bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-physician communication about code status preferences: A randomized controlled trial.
Authors: Rhondali Wadih , Perez-Cruz Pedro Emilio , Hui David , Chisholm Gary B. , Dalal Shalini , Baile Walter F. , Chittenden Eva , Filbet Marilène , Bruera Eduardo
Published: March 2020

9049

Background: Code status discussions are important in cancer care. The best modality for such discussions has not been established. Our objective was to determine the impact of a physician ending a code status discussion with a question (autonomy approach) versus a recommendation (beneficence approach) on patients’ do-not-resuscitate (DNR) preference. Methods: Patients in a supportive care clinic watched two videos showing a physician-patient discussion regarding code status. Both videos were identical except for the ending: one ended with the physician asking for the patient’s code status preference and the other with the physician recommending DNR. Patients were randomly assigned to watch the videos in different sequences. The main outcome was the proportion of patients choosing DNR for the video patient. Results: 78 patients completed the study. 74% chose DNR after the question video, 73% after the recommendation video (p=NS). Median physician compassion score was very high and not different for both videos (p=0.73). 30/30 patients who had chosen DNR for themselves and 30/48 patients who had not chosen DNR for themselves chose DNR for the video patient (100% v/s 62%, p<0.001). Age (OR=1.1/year, p=0.01) and white ethnicity (OR=9.43, p=0.004) predicted DNR choice for the video patient. Conclusions: Ending DNR discussions with a question or a recommendation did not impact DNR choice or perception of physician compassion. Therefore, both approaches are clinically appropriate. All patients who chose DNR for themselves and most patients who did not choose DNR for themselves chose DNR for the video patient. Age and race predicted DNR choice.
The effect of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: A double-blind placebo-controlled trial.
Authors: Del Fabbro Egidio , Dev Rony , Hui David , Palmer J. Lynn , Bruera Eduardo
Published: March 2020

9062

Background: Patients with advanced cancer experience anorexia and weight loss which impairs their quality of life. Prior studies suggest melatonin, a frequently used integrative medicine may attenuate weight loss, anorexia, fatigue, and depression. These studies were limited by a lack of blinding and absence of placebo controls. The primary objective of this study was to compare melatonin to placebo for appetite in patients with cachexia. Methods: A randomized, double-blind, 28 day trial of melatonin 20mg vs. placebo in patients with advanced lung or gastrointestinal cancer, appetite scores >3 on a 0 to 10 scale (10 = worst appetite) and a history of weight loss ≥ 5% within 6 months. Patients unable to maintain oral intake, thyroid or adrenal dysfunction, or with a karnofsky <40 were excluded from the study. The assessments included weight, symptom severity by Edmonton Symptom Assessment Scale (ESAS) and quality of life by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT).Differences between groups from baseline to day 28 were analyzed using one-sided two sample t tests (appetite, pain and well-being) or Wilcoxon two-sample tests for the other variables. Interim analysis at half point had a Lan-DeMets monitoring boundary with an O’Brien-Fleming stopping rule. The decision boundaries for the interim test was to accept the null hypothesis of no treatment difference (futility) if the test statistic Z < 0.39 (p ≥ 0.348). Results: After interim analysis of 48 patients, the study was closed by the Data Safety Monitoring Board for futility. There were no significant differences between groups in appetite (p=0.78), weight (p= 0.17), FAACT score (p=0.95), insomnia (p=0.62) or other symptoms measured by the ESAS from baseline to day 28.No significant toxicities were observed. Conclusions: In cachectic patients with advanced cancer, 20mg oral Melatonin at night does not improve appetite, weight or quality of life compared to placebo.
Decision-making preferences of advanced cancer Hispanic patients from the United States and Latin America.
Authors: Parsons Henrique Afonseca , Yennurajalingam Sriram , Rosina Duarte Eva , Palma Alejandra , Bunge Sofia , Palmer J. Lynn , Delgado-Guay Marvin Omar , Bruera Eduardo
Published: March 2020

9063

Background: To determine whether preferences in frequency of passive decision making differ between Hispanic patients from Latin America (HLA) and Hispanic-American (HA) patients. Methods: We conducted a survey of advanced cancer Hispanic patients referred to outpatient palliative care clinics in the U.S, Chile, Argentina, and Guatemala. Information on demographic variables, PS,andMarin Acculturation Assessment Tool (only U.S. patients) was collected. Decision-making preference was evaluated by the decision-making assessment tool. Results: A total of 387 patients with advanced cancer were surveyed: 91 (24%) in the US, 100 (26%) in Chile, 94 (25%) in Guatemala, and 99 (26%) in Argentina. Median age was 59 years, and 61% were female. HLA preferred passive decision-making strategies significantly more frequently with regard to involvement of the family (24% versus 10%, p=0.009) or the physician (35% versus 26%, p<0.001), even after controlling for age and education (OR 3.8, p<0.001 for physician and 2.4, p=0.03 for family) (Table 1). 76/91 HA (83.5%), and 242/293 HLA (82%) preferred family involvement in decision-making (p=NS). No differences were found in decision-making preferences between low- and highly acculturated U.S. Hispanics. Conclusions: HA prefer more active decision-making as compared to HLA. Among HA, acculturation did not seem to play a role in decision-making preference determination. Our findings in this study confirm the importance of family participation in decision making in both HA and HLA. However, HA patients were much less likely to want family members or physicians to make decisions on their behalf. [Table: see text] [Table: see text]
Clostridium difficile-associated diarrhea in cancer patients treated with fidaxomicin or vancomycin.
Authors: Cornely Oliver A. , Miller Mark , Fantin Bruno , Mullane Kathleen M. , Kean Yin , Gorbach Sherwood
Published: March 2020

9067

Background: Oncology patients are at risk for infections, including C difficile infection (CDI). Fidaxomicin (FDX) is a novel antibiotic highly specific for C difficile with improved sustained response compared with vancomycin (VAN). Another important clinical outcome of CDI is time to resolution of diarrhea (TTROD), corresponding to the duration of passing unformed bowel movements. Methods: 183 patients with a current diagnosis of cancer were compared to non-cancer patients from a combined population of 1105 subjects with CDI in two phase 3 trials comparing 10 days of treatment with FDX (400 mg/day) or VAN (500 mg/day). Number of unformed bowel movements (UBM) per 24 h was monitored. Response was considered as ≤3 UBM/24 h. Time to resolution of diarrhea was defined as time in hours from the first dose of study drug to the last UBM on the day preceding two days of ≤3 UBM/24 h. Kaplan-Meier survival analysis (K-M) used the log rank test for significance (p<0.05). Results: The response rate at end of treatment was 79.2% for 183 patients with cancer, compared to 88.6% for 922 patients without cancer (p<0.001). Median TTROD was longer by 45 h in patients with cancer than those without. In the VAN treatment group, median TTROD was 65 h longer in patients with cancer vs those without and significant by K-M. In the FDX group, although median TTROD was longer by 20 h in patients with cancer vs those without, the difference was not significant by K-M. For patients with cancer, TTROD was significantly shorter during treatment with FDX than with VAN. Conclusions: Patients with cancer responded more slowly to treatment for CDI than did non-cancer patients; however, resolution of diarrhea was more rapid by 49 h during treatment with FDX than with VAN. [Table: see text]
Development of a geriatric vulnerability score (GVS) in elderly advanced ovarian cancer (AOC) patients (pts) treated in first line: A prospective GINECO trial.
Authors: Freyer Gilles , Weber Beatrice E. , Lebrun-Jezekova Daniela , Tinquaut Fabien , Tredan Olivier , Sevin Emmanuel , Stefani Laetitia , Pujade-Lauraine Eric , Falandry Claire
Published: March 2020

9079

Background: Two previous prospective GINECO studies in elderly patients have underlined the prognostic value of geriatric covariates (Co) on overall survival (OS) (Freyer G., et al. Ann Oncol. 2005 and Tredan O, et al Ann Oncol 2007). Methods: This open prospective trial was designed to confirm the impact of geriatric Co including psycho-geriatric Co on OS of elderly pts (≥70) with stage III-IV AOC treated in first line with 6 courses of carboplatin AUC5/3weeks. Geriatric Co were tested for their impact on OS in uni- and multivariate analyses. The best fitting proportional hazard model (GVS) was developed with the inclusion of major (MaC) and minor Co (miC). Results: From 08/2007 to 01/2010, 111 pts were included in 21 centres. A majority of pts displayed characteristics of vulnerability: age (median:78, range: 70-93, ≥80:41%), PS≥2: 43%, ≥3 major comorbidities: 27%, ≥4 comedications: 69%, ADL score<6: 55%, IADL score<25: 75%, HADS≥15:37%. A total of 74% of pts, however, completed planned chemotherapy. Gr3-4 haematological toxicity was observed in 50% of pts (thrombocytopenia [27%], anaemia [19%], and neutropenia [30%]) and gr3-4 non-haematological toxicity was fatigue (16%), anorexia (13%) and infection (10%). Median OS was 16.2 months (95%CI[14-21]). MaC were: albuminemia<35g/L; ADL score <6; IADL score <25 and miC: lymphopenia<1G/L; HADS£14. The survival score=exp(0.320*Number [MaC] +0.354*Number[miC]) was validated upon a bootstrap analysis. Using a cutoff of 3, the simplified GVS score = Number[MaC] + Number[miC] discriminated two groups with significantly different OS :11.5 vs 21.7 months; HR=2.94; p<10-4, but also treatment completion rates: 65.4% vs 82.1%; OR=0.41; p=0.04; severe adverse events (SAE): 52.7% vs 28.6%; OR=2.8; p=0.009 and unplanned hospital admissions: 52.8% vs 30.3% OR=2.6; p=0.02. Conclusions: The GVS identified a group of pts at high risk of severe toxicity, early treatment stopping, unplanned hospitalization and poor outcome. GVS provides a useful tool to identify vulnerable pts in future elderly AOC trials.
Correlations between depression according DSM-IV-TR (DSM) criteria, three validated scales, oncologist assessment, and clinical psychiatric interview in elderly advanced ovarian cancer (AOC) patients (pts): A GINECO study.
Authors: Filbet Marilène , Rhondali Wadih , Freyer Gilles , ADAM Virginie , Dezerlle Martine , Abgrall-Barbry Gaelle , Gobet-Bourcelot Sophie , Machavoine Jean-Luc , Chomat-Neyraud Muriel , Gane Nicolas , Saltel Pierre , Falandry Claire
Published: March 2020

9080

Background: Depression is a major outcome in cancer pts. Clinicians typically rely on their clinical impression of depression rather than pts self-reports. Our aim was to explore the association between patient-reported depression, oncologist assessment (OA) and a clinical psychiatric interview (CPI) in elderly AOC pts. Methods: This analysis was a secondary endpoint of theElderly Women AOC trial, designed to assess the impact of geriatric covariates, notably depression, on survival in pts over 70 receiving 6 courses of carboplatin. Depression was assessed using the Geriatric Depression Scale-30 (GDS; cut off score of 10/30), the Hospital Anxiety Depression Scale (HADS; cut off score of 15/42), the distress thermometer (DT; cut off score of 4/10) and OA (yes/no). CPI was conducted by psychologists within 10 days after inclusion. The interview guide for CPI (yes/no) was constructed and adapted from three validated scale: GDS, Hamilton Depression Rating Scale Hamilton (HDRS), Montgomery Asberg Depression Rating Scale (MADRS) and the DSM criteria. DSM was considered as the gold standard. Results: Out of 111 pts, 100 (90.1 %) completed all the assessment (OA, GDS, HADS, DT, CPI). Patients characteristics were: mean age 78, performance status ≥2: 48 (55%). Thirty six pts (36%) were identified as depressed by the CPI versus 17 (17%) by OA, 32 (32%) by the GDS, 36 (36%) by the HADS, 58 (58%) by the DT and 16 (16%) according to DSM. We found a significant correlation between DSM and GDS (r=0.58; p<0.001), DSM and CPI (r=0.53; p<0.001). We did not find any significant correlation between DSM and OA (r=-0.05;p=0.733), DSM and DT (r=-0.07;p=0.583), and between DSM and HADS (r=0.127;p=0.258). Identification according to OA (yes/no) resulted in 87% false negatives and 18% false positives rates. The best sensitivity and specificity as a screening tool was found for GDS, 94% and 80% respectively. Conclusions: The use of validated tools such as GDS and a collaboration between psychologists and oncologists are warranted to better identify emotional disorders in elderly women with AOC.
Feasibility of screening hospitalized cancer patients for palliative care.
Authors: Glare Paul A. , Plakovic Mary K. , Schloms Anna , Egan Barbara , Saltz Leonard , Kelsen David Paul
Published: March 2020

9094

Background: The National Comprehensive Cancer Network Palliative Care (PC) Guideline recommends screening all oncology patients for PC needs, and to call a PC consult when referral criteria are met. There are no data on the feasibility or impact of this approach. The aim of this pilot study was to assess the feasibility of PC screening in patients admitted to a comprehensive cancer center (CCC). Methods: Design: Observational study. From 11/1/10 to 1/31/11, floor nurses screened all patients the day after admission under the two teams (“Team A” and “Team B”) of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center. Team A patients were also evaluated by the referral criteria. Endpoints: Patients screened ‘positive’ if they had advanced disease and any of the clinical situations nominated in the Guideline. The referral criteria triggered PC consults in Team A patients; clinical judgment triggered Team B consults. Outcomes: Screening rates, nursing satisfaction survey, clinical and operational metrics. Results: Ninety percent (229 of 254) of admissions were screened. Both Teams’ patients were seriously ill (see Table), and it was no surprise that 63% (145 of 229) screened positive. Survey respondents (response rate 50%) rated screening as simple, quick and helpful, although nurses scored the extent of disease wrong in 16%. Sixty eight percent (55 of 780) of Team A patients who screened positive met the referral criteria. This generated more consults on Team A, but the effect on key outcomes was not significant (n.s.). Conclusions: Screening for PC was feasible in this setting, but is a challenging concept in terms of reliability, validity and timing. The value to a CCC of increasing PC access via referral criteria needs evaluation in well-designed trials. [Table: see text]
A randomized trial evaluating the integration of online questionnaires into follow-up (FU) care for early-stage breast cancer (ESBC).
Authors: Wheelock Alyse , Bock Meredith , Mihalis Eva , Shepard Nancy , Moore Dan H. , Ernest Mary Lou , Rugo Hope S. , Esserman Laura , Melisko Michelle E.
Published: March 2020

9107

Background: Large numbers of cancer survivors have led to the need for FU care addressing lasting effects of BC and its treatment. We conducted a trial evaluating formats of FU care to determine if integration of remote electronic questionnaire FU provides for timely symptom management and more efficient care than routine clinic visits alone. Methods: Patients (pts) with ESBC were randomized to either usual care (UC, frequency of visits determined by oncology providers) with completion of an optional online health and symptom questionnaire (Q) before each clinic visit, or to SIS.NET FU care, in which pts were scheduled for up to 3 routine oncology related clinic visits over 18 mos and completed the online Q every 3 mos. Qs were reviewed by a survivorship nurse practitioner (NP) with pt phone contact for symptoms requiring urgent attention. We recorded the time between electronic symptom reporting and FU for pts in the SIS.NET arm. Data included the number of oncology related clinic visits, total number of physician visits, and number of medical tests including labs and imaging studies ordered. Kolmogorov-Smirnov tests for equal distributions were used to determine if there were any significant differences between SIS.NET and UC. Results: 100 pts were enrolled, 75 completed the 18 month study and 25 pts remain in FU. For the 75 pts, 85% received chemotherapy and 77% received hormone therapy. Pts in the SIS.NET arm completed an average of 3.8 out of 7.2 emailed surveys (52.6%), and pts in the UC arm completed an average of 2.2 out of 3.4 (69.1%) routine pre-clinic surveys. For pts in the SIS.NET arm, 75% of reported symptoms were reviewed by a NP in < 3 days. There was no significant difference between SIS.NET and UC FU for oncology related clinic appointments, total number of physician visits, or number of medical tests performed. Conclusions: Use of on-line health and symptom surveys with remote NP review provided timely symptom FU but did not reduce clinic visits or medical testing in pts with ESBC. Further analyses of these data as well as additional studies are necessary to understand the barriers to integration of web-based tools to achieve more efficient FU care for BC survivors.
Determinants of fatigue improvement in outpatient oncology according to baseline categories of fatigue severity.
Authors: Fisch Michael , Zhao Fengmin , O'Mara Ann M. , Wang Xin Shelley , Cella David , Cleeland Charles S. ,   Eastern Cooperative Oncology Group
Published: March 2020

9112

Background: Understanding the determinants of fatigue response may help distinguish between different fatigue phenotypes and inform trial designs. Methods: Patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites. At baseline and 4-5 weeks later patients rated their symptoms on a 0-10 numerical rating scale. A 2-point change was considered clinically significant for fatigue change. Logistic regression models and ordinal logistic regression models were used to examine the effects of demographic and clinical factors on fatigue change. Separate models were constructed for fatigue deterioration in patients with mild fatigue at baseline and lack of improvement for those with severe fatigue at baseline or any significant change for those with moderate baseline fatigue. Results: 3,106 pts were enrolled at baseline and 3,032 were analyzable for fatigue change. At baseline, 23% had no fatigue, 35% mild, 25% moderate, and 17% severe. Improvement varied by baseline fatigue score with response in 54% with severe fatigue, 31% with moderate, and 9% with mild. Overall, 13 different parameters were significant in these 3 models of fatigue change, but no single parameter was common to all 3 categories of fatigue. Exposure to anxiolytics and duration of current treatment were significant in models of mild and severe fatigue; antidepressant exposure was significant for mild and moderate fatigue, and baseline fatigue level was a significant parameter in moderate and severe fatigue. In colorectal and lung cancer patients, gender was not significant for fatigue change in patients with mild or moderate fatigue, but gender was the strongest predictor fatigue improvement in patients with severe fatigue with men most likely to significantly improve (OR=2.49, 95% CI 1.15-5.41, p=0.021). Conclusions: Clinically significant improvement in fatigue varies between 9% and 54%. Predictors of fatigue change vary depending on categories of baseline fatigue severity. Gender is the strongest predictor for fatigue improvement among lung and colorectal outpatients with severe baseline fatigue. Future trial designs should account for gender and baseline fatigue severity.
Clinical ethics consultation in oncology.
Authors: Shuman Andrew G , Montas Sacha M , Barnosky Andrew R , Smith Lauren B , Kissane David W , Fins Joseph J , McCabe Mary S.
Published: March 2020

9121

Background: There is limited empirical research exploring the nature of clinical ethical consultations within the oncology population. Our objective is to review, describe and compare clinical ethics consultations at two NCI-designated comprehensive cancer centers, in order to identify opportunities for systems improvement in clinical care. Methods: This case series is derived from prospectively-maintained clinical ethics consultation databases at each institution. All adult oncology patients receiving ethics consultation from 2007 through 2011 were included as eligible cases. Both qualitative and quantitative analyses were undertaken. Demographic and clinical information were obtained from the databases for all patients, and verified via chart abstraction. Additional variables studied included the reason for and context of the ethical consultation, the patient’s code status before and after consultation, and involvement of palliative care or other adjuvant services. Opportunities for systems-level improvements and/or educational initiatives were identified. Results: A total of 207 eligible cases were identified. The most common primary issues leading to ethics consultation were code status and advance directives (25%), surrogate decision-making (17%), and medical futility (13%). Communication lapses were identified in 41%, and interpersonal conflict arose in 51%. Prior to ethics consultation, 26% of patients were DNR; 60% were DNR after ethics consultation. Palliative care consultation occurred in 41% of cases. Opportunities for systems improvement and professional education related to goals of care at the end of life, the role of palliative care involvement, and improved communication. Conclusions: Ethics consultations among cancer patients reflect the realities inherent to their clinical management. Appropriately addressing advance directives within the context of overall goals of care is crucial. Thoughtful consideration of communication barriers, sources of interpersonal conflict, symptom control, and end-of-life care are paramount to optimal management strategies in this patient population.
Caring for people at the end of life: How do cancer caregivers differ from other caregivers?
Authors: Girgis Afaf , Abernethy Amy Pickar , Currow David C
Published: March 2020

9128

Background: The size of the population in receipt of cancer care is growing as the population ages and grows, with many receiving outpatient care, living for longer and wishing to be cared for at home. Hence, cancer is now one of the most common health conditions in receipt of informal care giving. Methods: The South Australian Health Omnibus is an annual, face-to-face, cross-sectional, whole-of-population, multi-stage, systematic area sampling survey which seeks a minimum of 3,000 respondents each year state-wide. From 2000-2007, questions about end of life were asked. This study compares people who cared for someone with cancer until death (cancer caregivers) with caregivers of people with other life limiting illnesses (non-cancer caregivers). Results: 4,665/14,624 (31.9%; participation rate 71.6%) had someone close to them die from an “expected” death in the 5 years prior to being surveyed. One in 10 (10%; 1,504/14,624) provided hands-on (day-to-day or intermittent) care; the majority (79.5%) having cared for someone with cancer. Compared to non-cancer caregivers, cancer caregivers cared for someone who was significantly younger (mean age 66 vs 74 years; p<0.0001), and to have had a palliative care service involved in the care of that person (64.9% vs 39%; p=0.000). Whilst not statistically significant, cancer caregivers were somewhat less likely to be the spouse of the person they cared for (11.8% vs 16.8%); more likely to be of non-English speaking background (11% vs 7.5%); more likely to report that the deceased was comfortable in the last 2 weeks of life (44.1% vs 31.7%); and prepared to care again for someone with a life-limiting illness (81.3% vs 71.4%). Conclusions: Caring for someone with cancer at the end of life appears to be fundamentally different to other caregiver populations, particularly in relation to age of, and relationship to, the patient, which may contribute to their substantially greater utilisation of palliative care services. Being a younger caregiver increases the likelihood of them caring again in the future.
Associations between receipt of a treatment summary, emotional concerns, and patterns of care among post-treatment cancer survivors.
Authors: Rechis Ruth , Beckjord Ellen Burke , Nutt Stephanie , Reynolds Kerry , Hayes-Lattin Brandon M.
Published: March 2020

9136

Background: Treatment summaries (TS), a critical component of survivorship care plans, were identified as a tool to improve long-term outcomes for the 12 million cancer survivors alive in the US. Methods: In 2010, the Lance Armstrong Foundation fielded the LIVESTRONG Survey for People Affected by Cancer. Respondents were recruited through several channels including partnerships with national organizations such as ASCO. Over a 9 month period, more than people completed the survey, including 3,682 post-treatment cancer survivors (PTCS). The survey addressed post-treatment concerns including receipt of TS. Full survey results were presented at the 2011 ASCO Conference. Results: Receipt of TS data was available for 3042 PTCS: average age (50); female (65%); average time since diagnosis (6 years); received a TS (34%). PTCS who received TS reported that they were: Closer to time since diagnosis or since treatment ended (p<0.01); more likely to have received chemotherapy (p<0.01); more often receiving the majority of their health care from a medical oncologist (p<0.05); experiencing significantly fewer (p<0.05) post-treatment emotional concerns (including emotional distress; fears of recurrence; concerns about family risk; and appearance concerns) and were more likely to have received care; significantly less likely to say that they had “learned to live with” their concerns (p<0.05) – the most common reason among participants for not receiving care. Finally, receipt of a TS was related to higher information efficacy (p<0.01; which appeared to mediate the relationship between receipt of a TS and fewer emotional concerns). PTCS who received a TS more often reported that their needs were met including information received about possible late-effects; care they got during treatment; and care they received after treatment. Conclusions: These results support the provision of TS to PTCS. Receipt of TS was associated with a variety of positive outcomes; however, only about one-third of PTCS received one. Future studies focused on patient perspectives on care planning tools, such as treatment summaries and care plans, can help to improve optimal survivorship care delivery.
Validation of the chemotherapy-induced neuropathy assessment scale.
Authors: Thomas Sheeba K. , Mendoza Tito R. , Vichaya Elisabeth G. , Wang Xin Shelley , Sailors Mary H , Williams Loretta A. , Dougherty Patrick M. , Cleeland Charles S.
Published: March 2020

