Factors associated with a prolonged hospital stay during induction chemotherapy in newly diagnosed high risk pediatric acute lymphoblastic leukemia

Background High Risk (HR) or Very High Risk (VHR) acute lymphoblastic leukemia (ALL) treated with 4 drug induction chemotherapy is often associated with adverse events. The aim of this study was to identify risk factors associated with a prolonged inpatient length of stay LOS during induction chemotherapy. Procedure Data from patients (N = 73) (age<21 years) was collected through a retrospective chart review. Univariable and multivariable logistic regression was used to test for statistical significance. The overall survival and disease (leukemia)-free survival were analyzed using the Kaplan–Meier method and log-rank test. Results Of the 73 patients, 42 (57%) patients were discharged on day 4 of induction (short LOS, group A), while 31 (43%) patients (group B) experienced a prolonged LOS or an ICU stay (16 ± 27.7 days, median hospital stay = 8 days vs 4 days (group A), p = 0.02) due to organ dysfunction, infectious or metabolic complications. Group B patients were more likely to have a lower platelet count, serum bicarbonate, and a higher blood urea nitrogen (BUN) on day 4 of treatment (OR = 4.52, 8.21, and 3.02, respectively, p < 0.05). Multivariable analysis identified low serum bicarbonate (p = 0.002) and a platelet count<20,000/μL (p = 0.02) on day 4 of induction to be predictive of a prolonged LOS. Twenty six (group A (n = 16, 36%) and B (n = 11, 35%), p = 0.8) patients experienced unplanned admissions, within 30 days of discharge. Conclusions A significant proportion of newly diagnosed HR or VHR pediatric ALL patients experience a prolonged LOS and unplanned re-admissions. Aggressive discharge planning and close follow up is indicated in this cohort of patients

Presenting Stool Testing as the Default Option for Colorectal Cancer Screening: Results of a Randomized Trial

Individuals eligible for colorectal cancer (CRC) screening can choose from multiple approved tests, including colonoscopy and stool testing. The existence of multiple options allows patients to choose a preferred strategy but also may lead to indecision and delay. Behavioral economics suggests presenting one option as a default choice, i.e. the one that patients should receive if they do not wish to decide. We conducted a randomized trial to measure the impact of describing stool testing as the default option for CRC screening in a decision aid (DA)

Impact of primary breast cancer therapy on energetic capacity and body composition

PURPOSE: This observational study was designed to measure baseline energy parameters and body composition in early-stage breast cancer patients, and to follow changes during and after various modalities of treatment. This will provide information to aid in the development of individualized physical activity intervention strategies. METHODS: Patients with newly diagnosed stage 0-III breast cancer were enrolled into three cohorts: A (local therapy alone), B (endocrine therapy), or C (chemotherapy with or without endocrine therapy). At baseline, 6 months, and 12 months, subjects underwent a stationary bicycle protocol to assess power generation and DEXA to assess body composition. RESULTS: Eighty-three patients enrolled. Patients had low and variable levels of power generation at baseline (mean power per kilogram lean mass 1.55 W/kg, SD 0.88). Power normalized to lean body mass (W/kg) decreased significantly, and similarly, by 6 months in cohorts B (1.42-1.04 W/kg, p = 0.008) and C (1.53-1.18 W/kg, p < 0.001). In all cohorts, there was no recovery of power generation by 12 months. Cohort C lost lean body mass (- 1.5 kg, p = 0.007), while cohort B maintained lean body mass (- 0.2 kg, p = 0.68), despite a similar trajectory in loss of power. Seven patients developed sarcopenia during the study period, including four patients who did not receive any chemotherapy (cohort B). CONCLUSIONS: The stationary bike protocol was feasible, easy, and acceptable to patients as a way to measure energetic capacity in a clinical setting. Early-stage breast cancer patients had low and variable levels of power generation, which worsened following primary therapy and did not show evidence of 'spontaneous recovery' by 12 months. Effective physical activity interventions will need to be personalized, accounting for both baseline ability and the effect of treatment

Blood Product Utilization Among Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Ex

