKT) rate was assessed using interrupted time series analysis and time-to-event analysis. Two allocation eras were defined with an intermediary washout period: Era 1 (01/01/2013-09/01/2014), Era 2 (09/01/2014-03/01/2015), and Era 3(03/01/2015-03/01/2017). When using Cox proportional hazards, there was no significant association between allocation era and DDKT likelihood as compared to Era 1 (Era 3: aHR: 1.07, 95% CI: 0.97-1.18, P = .17). However, this was not consistent across all subgroups. Specifically, while highly sensitized pediatric registrants were consistently less likely to be transplanted than their less sensitized counterparts, this disparity was attenuated in Era 3 (Era 1 aHR: 0.04, 95%CI: 0.01-0.14, P < .001; Era 3 aHR: 0.33, 95% CI: 0.21-0.53, P < .001) whereas the youngest registrants aged 0-6 experienced a 21% decrease in DDKT likelihood in Era 3 as compared to Era 1 (aHR: 0.79, 95% CI: 0.64-0.98, P = .03). Thus, while overall DDKT likelihood remained stable with the introduction of KAS, registrants ≤ 6 years of age were disadvantaged, warranting further study to ensure equitable access to transplantation.

Investigation of health inequities in maternal and neonatal outcomes of patients with placenta accreta spectrum: a multicenter study.

BACKGROUND: Placenta accreta spectrum is associated with significant maternal and neonatal morbidity and mortality. There is limited established data on healthcare inequities in the outcomes of patients with placenta accreta spectrum. OBJECTIVE: This study aimed to investigate health inequities in maternal and neonatal outcomes of pregnancies with placenta accreta spectrum. STUDY DESIGN: This multicentered retrospective cohort study included patients with a histopathological diagnosis of placenta accreta spectrum at 4 regional perinatal centers between January 1, 2013, and June 30, 2022. Maternal race and ethnicity were categorized as either Hispanic, non-Hispanic Black, non-Hispanic White, or Asian or Pacific Islander. The primary outcome was a composite adverse maternal outcome: transfusion of ≥4 units of packed red blood cells, vasopressor use, mechanical ventilation, bowel or bladder injury, or mortality. The secondary outcomes were a composite adverse neonatal outcome (Apgar score of <7 at 1 minute, morbidity, or mortality), gestational age at placenta accreta spectrum diagnosis, and planned delivery by a multidisciplinary team. Multivariable logistic regression was used to estimate the associations of race and ethnicity with maternal and neonatal outcomes. RESULTS: A total of 408 pregnancies with placenta accreta spectrum were included. In 218 patients (53.0%), the diagnosis of placenta accreta spectrum was made antenatally. Patients predominantly self-identified as non-Hispanic White (31.6%) or non-Hispanic Black (24.5%). After adjusting for institution, age, body mass index, income, and parity, there was no difference in composite adverse maternal outcomes among the racial and ethnic groups. Similarly, adverse neonatal outcomes, gestational age at prenatal diagnosis, rate of planned delivery by a multidisciplinary team, and cesarean hysterectomy were similar among groups. CONCLUSION: In our multicentered placenta accreta spectrum cohort, race and ethnicity were not associated with inequities in composite maternal or neonatal morbidity, timing of diagnosis, or planned multidisciplinary care. This study hypothesized that a comparable incidence of individual risk factors for perinatal morbidity and geographic proximity reduces potential inequities that may exist in a larger population.

Serum urate: a biomarker or treatment target in pediatric hypertension?

PURPOSE OF REVIEW: Studies have shown an association between hyperuricemia and essential hypertension in children, presenting the possibility for serum uric acid level to serve as a biomarker for diagnosis and potential treatment target. RECENT FINDINGS: The proposed mechanism of uric acid-induced hypertension is biphasic, with a reversible early phase, implying added significance for new-onset hypertension. Current evidence shows a strong correlation between uric acid level and essential hypertension, supporting its use in diagnosis. Small studies have shown that the use of uric acid-lowering agents allopurinol and probenecid can lower blood pressure in adolescents. These medications require further study in large populations and careful consideration of their side-effect profiles prior to clinical use as antihypertensive agents. Recent studies have also linked dietary fructose intake to hyperuricemia and hypertension, but the clinical effect of fructose reduction on blood pressure has not been confirmed. SUMMARY: Current evidence supports use of serum uric acid level as a biomarker for diagnosis of essential hypertension in children. More research is needed to evaluate the utility of pharmacologic and nonpharmacologic means of serum uric acid reduction prior to clinical use as a therapy for hypertension.

Influence of Kidney Transplant Status on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage.

STUDY DESIGN: To assess whether warfarin dose requirement, anticoagulation control, and risk of hemorrhage differ in kidney transplant recipients (KTRs) compared with patients without kidney transplants (non-KTRs). DESIGN: Analysis of data from the Warfarin Pharmacogenetics Cohort, a prospective cohort of first-time warfarin users followed at two anticoagulation clinics. SETTING: Two outpatient anticoagulation clinics at two large, academic, tertiary care hospitals. PATIENTS: Adults aged 20 years or older starting warfarin for anticoagulation with a therapeutic international normalized ratio (INR) goal of 2-3 who were KTRs (n=65) or non-KTRs (n=1630). MEASUREMENTS AND MAIN RESULTS: Warfarin dose requirement, anticoagulation control, and risk of hemorrhage were assessed in each group. KTRs required an approximately 20% lower warfarin dose (4.7 vs 5.6 mg/day, p=0.0005) compared with non-KTRs. Genetic variants had similar effects on dose in both groups. Mean percentage of time in therapeutic range (PTTR) was similar among KTRs and non-KTRs. Although the proportion of patients achieving good anticoagulation control (PTTR ≥ 60%) was low in both groups, it was similar among KTRs and non-KTRs. KTRs had a higher risk of major hemorrhage (hazard ratio 2.1, p=0.0081), but this difference was not statistically significant after controlling for kidney function, clinical, and genetic factors. CONCLUSION: KTRs initiating warfarin require lower doses and closer monitoring to optimize anticoagulation therapy. Additional studies are needed to confirm these findings.

Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable ß-catenin Overexpression and a ß-catenin Mutation.

Objective Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options. Methods We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We performed immunohistochemical stains for ß-catenin on paraffin-embedded tissue on the index tumor and a subsequent teratocarcinosarcoma. Online databases of cancer mutations (Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas) were accessed. Results We identified an activating p.S45F mutation in ß-catenin in our index sinonasal teratocarcinosarcoma. This mutation results in constitutive signaling in the Wnt/ß-catenin pathway. We confirmed ß-catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and a second patient. The p.S45F activating mutation was found in a variety of solid tumors, and accounts for 3.3 to 10.4% of all known ß-catenin mutations. Conclusion We identified a potential driver mutation in ß-catenin in a sinonasal teratocarcinosarcoma, resulting in ß-catenin overexpression. These findings suggest a role for the Wnt/ß-catenin pathway in sinonasal teratocarcinosarcoma tumorigenesis and a role for anti-ß-catenin targeted therapy.

Correlation of Crtc1/3-Maml2 fusion status, grade and survival in mucoepidermoid carcinoma.

OBJECTIVE: Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands. Tumor stage and grade have historically been important predictors of survival. An oncogenic CRTC1- or CRTC3-MAML2 gene fusion has been identified in a number of MECs. Historically, these gene fusions have been associated with lower grade tumors and better survival. However, reported gene fusion rates and prognosis varies widely across studies, and have not controlled for tumor grade. We sought to identify gene fusion rates and outcomes in our cohort of MEC patients. MATERIALS AND METHODS: An IRB-approved retrospective cohort of patients with MEC was identified at the University of Michigan. Clinical, histologic, and outcome data was collected from medical records. RNA was isolated from formalin fixed paraffin-embedded tumor sections, and qRT-PCR was performed to identify CRTC1/3-MAML2 gene fusions. Sanger sequencing of qRT-PCR products was used to confirm gene fusions. RESULTS: Overall, 90 patient MEC tumors were collected (58 low-grade, 25 intermediate-grade, and 7 high-grade). Gene fusions were identified in 59% (53/90) of tumors. On univariate and bivariate analysis, fusion status did not significantly associate with grade or survival. CONCLUSION: We have identified a high rate of CRTC1/3-MAML2 gene fusions in a large cohort of MEC. We do not identify any correlation between fusion status with tumor grade or survival. These findings suggest further characterization of MECs is needed before considering the CRTC1/3-MAML2 gene fusion as a prognostic biomarker. Additional genetic drivers may account for survival and grade in MECs.

