Joanne Knight Breast Health Cohort at Siteman Cancer Center.

PURPOSE: The Joanne Knight Breast Health Cohort was established to link breast cancer risk factors, mammographic breast density, benign breast biopsies and associated tissue markers, and blood markers in a diverse population of women undergoing routine mammographic screening to study risk factors and validate models for breast cancer risk prediction. METHODS: Women were recruited from November 2008 to April 2012 through the mammography service at the Joanne Knight Breast Health Center at Washington University in St. Louis, Missouri. Baseline questionnaire risk factors, blood, and screening mammograms were collected from 12,153 women. Of these, 1,672 were excluded for prior history of any cancer (except non-melanoma skin) or diagnosis of breast cancer within 6 months of blood draw/registration for the study, for a total of 10,481 women. Follow-up is through linking to electronic health records, tumor registry, and death register. Routine screening mammograms are collected every 1-2 years and incident benign breast biopsies and cancers are identified through record linkage to pathology and tumor registries. Formal fixed tissue samples are retrieved and stored for analysis. County-level measures of structural inequality were derived from publicly available resources. RESULTS: Cohort Composition: median age at entry was 54.8 years and 26.7% are African American. Through 2020, 74% of participants have had a medical center visit within the past year and 80% within the past 2 years representing an average of 9.7 person-years of follow-up from date of blood draw per participant. 9,997 women are continuing in follow-up. Data collected at baseline include breast cancer risk factors, plasma and white blood cells, and mammograms prior to baseline, at baseline, and during follow-up. CONCLUSION: This cohort assembled and followed in a routine mammography screening and care setting that serves a diverse population of women in the St. Louis region now provides opportunities to integrate study of questionnaire measures, plasma and DNA markers, benign and malignant tissue markers, and repeated breast image features into prospective evaluation for breast cancer etiology and outcomes.

Prevalence of hearing screening failures in low-risk childhood cancer survivors.

BACKGROUND: We sought to estimate the frequency of hearing screening failures in pediatric cancer survivors at low risk for hearing loss and evaluate the feasibility of administering screenings in this population. PROCEDURE: Survivors in the St. Louis Children's Hospital Late Effects Clinic were recruited. Eligibility included (a) diagnosis of a pediatric cancer treated without platinum chemotherapy or cranial radiation, (b) at least 6 months from completion of therapy, (c) between the ages of 7 and 18 years, (d) cognitively/behaviorally able to participate, and (e) English speaking. Behavioral hearing screenings from 1000 to 8000 Hz were performed by trained personnel using a calibrated audiometer. A failed screen was defined by a participant not responding to two or more of the three screening attempts for at least one frequency in at least one ear. RESULTS: One hundred nine patients met eligibility criteria with 78 enrolled (71.5%). Diagnoses included leukemia (57.7%), sarcoma (11.5%), Wilms tumor (14.1%), lymphoma (12.8%), and other solid tumors (3.9%). The median age was 13.2 years (Q1-Q3: 9.6-15.4) and the median time from treatment completion was 3.7 years (Q1-Q3: 2.3-7.4). Eighteen patients (23%) failed the hearing screen (95% CI: 14%-34%). No demographic or treatment-related variables were significantly correlated to screening failure. Six screen failures (33%) underwent formal audiology assessments, with three demonstrating unilateral hearing loss: two conductive and one sensorineural. CONCLUSIONS: A significant fraction of pediatric cancer survivors at low risk for hearing loss failed hearing screening. Broader use of hearing screening should be considered.

Anti-CD47 monoclonal antibody therapy reduces ischemia-reperfusion injury of renal allografts in a porcine model of donation after cardiac death.