Background: Adolescent and young adult (AYA, 15-39 years old) patients with acute lymphoblastic leukemia (ALL) often experience pancytopenia and severe immunosuppression. Particularly during intensive phases of chemotherapy, allogeneic blood transfusion support is essential in their care. The utilization of both red blood cell (RBC) and platelet transfusions, as well as the thresholds used to determine when transfusions are needed, are poorly described in this population. The objective of this study is to describe blood product utilization in AYA patients with ALL treated at our institution. Methods: A cohort of 20 AYA patients with ALL treated at Riley Hospital for Children from October 2020 to July 2023 were identified for data collection. Pre- and post-transfusion laboratory values, transfusion totals, comorbid events or complications, transfusion reactions, and minimal residual disease (MRD) values were collected and analyzed. All values reported are mean ± standard deviation for continuous variables and n (%) for categorical variables. Values were calculated individually for each patient for each phase of therapy and averaged across all patients. Results: Patients studied had varying needs for transfusions throughout their therapy (50.75 ± 48.06), with an average of 22.95 ± 15.65 RBC transfusions and 25.60 ± 29.65 platelet transfusions. Patients being treated with standard chemotherapy protocols required moretransfusions during induction (14.13 ± 21.56) and delayed intensification (14.07 ± 24.29) phases compared to other phases. Patients with MRD positive status required more transfusions (69.14 ± 58.14) than patients with MRD negative status (40.92 ± 40.84). Conclusions and Potential Impacts: This study helped to elucidate the need for transfusions among the AYA ALL patient population, throughout the different phases of treatment. These findings hold implications for establishing guidelines that could clarify when transfusions should be given in this population, helping physicians provide the best care to future patients

Prognostic variables associated with improved outcomes in patients with stage III NSCLC treated with chemoradiation followed by consolidation Pembrolizumab: a subset analysis of a phase II study from the Hoosier Cancer Research Network LUN 14-179

Introduction HCRN LUN 14-179 is a phase II trial of consolidation pembrolizumab following concurrent chemoradiation for the treatment of patients with stage III NSCLC. Time to metastatic disease, progression free survival and overall survival appear superior to historical controls of chemoradiation alone. Unfortunately, not all patients benefit from consolidation immunotherapy. We performed a univariate analysis evaluating variables associated with PFS, metastatic disease, and OS. Methods We conducted a retrospective analysis from patients enrolled on HCRN LUN14-179. Data collected included age, sex, stage, smoking status, PD-L1 status, >G2 vs G3 pneumonitis, duration of pembrolizumab (4 cycles), chemotherapy regimen, PS 0 vs 1, time to start pembrolizumab (4-6 vs. 6-8 weeks from radiation), V20 (20%). Univariable Cox regression was performed to determine the variables associated with 3 endpoints: TMDD; PFS; and OS. Results From April 2015 to December 2016, 93 patients were enrolled and 92 were included in the efficacy analysis (1 patient was ineligible). For TMDD, improved outcomes may be associated (p4 cycles of pembrolizumab, and V204 cycles of pembrolizumab, and V204 cycles of pembrolizumab. Conclusion Non-squamous NSCLC, longer duration of pembrolizumab, and V20< 20% may be associated with prolonged time to metastatic disease or death, PFS, and OS for patients with stage III NSCLC treated with chemoradiation followed by pembrolizumab

Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis

BACKGROUND: The majority of estrogen receptor-positive (ERα+) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown. METHODS: We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα+ MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses. RESULTS: Knockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERα signaling, as evident from ligand-independent activity of ERα, altered turnover of phosphorylated ERα, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ∆Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERα. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14+/KRT19+ and CD49f+/EpCAM+ phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERα+/PR+/HER2- tumors, was associated with poor outcome. CONCLUSION: These studies reveal an unexpected role of the axon guidance receptor UNC5A in fine-tuning ERα and EGFR signaling and the luminal progenitor status of hormone-sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERα+ breast cancers

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy

Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking (P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased (P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs

Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation

Efficacy of postoperative seizure prophylaxis in intra-axial brain tumor resections

The effectiveness of seizure prophylaxis in controlling postoperative seizures following craniotomy for tumor resection is unclear. Most patients are seizure-free before surgery. To prevent seizures, it is common to treat tumor craniotomy patients postoperatively with an antiepileptic drug (AED). The authors retrospectively analyzed seizure occurrence with and without postoperative prophylactic AEDs. Between 2005 and 2011 at the authors’ institution, 588 patients underwent craniotomy for brain tumors and were screened. Data on seizures, AED use, histopathology, comorbidities, complications, and follow-up were collected. Exclusion criteria included lack of follow-up data, previous operation, preoperative seizures, or preoperative AED prophylaxis. The incidence of postoperative seizures in patients with and without prophylactic AEDs was compared using logistic regression analysis. A total of 202 patients (50.5 % female) were included. The most common tumor diagnosis was metastasis (42.6 %). Of the 202 patients, 66.3 % were prescribed prophylactic AED after surgery. Forty-six of 202 (22.8 %) suffered a postoperative seizure. The odds of seizure for patients on prophylactic AED was 1.62 times higher than those not on AED (p = 0.2867). No difference was found in seizure occurrence between patients with glioblastoma multiforme compared with other tumor types (odds ratio 1.75, p = 0.1468). No difference was found in time-to-seizure between the two groups (hazard ratio 1.38, p = 0.3776). These data show no statistically significant benefit to prophylactic postoperative AED and a nonsignificant trend for increased seizure risk with AEDs. A randomized, placebo-controlled trial is needed to clarify the benefit of postoperative AED use for brain tumor resection

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization