Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast-phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multi-center analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. Two-hundred two patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the three most common approaches were intensive chemotherapy (IC) (n=65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n=65), and DNMTi + venetoclax (VEN)-based regimens (n=54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet (ELN) AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HCT); median OS was 2.30 years from time of allo-HCT. Our study demonstrates that survival amongst patients with MPN-AP/BP is limited in the absence of allo-HCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.

First-Line Respiratory Support for Children With Hematologic Malignancy and Acute Respiratory Failure.

OBJECTIVES: To characterize trends in noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) use over time in children with hematologic malignancy admitted to the PICU with acute respiratory failure (ARF), and to identify risk factors associated with NIV failure requiring transition to IMV. DESIGN: Retrospective cohort analysis using the Virtual Pediatric Systems (VPS, LLC) between January 1, 2010 and December 31, 2019. SETTING: One hundred thirteen North American PICUs participating in VPS. PATIENTS: Two thousand four hundred eighty children 0-21 years old with hematologic malignancy admitted to participating PICUs for ARF requiring respiratory support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 3013 total encounters, of which 868 (28.8%) received first-line NIV alone (NIV only), 1544 (51.2%) received first-line IMV (IMV only), and 601 (19.9%) required IMV after a failed NIV trial (NIV failure). From 2010 to 2019, the NIV only group increased from 9.6% to 43.1% and the IMV only group decreased from 80.1% to 34.2% (p < 0.001). The NIV failure group had the highest mortality compared with NIV only and IMV only (36.6% vs. 8.1%, vs. 30.5%, p < 0.001). However, risk-of-mortality (ROM) was highest in the IMV only group compared with NIV only and NIV failure (median Pediatric Risk of Mortality III ROM 8.1% vs. 2.8% vs. 5.5%, p < 0.001). NIV failure patients also had the longest median PICU length of stay compared with the other two study groups (15.2 d vs. 6.1 and 9.0 d, p < 0.001). Higher age was associated with significantly decreased odds of NIV failure, and diagnosis of non-Hodgkin lymphoma was associated with significantly increased odds of NIV failure compared with acute lymphoid leukemia. CONCLUSIONS: For children with hematologic malignancy admitted to the PICU with ARF, NIV has replaced IMV as the most common initial therapy. NIV failure rate remains high with high-observed mortality despite lower PICU admission ROM.

Predictors of Acute Hematologic Toxicity in Women Receiving Extended-Field Chemoradiation for Cervical Cancer: Do Known Pelvic Radiation Bone Marrow Constraints Apply?

Purpose: Patients with cervical cancer who are at high risk for para-aortic lymphatic involvement may receive extended-field chemoradiation (EF-CRT), with inclusion of the para-aortic region. Increased radiation to bone marrow (BM) may heighten hematologic toxicity (HT) and affect timely delivery of chemoradiation. Factors associated with HT in this setting have not been well studied. Methods and Materials: This study was a retrospective analysis of women treated with EF-CRT from 2012 to 2018 with platinum-based chemotherapy. Factors including age, body mass index (BMI), race, Charlson Comorbidity Index (CCI), and nadirs for white blood cell count, absolute neutrophil count, hemoglobin, and platelet count were collected. The BM metrics included V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy and V45Gy (VxGy was defined as the percentage of BM volume receiving x Gy). Hematologic toxicity was defined as grade ≥2 (Cooperative Group Common Toxicity Criteria) leukopenia, anemia, neutropenia, or thrombocytopenia. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the χ2 test, the Fisher exact test, and logistic regression. Previously published dosimetric BM constraints were examined as detailed in each respective study. Results: Fifty-two women underwent EF-CRT with cisplatin. UVA showed no association between HT and age, BMI, or CCI. When accounting for race, V5Gy ≥98% was associated with grade ≥2 leukopenia (P = .02) and grade ≥2 HT (P = .05). Most previously described radiation metrics were not reproduced in our cohort, but a similar constraint, V20Gy <70%, was associated with reduced leukopenia of grade ≥2 on UVA (P = .02) and MVA (P < .05). Conclusions: Acute HT in patients receiving EF-CRT was associated with large volumes of low-dose radiation to the BM and was also associated with race. Restricting the BM V20Gy to less than 70% to 75% may be beneficial in reducing HT, but other pelvic radiation BM constraints may not be applicable to this population.