Fibroblast growth factor family aberrations as a putative driver of head and neck squamous cell carcinoma in an epidemiologically low-risk patient as defined by targeted sequencing.

BACKGROUND: Targeted sequencing of patients with epidemiologically low-risk (ELR) head and neck squamous cell carcinoma (HNSCC) could help identify novel drivers or lost suppressors leading to precision medicine protocols and improved survival rates. METHODS: A patient with ELR-HNSCC was selected for targeted sequencing. We then assessed next generation sequencing cohorts from the Oncomine Powertool Database, which contains pan-cancer data from The Cancer Genome Atlas (TCGA). RESULTS: Targeted sequencing revealed fibroblast growth factor receptor-1 (FGFR1) amplifications as a putative driver of the patient's tumor. Patients with HNSCC from TCGA data demonstrated fibroblast growth factor (FGF) family mutations, rearrangements, or amplifications in over 35% of HNSCC cases, with a statistically significant higher frequency in African American populations. FGF alterations were unique from activating phosphatidylinositol 3-kinase (PIK3CA) mutations. CONCLUSION: Together, these data suggest that FGF signaling may be critical for a subset of patients with HNSCC independent of other known pathways and provides rationale for leveraging patients with ELR-HNSCC to define molecular subsets of high-risk HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1646-E1652, 2016.

Identification of Targetable ERBB2 Aberrations in Head and Neck Squamous Cell Carcinoma.

IMPORTANCE: ERBB2 (formerly HER2) is an important drug target in breast cancer, where anti-ERBB2 therapy has been shown to lead to improvements in disease recurrence and overall survival. ERBB2 status in head and neck squamous cell carcinoma (HNSCC) has not been well studied. Identification of ERBB2-positive tumors and characterization of response to ERBB2 therapy could lead to targeted treatment options in HNSCC. OBJECTIVE: To identify ERBB2 aberrations in HNSCCs and investigate the potential for ERBB2-targeted therapy in HNSCCs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case series of patients with laryngeal (42 tumor specimens) and oral cavity (94 tumor specimens) SCC enrolled in the University of Michigan Head and Neck Specialized Program of Research Excellence was conducted. Publicly available sequencing data (The Cancer Genome Atlas), as well as data from other studies, were reviewed to identify additional mutations and overexpression in ERBB2 in HNSCC. Established HNSCC cell lines were used for follow-up in vitro analysis. The study was conducted from October 1, 2014, to August 30, 2015. INTERVENTIONS: With the use of targeted, amplicon-based sequencing with the Oncomine Cancer Panel, the copy number and mutation status of commonly altered genes in HNSCCs were assessed. Immunohistochemical staining was performed on tissue microarrays of HNSCCs to assess the expression of ERBB2. Western blotting for HNSCC cell line ERBB2 expression and cell survival assays after treatment with ERBB2 inhibitors were performed. MAIN OUTCOMES AND MEASURES: The prevalence of ERBB2 genetic aberrations and ERBB2 overexpression in laryngeal and oral cavity SCCs, prevalence of ERBB2 aberrations in HNSCC in The Cancer Genome Atlas, ERBB2 protein expression in HNSCC cell lines, and response of HNSCC cell lines to targeted ERBB2 inhibitors. RESULTS: Of the 42 laryngeal SCC samples screened by targeted sequencing, 4 (10%) were positive for ERBB2 amplification. Two of these samples showed ERBB2 overexpression on immunohistochemistry. Two of the 94 oral cavity SCC samples (2%) were positive for ERBB2 on immunohistochemistry. Analysis of 288 patients from publicly available HNSCC sequencing data revealed 9 amplifications (3%) in ERBB2. Protein expression was variable across HNSCC cell lines, and a subset of these cell lines showed responsiveness to anti-ERBB2 therapy. CONCLUSIONS AND RELEVANCE: ERBB2 aberrations were identified in a subset of HNSCCs. These tumors may be responsive to targeted therapy against ERBB2. Screening for ERBB2 aberrations and applying targeted therapy in ERBB2-positive patients may be useful in personalized therapy trials, particularly in patients who are refractory to current treatment paradigms.