We investigated whether blockade of the CD47 signaling pathway could reduce ischemia-reperfusion injury (IRI) of renal allografts donated after cardiac death (DCD) in a porcine animal model of transplantation. Renal allografts were subjected to 30 minutes of warm ischemia, 3.5 hours of cold ischemia, and then perfused with a humanized anti-CD47 monoclonal antibody (CD47mAb) in the treatment group or HTK solution in the control group (n = 4/group). The animals were euthanized five days after transplantation. At the time of reperfusion, indocyanine green-based in vivo imaging showed that CD47mAb-treated organs had greater and more uniform reperfusion. On post-transplant days 3-5, the treatment group had lower values compared to the control for creatinine and blood urea nitrogen. Histological examination of allograft tissues showed a significant decrease of acute tubular injury in the CD47mAb-treated group compared to control. Compared to the control group, CD47mAb treatment significantly decreased genes expression related to oxidative stress (sod-1, gpx-1, and txn), the inflammatory response (il-2, il-6, inf-g, and tgf-b), as well as reduced protein levels of BAX, Caspase-3, MMP2, and MMP9. These data demonstrate that CD47mAb blockade decreases IRI and subsequent tissue injury in DCD renal allografts in a large animal transplant model.

Evaluation of [89Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer.

PURPOSE: To evaluate whether tumor uptake of [89Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer. METHODS: Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 ± 2 days following [89Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [89Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUVmax), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [89Zr]trastuzumab uptake was evaluated. RESULTS: On a per-patient basis, [89Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2-positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUVmax was not significantly different in patients with HER2-positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUVmax was significantly higher in HER2-positive compared to HER2-negative patients (p = 0.003). A cutoff SUVmax of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2-positive from HER2-negative lesions. There was intrapatient heterogeneity of [89Zr]trastuzumab uptake in 20% of patients with multiple lesions. CONCLUSIONS: [89Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.

Yield of Cytology Surveillance After High-Grade Vulvar Intraepithelial Neoplasia or Cancer.

OBJECTIVES: The aim of the study was to estimate the risk of high-grade cervical and vaginal intraepithelial neoplasia (CIN/VAIN 2+) and cancer among women treated surgically for high-grade vulvar intraepithelial neoplasia (HGVIN) and vulvar cancer. MATERIALS AND METHODS: We performed a retrospective cohort study of women who underwent surgery for HGVIN/vulvar cancer between 2006 and 2010. Univariate and multivariate analyses using stepwise selection were used to identify correlates of abnormal cytology after treatment for VIN and vulvar cancer. RESULTS: Among 191 women under surveillance for a median of 3.7 years who underwent treatment for HGVIN/vulvar cancer, primary vulvar lesions included VIN 2 (10, 5%), VIN 3 (102, 53%), and carcinoma (79, 41%). During follow-up, 71 (37%) had abnormal cytology, including 47 (25%) low grade, 23 (12%) high grade, and 1 (0.5%) carcinoma. Subsequent risk for VAIN 2+ was 11% (6/57) after previous hysterectomy and 8% for CIN 2+ (10/124) with intact cervix. Overall risk for CIN 3+ was 5%. Correlates of high-grade cytology after treatment for HGVIN/vulvar cancer included nonwhite race (odds ratio [OR] = 3.3, 95% CI = 1.50-7.36), immunodeficiency (OR = 4.2, 95% CI = 1.76-9.94), and previous abnormal cytology (OR = 2.7, 95% CI = 1.29-5.78). Stepwise multivariate analysis revealed immunosuppression as the only significant correlate of high-grade cytology after vulvar treatment (adjusted OR = 3.7, 95% CI = 1.26-10.83). CONCLUSIONS: Women with HGVIN/cancer should have cervical/vaginal cytology before vulvar surgery. Those with a negative cervical or vaginal cytology result should undergo cytology testing at 1- to 3-year intervals, based on the threshold for CIN 3+ set forth by the American Society for Colposcopy and Cervical Pathology.

Gender Differences in Wear Rates for 28- vs 32-mm Ceramic Femoral Heads on Modern Highly Cross-linked Polyethylene at Midterm Follow-Up in Young Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: We report on the midterm linear and volumetric wear of highly cross-linked polyethylene (HXLPE) and survivorship of 2 prospective young total hip arthroplasty (THA) cohorts that differed by the size of ceramic femoral head used: 28 vs 32 mm. METHODS: We prospectively analyzed 220 consecutive primary THAs in patients aged ≤50 years who received a cementless THA with a ceramic femoral head on HXLPE liner (C-HXLPE). There were 101 patients (46%) with 28-mm heads and 119 patients (54%) who received 32-mm heads at a mean follow-up of 5.5 years (range, 60-109 months). Wear was calculated using Martell Software. RESULTS: The 28-mm C-HXLPE cohort demonstrated average linear and volumetric wear of 0.020 mm/y (standard deviation [SD], 0.074; 95% CI, 0.003-0.037) and 18.775 mm(3)/y (SD, 21.743; 95% CI, 13.773-23.778) compared with 0.032 mm/y (SD, 0.087; 95% CI, 0.013-0.050]) and 29.847 mm(3)/y (SD, 35.441; 95% CI, 22.294-37.401) in the 32-mm C-HXLPE group. Subgroup analysis by gender and head size discovered significantly greater wear in females with 32-mm heads compared with 28-mm heads in both linear (0.01, 95% CI = -0.014 to 0.033 vs 0.048, 95% CI = 0.022-0.074 mm/y, P = .004) and volumetric wear (14.11, 95% CI = 8.957-19.271] vs 29.71, 95% CI = 17.584-41.840] mm(3)/y, P = .009). We found a 96% (95% CI = 92.30%-97.94%]) survivorship by Kaplan-Meier analysis at minimum 5 years with no failures because of osteolysis. CONCLUSIONS: Ceramic on HXLPE demonstrates extremely low wear properties in young patients at midterm follow-up. We identified a gender-dependent difference in wear based on head size, with 32-mm heads being associated with increased wear in females.

Preoperative Joint Space Width Predicts Patient-Reported Outcomes After Total Hip Arthroplasty in Young Patients.

BACKGROUND: In a new health care economy, there is an emerging need to understand and quantify predictors of total hip arthroplasty (THA) outcomes. We investigated the association between preoperative radiographic disease (as measured quantitatively by joint space width [JSW]) and patient-reported function, activity, pain, and quality of life after THA. METHODS: We retrospectively analyzed 146 patients (146 hips) 55 years or younger with a diagnosis of osteoarthritis who underwent cementless THA between January 2009 and December 2010. Preoperative pelvic radiographs were measured by 1 author blinded to clinical outcomes to establish JSW, defined as the shortest distance between the femoral head margin and the superolateral weight-bearing portion of the acetabulum. The JSW value was treated as a continuous variable when applied to statistical modeling. The relationship between the JSW and the improvement of clinical outcome was examined via a general linear modeling approach with adjustments for patients' age, body mass index, and sex. RESULTS: We identified an inverse relationship between preoperative JSW and improvements in functional, activity, pain, and quality of life. We found that, as JSW decreased by 1 mm, the outcome measure improvements were modified Harris Hip Score of 6.3 (p<0.001); SF-12 physical: 2.1 (p=0.027); WOMAC-pain: 4.8 (p=0.01); and UCLA Activity: 0.44 (p=0.02). CONCLUSIONS: Our results demonstrate that patients with greater preoperative joint space have less predictable improvement in terms of function, pain relief, and activity. These findings suggest that THA in young patients with a JSW less than 1.5 to 2 mm provides more predictable improvements in pain and functional outcomes.

High-Grade Cervical Dysplasia After Negative Loop Electrosurgical Excision Procedure.

OBJECTIVES: To describe the prevalence and correlates of high-grade cervical intraepithelial neoplasia (CIN2+) after a negative loop electrosurgical excision procedure (LEEP), performed for high-grade squamous intraepithelial lesion (HSIL) cervical cytology. METHODS: One hundred six women from our university-based colposcopy clinic underwent LEEP between 2007 and 2014. Negative LEEP was defined as CIN1 or less. Persistence/recurrence estimates were calculated by treatment (see-and-treat vs 3-step conventional strategy-cervical cytology, colposcopic biopsy, LEEP) and LEEP results (negative vs positive) using the Kaplan-Meier method. Predictors of CIN2+ after a negative LEEP were examined by multivariate Cox proportional hazards model. RESULTS: Overall, the prevalence of CIN2+ after a negative LEEP for HSIL was 14%. Persistence/recurrence of CIN2+ was similar between women with a negative and positive see-and-treat LEEP (25% vs 15%) and those with a negative or positive 3-step conventional LEEP (7% vs 22%) (log-rank, P = 0.58). Positive LEEP margin was more common among women with a positive LEEP (53.7% see-and-treat vs 42.6% conventional) compared with a negative result (0% see-and-treat vs 3.7% conventional, P < 0.0001). The risk of CIN2+ after a negative LEEP did not differ by management strategy (log-rank, P = 0.85) or LEEP result (log-rank, P = 0.58). In multivariate analysis, correlates of persistent/recurrent CIN2+ included older age (adjusted odds ratio [aOR], 1.09; P = 0.0003), history of previous LEEP (aOR, 8.99; P < 0.0001), and positive LEEP margin (aOR, 13.56; P = 0.0005). CONCLUSIONS: A negative LEEP does not allow less stringent surveillance, as CIN2+ risk is similar to that after CIN2+ is found in the LEEP specimen, whether the specimen was obtained by see-and-treat or conventional 3-step approach.

Comparison of brain structural variables, neuropsychological factors, and treatment outcome in early-onset versus late-onset late-life depression.

OBJECTIVE: To compare differences in gray matter volumes, white matter and subcortical gray matter hyperintensities, neuropsychological factors, and treatment outcome between early- and late-onset late-life depressed (LLD) subjects. METHODS: We conducted a prospective, nonrandomized, controlled trial at the outpatient clinics at Washington University and Duke University on 126 subjects, aged 60 years or older, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received neuropsychological testing and magnetic resonance imaging. Subjects were excluded for cognitive impairment or severe medical disorders. After 12 weeks of sertraline treatment, subjects' MADRS scores over time and neuropsychological factors were studied. RESULTS: Left anterior cingulate thickness was significantly smaller in the late-onset depressed group than in the early-onset LLD subjects. The late-onset group also had more hyperintensities than the early-onset LLD subjects. No differences were found in neuropsychological factor scores or treatment outcome between early-onset and late-onset LLD subjects. CONCLUSION: Age at onset of depressive symptoms in LLD subjects are associated with differences in cortical thickness and white matter and subcortical gray matter hyperintensities, but age at onset did not affect neuropsychological factors or treatment outcome.

Integration of Clinical Trial Development in Hematology-Oncology Fellowship Training.

PROBLEM: Several barriers to physicians becoming clinical investigators exist, including inexperience, lack of available mentors, and inconsistent instructive approaches with varying degrees of participation during training. These barriers cause fewer hematology-oncology fellows to pursue academic careers. A consensus is needed on structuring education in clinical investigation paired with active participation in development of a clinical trial guided by a mentor with the goal of increasing fellow interest in clinical research and pursuit of careers in academic medicine. APPROACH: The clinical trial development (CTD) program was initiated at Washington University School of Medicine in St. Louis in 2002 as a hands-on learning experience for hematology and oncology fellows in the design, implementation, and publication of clinical trials. Each fellow was required to identify a mentor and propose at least 1 prospective investigator-initiated clinical trial. OUTCOMES: At the time of data abstraction in July 2023, 118 fellows had participated in the CTD program and initiated protocols in a variety of areas according to their interests. Fellows were included in data abstraction if their fellowship began in 2002 through 2021; the program is ongoing, and the most recent class will graduate in 2024. Disease types were evenly distributed between solid tumor oncology (60 [51%]) or classic and malignant hematology (58 [49%]). Ninety-three fellows (79%) obtained institutional review board approval, and 60 (65%) published their results. Among graduating fellows, 67 (66%) secured an academic faculty appointment. Fellows with institutional review board-approved projects had significantly higher odds of obtaining an academic faculty appointment (odds ratio, 4.96; 95% confidence interval, 1.54, 15.98; P = .007).Next StepsNext steps will be to further evaluate the effect of the mentorship network on early career productivity of trainees that graduate and the feasibility of extending the program to another institution.

Outcomes in Patients with Spinal Metastases Managed with Surgical Intervention.

BACKGROUND: Spinal metastases are a significant cause of morbidity in patients with advanced cancer, and management often requires surgical intervention. Although prior studies have identified factors that influence outcomes with surgery, the ability of these factors to predict outcomes remains unclear in the era of contemporary therapies, and there is a need to better identify patients who are likely to benefit from surgery. METHODS: We performed a single-center, retrospective analysis to evaluate risk factors for poor outcomes in patients with spinal metastases treated with surgery. The primary outcome was mortality at 180 days. RESULTS: A total of 128 patients were identified. Age ≥ 65 years at surgery (p = 0.0316), presence of extraspinal metastases (p = 0.0110), and ECOG performance scores >1 (p = 0.0397) were associated with mortality at 180 days on multivariate analysis. These factors and BMI ≤ 30 mg/kg2 (p = 0.0008) were also associated with worse overall survival. CONCLUSIONS: Age > 65, extraspinal metastases, and performance status scores >1 are factors associated with mortality at 180 days in patients with spinal metastases treated with surgery. Patients with these factors and BMI ≤ 30 mg/kg2 had worse overall survival. Our results support multidisciplinary discussions regarding the benefits and risks associated with surgery in patients with these risk factors.

Corrigendum: Factors influencing delayed clearance of high dose methotrexate (HDMTX) in pediatric, adolescent, and young adult oncology patients.

[This corrects the article DOI: 10.3389/fonc.2023.1280587.].

Factors influencing delayed clearance of high dose methotrexate (HDMTX) in pediatric, adolescent, and young adult oncology patients.

Purpose: To identify modifiable risk factors associated with prolonged clearance of methotrexate in pediatric, adolescent, and young adult (AYA) oncology patients receiving high dose methotrexate (HDMTX). Design/Method: A single institution, retrospective chart review of patients receiving HDMTX between 2010-2017. Patients had a diagnosis of either leukemia or osteosarcoma. Data included demographics, concurrent intravenous (IV) medications, IV fluids (IVF) administered, urine output (UO), and rises in serum creatinine (RSC) reflective of renal toxicity (RT). Outcome measures included 1) delayed targeted MTX clearance (DC), 2) actual time to clearance (TTC) and 3) length of stay (LOS). Results: Data from 447 HDMTX administrations were analyzed. The sample consisted of 241 (54%) osteosarcoma encounters, and 206 (46%) leukemia encounters, with an average patient age of 12.7 years. Multivariate analysis showed that DC was associated with the diagnosis of leukemia (OR 7.64, p <.0001), and less UO on day 1 (OR 0.76, p=0.005). Increased TTC was associated with increasing age (RR 1.02, p<0.0001), higher 24-hour MTX levels (RR 1.001, p=0.012) and 48-hour MTX levels (RR 1.02, p<0.0001), RT (RR 1.004, p<0.0001), use of IV lorazepam (RR 1.08, p=0.001) and IV metoclopramide (RR 1.08, p<0.001) both on day 3. Like TTC, LOS was affected by MTX levels at 24 (RR 1.001, p=0.025) and 48 hours (RR 1.03, p<0.0001), RT (RR 1.006, p<0.0001), total IV medications on day 3 (RR 1.042, p<0.0001), and the use of leucovorin on day 2 (RR 0.93, p=0.002). Conclusion: Multiple modifiable risk factors were identified which can be leveraged to improve HDMTX clearance. Subsequent efforts will assess whether acting on such risk factors can improve MTX clearance and shorten LOS.

National Trends and Outcomes in Adolescents Undergoing Bariatric Surgery.

BACKGROUND: In the US, obesity continues to be a severe health issue now affecting adolescents. Bariatric surgery remains the most effective treatment for obesity, but use among adolescents remains low. The objective of this study was to identify current national trends in bariatric surgery among adolescents. STUDY DESIGN: Using the Nationwide Inpatient Sample database, adolescents aged 9 to 19 with a diagnosis of morbid obesity who underwent a laparoscopic gastric bypass (Roux-en-Y gastric bypass) or laparoscopic sleeve gastrectomy (SG) between 2015 and 2018 were identified. Demographics, comorbidities, and in-hospital complications were collected. National estimates were calculated. The trend of annual number of operations was determined by Kruskal-Wallis rank test. RESULTS: Between 2015 and 2018, 1,203 adolescents were identified, resulting in a nationwide estimate of 4,807 bariatric cases. The number of bariatric operations increased annually from 1,360 in 2015 to 1,740 operations in 2018 (p = 0.0771). The majority of patients were female (76%), 17 to 19 years old (84.1%), and White (47.9%). Most patients underwent SG (82.0%). Black and Hispanic patients comprised 40.2% of the cohort. Significant comorbidities included diabetes, dyslipidemia, nonalcoholic fatty liver disease, hypertension, and sleep apnea. The average length of stay decreased from 2.12 days to 1.64 days. There were no in-hospital mortalities, and complications were less than 1%. CONCLUSIONS: With the increasing prevalence of obesity among adolescents in the US, bariatric surgery increased over time but was performed less in patients younger than 16 years of age and racial minorities. Bariatric surgery among adolescents remains safe, with extremely low complication rates and zero in-hospital mortality.

Association of PET-based estradiol-challenge test for breast cancer progesterone receptors with response to endocrine therapy.

Estrogen receptor (ER) testing of breast cancer imperfectly predicts response to endocrine therapy (ET). We hypothesize that a brief estradiol challenge will increase tumor progesterone receptor (PgR) levels only in tumors with functional ER. In this prospective, phase 2, single-center, single-arm trial (NCT02455453), we report the association of response to ET with change in tumor uptake of the progestin analog, 21-[18F]fluorofuranylnorprogesterone (FFNP), before and after a one-day estradiol challenge. In 43 postmenopausal women with advanced ER+ breast cancer, we show a post-challenge increase in tumor FFNP uptake only in 28 subjects with clinical benefit from ET (responders), but not in 15 without clinical benefit (nonresponders) (p < 0.0001), indicating 100% sensitivity and specificity. We further show significantly longer survival (p < 0.0001) in the responding subjects. Our results demonstrate that change in tumor FFNP uptake after estradiol challenge is highly predictive of response to ET in women with ER+ breast cancer.

Cisplatin Ototoxicity: Examination of the Impact of Dosing, Infusion Times, and Schedules In Pediatric Cancer Patients.

BACKGROUND: Sensorineural hearing loss is a well-known side effect of cisplatin (CDDP). There is limited research on the effect of dosing, infusion times, and schedules of cisplatin administration and their impact on hearing loss. METHODS: A retrospective review of 993 pediatric patients' medical and audiological charts from August 1990 to March 2015 was conducted using stringent inclusion criteria to characterize patients with hearing loss. 248 of these patients received CDDP. Of these, 216 patients had sufficient CDDP infusion data to assess for sensorineural hearing loss attributable to CDDP and its associated risk factors. Chart reviews were performed to extract clinical data including CDDP dosing information. Demographic and clinical characteristics were summarized by descriptive statistics, and univariate and multivariate logistic regressions were performed to examine the relationship between hearing loss and specific parameters of cisplatin administration (amount infused per dose, prescribed infusion time, total number of doses, number of doses per cycle, number of cycles, cumulative cisplatin exposure). Stepwise variable selection procedure was performed in the multivariate model building to extract the best subset of risk factors for the prediction of hearing loss and worsening ototoxicity grade using an established ototoxicity grading scale from the International Society of Pediatric Oncology (SIOP). RESULTS: A total of 153 patients with complete medical and audiologic data were evaluable for analysis. Hearing loss was identified in 72.6% of the patients. Multivariate analysis revealed that age [OR=0.90 (0.84-0.97), p-value=0.0086], radiation to any part of the body, [OR=3.20 (1.29-7.93), p-value=0.012], amount infused per dose (mg/m2) [OR=1.018 (1.002-1.033), p-value=0.029], and cumulative cisplatin exposure (mg/m 2) [OR=1.004 (1-1.008), p-value=0.027] were associated with hearing loss. Similar associations were also found between these risk factors and worsening SIOP grade. CONCLUSION: In one of the largest studies examining the influence of CDDP dosing and schedules on hearing loss, we found the amount of CDDP infused per dose is a significant risk factor. Considerations in designing regimens that reduce the amount of CDDP infused per dose may reduce the risk of hearing loss. Randomized prospective trials are needed.

Clostridioides difficile Infections in Inpatient Pediatric Oncology Patients: A Cohort Study Evaluating Risk Factors and Associated Outcomes.

BACKGROUND: Clostridioides difficile infection (CDI) is a significant source of morbidity in pediatric cancer patients. Few reports to date have evaluated risk factors and short-term outcomes for this population. METHODS: We retrospectively evaluated pediatric oncology admissions at St Louis Children's Hospital from 2009 to 2018. All inpatient cases of diagnosed initial CDI were identified. We aimed to investigate the prevalence of CDI and associated risk factors, including coadmission with another patient with CDI, and to evaluate short-term outcomes including length of stay and delays in subsequent scheduled chemotherapy. RESULTS: Review of 6567 admissions from 952 patients revealed 109 CDI cases (11.4% of patients). Patients with leukemia or lymphoma, compared to those with solid tumors, were more likely to have CDI (odds ratio [OR], 3 [95% CI, 1.4-6.6], and 3 [95% CI, 1.3-6.8], respectively). Autologous hematopoietic stem cell transplant (HSCT) was also a risk factor (OR, 3.5 [95% CI, 1.7-7.4]). Prior antibiotic exposure independently increased the risk for CDI (OR, 3.0 [95% CI, 1.8-4.8]). Concurrent admission with another patient with CDI also significantly increased the risk (OR, 84.7 [95% CI, 10.5-681.8]). In contrast to previous reports, exposure to acid-suppressing medications decreased the risk for CDI (OR, 0.5 [95% CI, .3-.7]). CDI was associated with increased length of stay (mean difference, 8 days [95% CI, 4.6-11.4]) and prolonged delays for subsequent chemotherapy (mean difference, 1.4 days [95% CI, .1-2.7]). CONCLUSIONS: CDI in pediatric oncology patients significantly prolongs hospitalization and delays chemotherapy treatment plans. Interventions to control CDI will improve the care of pediatric oncology patients.

A phase II study of everolimus in patients with advanced solid malignancies with TSC1, TSC2, NF1, NF2 or STK11 mutations.

BACKGROUND: Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in TSC1, TSC2, STK11 and NF1, can lead to the dysregulation of this pathway. Furthermore, mutations in TSC1 and NF2 are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in TSC1, TSC2, NF1, NF2, or STK11. METHODS: A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in TSC1, TSC2, NF1, NF2 or STK11 genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in TSC1, TSC2, NF1, NF2 or STK11 genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR). RESULTS: Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with NF1 or STK11 mutations, respectively. CONCLUSIONS: Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with STK11 or NF1 mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.

Care Fragmentation and Mortality in Readmission after Surgery for Hepatopancreatobiliary and Gastric Cancer: A Patient-Level and Hospital-Level Analysis of the Healthcare Cost and Utilization Project Administrative Database.

BACKGROUND: Hepatopancreatobiliary (HPB) and gastric oncologic operations are frequently performed at referral centers. Postoperatively, many patients experience care fragmentation, including readmission to "outside hospitals" (OSH), which is associated with increased mortality. Little is known about patient-level and hospital-level variables associated with this mortality difference. STUDY DESIGN: Patients undergoing HPB or gastric oncologic surgery were identified from select states within the Healthcare Cost and Utilization Project database (2006-2014). Follow-up was 90 days after discharge. Analyses used Kruskal-Wallis test, Youden index, and multilevel modeling at the hospital level. RESULTS: There were 7,536 patients readmitted within 90 days of HPB or gastric oncologic surgery to 636 hospitals; 28% of readmissions (n = 2,123) were to an OSH, where 90-day readmission mortality was significantly higher: 8.0% vs 5.4% (p < 0.01). Patients readmitted to an OSH lived farther from the index surgical hospital (median 24 miles vs 10 miles; p < 0.01) and were readmitted later (median 25 days after discharge vs 12; p < 0.01). These variables were not associated with readmission mortality. Surgical complications managed at an OSH were associated with greater readmission mortality: 8.4% vs 5.7% (p < 0.01). Hospitals with <100 annual HPB and gastric operations for benign or malignant indications had higher readmission mortality (6.4% vs 4.7%, p = 0.01), although this was not significant after risk-adjustment (p = 0.226). CONCLUSIONS: For readmissions after HPB and gastric oncologic surgery, travel distance and timing are major determinants of care fragmentation. However, these variables are not associated with mortality, nor is annual hospital surgical volume after risk-adjustment. This information could be used to determine safe sites of care for readmissions after HPB and gastric surgery. Further analysis is needed to explore the relationship between complications, the site of care, and readmission mortality.

Phase 1 study combining alisertib with nab-paclitaxel in patients with advanced solid malignancies.

AIM: Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). METHOD: This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. RESULTS: In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. CONCLUSIONS: The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01677559.