Phase I study of nab-paclitaxel-based induction followed by nab-paclitaxel-based concurrent chemotherapy and re-irradiation in previously treated head and neck squamous cell carcinoma.

BACKGROUND: Recurrent head and neck squamous cell carcinoma (HNSCC) is associated with poor overall survival (OS). Prior studies suggested incorporation of nab-paclitaxel (A) may improve outcomes in recurrent HNSCC. METHODS: This Phase I study evaluated induction with carboplatin and A followed by concomitant FHX (infusional 5-fluorouracil, hydroxyurea and twice-daily radiation therapy administered every other week) plus A with cohort dose escalation ranging from 10-100 mg/m2 in recurrent HNSCC. The primary endpoint was maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) of A when given in combination with FHX (AFHX). RESULTS: Forty-eight eligible pts started induction; 28 pts started AFHX and were evaluable for toxicity. Two DLTs occurred (both Grade 4 mucositis) at a dose level 20 mg/m2. No further DLTs were observed with subsequent dose escalation. The MTD and recommended Phase II dose (RP2D) of A was 100 mg/m2. CONCLUSIONS: In this Phase I study, the RP2D of A with FHX is 100 mg/m2 (AFHX). The role of re-irradiation with immunotherapy warrants further investigation. CLINICAL TRIAL INFORMATION: This clinical trial was registered with ClinicalTrials.gov identifier: NCT01847326.

High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas.

Glucocorticoid receptor can be associated with poor prognosis among a variety of solid tumors in the absence of other nuclear hormone receptors. Our objective was to characterize differences in glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor expression in the sarcomatous versus carcinomatous components of ovarian and uterine carcinosarcomas. Eighteen patients diagnosed with Mullerian carcinosarcoma between May 2009 and August 2014 were included. Nuclear receptor expression was evaluated by immunohistochemistry using whole tissue specimens. Receptor expression was quantified using the H-score. Mean H-scores were compared between the sarcomatous and carcinomatous components of tumors using Wilcoxon signed-rank tests. We found that GR expression was significantly higher in the sarcomatous components than in the carcinomatous components of the cancers (mean H score 144.4 vs 38.9, p = 0.002). Conversely, ER (3.1 vs 63.1, p = 0.002) and PR (1.7 vs 47.2, p < 0.0001) expression were significantly decreased in the sarcomatous component compared to the carcinomatous component. Androgen receptor expression was low overall (0 versus 2.8, p = 0.04). We hypothesize that GR-high, ER/PR-low expression is associated with epithelial to mesenchymal transition in the sarcomatous cells and may serve as a potential therapeutic target.

Risk and response adapted de-intensified treatment for HPV-associated oropharyngeal cancer: Optima paradigm expanded experience.

BACKGROUND: Favorable prognosis for Human papillomavirus-associated (HPV+) oropharyngeal cancer (OPC) led to investigation of response-adaptive de-escalation, yet long-term outcomes are unknown. We present expanded experience and follow-up of risk/response adaptive treatment de-intensification in HPV+ OPC. METHODS: A phase 2 trial (OPTIMA) and subsequent cohort of sequential off-protocol patients treated from September 2014 to November 2018 at the University of Chicago were reviewed. Eligible patients had T3-T4 or N2-3 (AJCC 7th edition) HPV+ OPC. Patients were stratified by risk: High-risk (HR) (T4, ≥N2c, or >10PYH), all others low-risk (LR). Induction chemotherapy (IC) included 3 cycles of carboplatin and nab-paclitaxel (OPTIMA) or paclitaxel (off-protocol). LR with ≥50% response received low-dose radiotherapy (RT) alone to 50 Gy (RT50). LR with 30-50% response and HR with ≥50% response received intermediate-dose chemoradiotherapy (CRT) to 45 Gy (CRT45). All others received full-dose CRT to 75 Gy (CRT75). RESULTS: 91 patients consented and 90 patients were treated, of which 31% had >10PYH, 34% had T3/4 disease, and 94% had N2b/N2c/N3 disease. 49% were LR and 51% were HR. Overall response rate to induction was 88%. De-escalated treatment was administered to 83%. Median follow-up was 4.2 years. Five-year OS, PFS, LRC, and DC were 90% (95% CI 81,95), 90% (95% CI 80,95), 96% (95% CI 90,99), and 96% (88,99) respectively. G-tube placement rates in RT50, CRT45, and CRT75 were 3%, 33%, and 80% respectively (p < 0.05). CONCLUSION: Risk/response adaptive de-escalated treatment for an inclusive cohort of HPV+ OPC demonstrates excellent survival with reduced toxicity with long-term follow-up.

Improving End of Life Cancer Outcomes Through Development and Implementation of a Spiritual Care Advocate Program.

BACKGROUND: Explored whether increased support for spiritual concerns between the healthcare team and patients through the provision of a Spiritual Care Advocate (SCA) would improve end of life outcomes in a metastatic cancer population. DESIGN: Newly diagnosed metastatic cancer patients were recruited at the University of Chicago Medical Center and received spiritual support from a Spiritual Care Advocate during chemotherapy treatments. The final sample consisted of 42 patients (58% of those approached) who completed the baseline survey and had known survival status. MEASUREMENT: Patients completed pre/post surveys measuring spiritual support and palliative quality of life. Baseline measurements of religious practice and externalizing religious health beliefs were also obtained. Receipt of aggressive EOL care was derived from the electronic medical record. RESULT: Median age was 61 years, with 48% Black, and predominantly male (62%). Of the 42 patients, 30 (70%) had died by the time of this analysis. Perceived spiritual support from the medical team increased in 47% of those who received non-aggressive EOL care and by 40% in those who received aggressive EOL care (p=0.012). Patient perceptions of spiritual support from the medical community increased from 27% at baseline to 63% (p=0.005) after the SCA intervention. Only 20% of recipients received aggressive treatments at end of life. CONCLUSION: The SCA model improved the perceived spiritual support between the healthcare team and patients. Although limited by a small sample size, the model was also associated with an improvement in EOL patients' quality of life, spiritual wellbeing, and decreased aggressive EOL care.

Fewer actionable mutations but higher tumor mutational burden characterizes NSCLC in black patients at an urban academic medical center.

Background: Black patients have been historically underrepresented in studies investigating molecular patterns in non-small cell lung cancer (NSCLC). We aimed to investigate differences in actionable mutations among patients at our urban, diverse medical center. Results: 146 patients were included (59 black, 76 white, 7 Asian, 3 Hispanic, 1 mixed). 35 patients had a targetable mutation. Seven black patients (11.8%) had a targetable mutation compared to 28 non-black patients (32.2%, p = 0.005). 15 black patients had PD-L1 expression ≥50% compared to 19 non-black (25.4% vs 21.8%, p = 0.69). Black patients had a higher TMB compared to non-black (15.3 mutations/Mb compared to 11.5 mutations/Mb, p = 0.001). In a multivariate analysis, TMB was driven by smoking (p < 0.01), without any additive interaction in black patients who smoke (p = 0.8). Conclusion: NSCLC tumors from black patients had a higher TMB and were less likely to carry a targetable mutation. The higher TMB seen was driven by a higher prevalence of smoking among black patients in our study, which may not reflect nationwide trends. Our results serve as a proof of concept that differences in molecular markers exist between black and non-black patients, and that these differences may impact the treatment options available to black patients. Methods: Retrospective chart review of patients with a diagnosis of NSCLC who underwent both PD-L1 testing and massively parallel sequencing (UCM-OncoPlus) was conducted. We examined whether high PD-L1 expression, tumor mutational burden (TMB), and presence of targetable mutations (EGFR, BRAF, ERBB2, RET or ALK translocations, ROS1 rearrangements) occur at different frequencies in tumors from black patients compared to non-black patients.

Adapting a religious health fatalism measure for use in Muslim populations.

OBJECTIVE: Fatalism has been shown to influence health behaviors and outcomes among different populations. Our study reports on the adaptation of the Religious Health Fatalism Questionnaire for a Muslim population (RHFQ-M). DESIGN: The original RHFQ wording was modified for a Muslim context and cognitively tested in 6 focus groups (FG). Items were revised by Muslim and non-Muslim healthcare researchers based on FG responses regarding the theological "accurateness" of the questions. The revised 9-item measure was administered to 58 English-speaking Muslim women (≥40 years old) recruited from two mosques in the Chicago area in order to assess psychometric properties. MAIN OUTCOME MEASURES: Cronbach's alpha and exploratory factor analyses were used to assess internal consistency and measure dimensionality, respectively. Statistical correlations with several fatalism and religiosity measures were computed to assess convergent and discriminant validity. RESULTS: After testing with an ethnically and racially diverse group of Muslims, the RHFQ-M was found to be reliable (Cronbach's α is 0.79), comprised of two distinct underlying subscales, and is correlated with, but distinct from, other measures of fatalism and Islamic religiosity. CONCLUSION: Our adapted measure, RHFQ-M, appears to accurately assess Islamic dimensions of fatalism and is ready for use in the health literature.

Lifestyle intervention and cardiovascular disease risk reduction in low-income Hispanic immigrant women participating in the Illinois WISEWOMAN program.

Cardiovascular disease (CVD) is the leading cause of death for Hispanic women in the United States. In 2001, the Illinois Department of Public Health received funding from the Centers for Disease Control and Prevention to implement the enhanced WISEWOMAN program (IWP) to address the disproportionate CVD risk among uninsured and underinsured women enrolled in the Illinois Breast and Cervical Cancer Early Detection Program. This paper presents the results of the Spanish-language arm of the IWP. Spanish speaking IWP participants were recruited from two sites, and randomized into either the minimum intervention (MI) or the enhanced intervention (EI) group. Both groups received CVD risk factor screening and educational handouts. The EI group also received an integrated 12-week nutrition and physical activity lifestyle change intervention. Of the 180 Spanish-speaking immigrants in this sample, 90 (50%) received the EI and 90 (50%) received the MI. At baseline there were no significant differences between group demographics or clinical values. At post-intervention, the EI group showed improvements in fat intake, fiber intake, moderate intensity physical activity, and total physical activity. At 1 year only the change in fiber intake remained. A significant improvement was also seen in body mass index (BMI) at the 1-year follow-up. The IWP Spanish-language arm was moderately successful in addressing risk factors for CVD in this population. The behavior changes that sustained up to a year were an increase in fiber intake and a decrease in BMI.

Lifestyle intervention and cardiovascular risk reduction in the Illinois WISEWOMAN Program.

BACKGROUND: The Illinois WISEWOMAN Program (IWP) was designed to address the disproportionate risk of cardiovascular disease (CVD) among disadvantaged, low-income women. In total, 1021 women aged 40 to 64 years were recruited from the Illinois Breast and Cervical Cancer Program. The women were randomized to either a minimum intervention (MI) or an enhanced intervention (EI) group. Both groups received CVD risk factor screening and educational materials, and the EI group received a 12-week lifestyle change intervention. METHODS: Demographic and clinical data were collected in addition to data on CVD risk, which was measured in terms of nutritional and physical activity behavior, using culturally adapted versions of three valid and reliable questionnaires. IWP data were analyzed for demographic characteristics and clinical and behavioral outcomes at baseline, post-intervention, and follow-up at 1 and 2 years from baseline. This article reports the change in these outcomes up to the 1-year follow-up. RESULTS: Participants in the EI group showed significant improvement on some of the dietary and physical activity outcomes both at post-intervention and 1-year follow-up. Compared with the MI group, the EI group showed more improvement in dietary fat- and fiber-related behaviors and increased physical activity levels. There were improvements in all of the cardiovascular outcomes at post-intervention in both the EI and MI groups; however, these changes were not statistically significant. CONCLUSION: As an integrated physical activity and nutrition intervention, the IWP has shown its strength in addressing some of the lifestyle behaviors for CVD prevention in this at-risk target population.

A lifestyle approach to reducing cardiovascular risk factors in underserved women: design and methods of the Illinois WISEWOMAN Program.

BACKGROUND: Few lifestyle intervention programs address the needs of financially disadvantaged, low literacy populations. The overall goal of the Illinois WISEWOMAN Program (IWP) was to design such a program and test its effectiveness in reducing cardiovascular disease (CVD) risk, specifically physical activity and nutrition factors. The purpose of this paper is to describe the IWP study design and methods, development of the evidence-based curriculum appropriate for a low socioeconomic status (SES) population, and baseline characteristics of IWP participants. METHODS: The Cooper Institute, in collaboration with the Illinois Department of Public Health and the University of Illinois at Chicago, adapted evidence-based interventions for financially disadvantaged, low literacy populations. The study used a randomized, two-group, experimental design. In total, 1021 women were recruited from the Illinois Breast and Cervical Cancer Program, which serves uninsured and underinsured women, aged 40-64, at or below 200% of poverty. The women were randomized to either a minimum intervention (MI) or an enhanced intervention (EI) group. Both groups received CVD risk factor screening and educational materials. Additionally, the EI group received a 12-week lifestyle intervention. RESULTS: Baseline comparisons show equivalent groups. IWP participants had a higher prevalence of obesity and smoking than similar national samples. CONCLUSIONS: IWP addressed many of the cultural and implementation barriers in programs that seek to improve the health of financially disadvantaged, low literacy populations. Because of the high burden of disease, the unique study population, and the sound design, we anticipate that our future results will contribute to the translation literature, which has largely ignored significant health disparities.

Platelet aggregation and recruitment with aspirin-clopidogrel therapy.

BACKGROUND: Aspirin-clopidogrel combination therapy inhibits platelet aggregation. The effect on platelet recruitment is unknown. METHODS: Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy had platelet reactivity tests performed over 3 months: ex vivo platelet aggregation, platelet recruitment and urinary 11-dehydro-thromboxane B(2) (11-dhTxB(2))excretion. Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel, and longitudinal regression analysis estimated platelet recruitment over time. Nonlinear mapping defined variable connections in each patient. RESULTS: Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for (1) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and (2) increasing inhibition of platelet recruitment over time. Urinary 11-dhTxB(2) excretion did not predict platelet aggregation response. Nonlinear mapping showed patient-unique variable interconnections. CONCLUSIONS: Platelet inhibition with aspirin-clopidogrel may increase over time, and future studies should focus on this finding in the context of vascular complications.

Data feedback for quality improvement of stroke care: CAPTURE Stroke experience.

BACKGROUND: Feedback on "quality indicators" collected from chart audit is a widely used quality-improvement strategy. Skeptics argue that temporal change in practice patterns or improvement of documentation as a result of implementation of chart audit can affect change in quality indicators rather than change in practice due to feedback. This study compared the effectiveness in quality improvement for stroke care of chart audit and feedback versus chart audit only. METHODS: Data were examined on quality indicators constructed from the performance measures abstracted from chart audit for 1953 stroke patients admitted to 13 hospitals. Seven of the 13 hospitals were provided with feedback on quality indicators from baseline audit, and 6 hospitals had chart audit only. RESULTS: Least-squares estimation was used to estimate the adjusted mean change in quality indicators between follow-up and baseline audits and differences in mean change between feedback and nonfeedback groups. Differences in adjusted mean change (with 90% confidence interval) were: deep vein thrombosis prophylaxis, 8.46 (-9.46 to 26.38); dysphagia screening, -3.78 (-21.37 to 13.81); antithrombotic therapy within 48 hours of hospitalization, 3.63 (-6.59 to 13.84); discharged on antithrombotic, -0.31 (-6.26 to 5.63); patients with atrial fibrillation discharged on warfarin/coumadin, 44.73 (-13.14 to 102.60); lipid screening, 19.93 (2.99 to 36.86); and smoking counseling, 17.47 (-12.13 to 47.08). CONCLUSIONS: Although not statistically significant, results suggest a potential for improvement with data feedback. There is a need for evaluation of the effectiveness of a multifaceted approach in a community setting.