9140

Background: Many of the assessment tools used to assess peripheral neuropathy in clinical trials focus on painful neuropathy. However, some chemotherapy agents cause both painful and non-painful peripheral neuropathy. The Chemotherapy-Induced Neuropathy Assessment Scale (CINAS) was designed to evaluate the multi-dimensional nature of chemotherapy-induced neuropathy, including non-painful sensory and motor deficits. This study evaluated the psychometric properties of the CINAS in patients with multiple myeloma (MM) receiving induction chemotherapy and/or autologous hematopoietic stem cell transplantation. Methods: We collected demographic and clinical data and administered 2 items measuring pain and numbness/tingling at its worst (0-10 scale), and the CINAS. A total CINAS score was computed by summing all 11 CINAS items. For reliability and validity analyses, we used the highest total CINAS score for each patient. Validity was assessed by factor analysis and by correlating CINAS subscales with the pain and numbness/tingling items. Cronbach alpha reliability coefficients were computed. To test sensitivity, we compared change in total CINAS score during induction from baseline to last total CINAS score in a subset of patients (N=20) receiving bortezomib or thalidomide. We hypothesized that such patients would develop neuropathy. Results: Ninety patients were enrolled. Participants were primarily white (90%) and male (63%). Factor analysis revealed 3 underlying constructs for the CINAS - sensory, motor functioning, and allodynia - explaining 74% of the common variance. Cronbach alphas were 0.84, 0.85, and 0.83 for the sensory, motor functioning, and allodynia subscales, respectively, while subscale correlations with the numbness/tingling item were 0.74, 0.56, and 0.52, respectively. Pain was only modestly correlated with these subscales (0.21, 0.36, 0.29). Total CINAS scores of patients receiving bortezomib or thalidomide induction worsened significantly (from 3.4 to 11.9, effect size=0.55, p<.02). Conclusions: The CINAS demonstrated validity, reliability and sensitivity in patients with MM during and after chemotherapy and can be used to assess the multidimensional aspects of chemotherapy-induced neuropathy.
Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study.
Authors: Mosse Yael P. , Balis Frank M. , Lim Megan S , Laliberte Julie , Voss Stephan D , Fox Elizabeth , Bagatell Rochelle , Weigel Brenda , Adamson Peter C. , Ingle Ashish M , Ahern Charlotte H , Blaney Susan
Published: March 2020

9500

Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma (NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK translocation. We performed a phase 1 dose-escalation and pharmacokinetic (PK) trial of crizotinib in patients (pts) with refractory solid tumors and ALCL. Methods: Crizotinib was administered bid without interruption in 28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2/dose) have been evaluated (A1). Pts with confirmed ALK fusion proteins, mutations or amplification (A2) could enroll at one dose level lower than part A1 and those with NB could enroll on a separate stratum (A3). PK studies were performed on day 1 and at steady state (SS). ALK genomic status in tumor tissue was evaluated and qPCR was used to measure NPM-ALK fusion transcript in bone marrow and blood samples of ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, [median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral hemorrhage) at 215 mg/m2 and 1/6 pts developed DLT (grade 4 liver enzyme elevation) at 365 mg/m2. In A2, 1 grade 4 DLT (neutropenia) occurred at 165 mg/m2; in A3, no DLTs occurred. Mean (±SD) Cave (=AUC0-12h/12h) of crizotinib at SS was 466±114 ng/mL at 215 mg/m2/dose (n=5), 443±121 ng/mL at 280 mg/m2/dose (n=8), and 720±230 ng/mL at 365mg/m2/dose (n=4). Response data for pts with ALCL (six at 165 mg/m2, two at 280 mg/m2) approved for release by the Data Safety Monitoring Committee demonstrates 7/8 (88%) complete response (CR) rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained and will be described. In addition, 2 pts with NB have had CRs, one with a documented ALK mutation. One patient with an inflammatory myofibroblastic tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in pediatric pts with ALK-driven tumors occurs with minimal toxicity and is associated with objective anti-tumor activity.
Efficacy of the Children's Oncology Group (COG) long-term follow-up (LTFU) guidelines in reducing risk of congestive heart failure (CHF) in childhood cancer survivors (CCS).
Authors: Wong F. Lennie , Bhatia Smita , Kurian Seira , Landier Wendy , Francisco Liton , Leisenring Wendy M. , Hudson Melissa M. , Armstrong Gregory T. , Mertens Ann , Stovall Marilyn , Robison Leslie L. , Lipshultz Steven E. , Armenian Saro
Published: March 2020

9505

Background: CCS are at risk for left ventricular dysfunction (LVD) and subsequent CHF due to exposure to anthracyclines and chest radiation (RT). COG LTFU guidelines recommend screening for LVD using echocardiograms (ECHOs) every 1-5y depending on anthracycline dose, RT, and age at cancer diagnosis. The relevance and cost-effectiveness of these consensus-based guidelines are unknown. Methods: Life expectancy and age at onset of CHF were projected in a simulated cohort (>1 million) of CCS undergoing screening ECHO per COG guidelines. Intervention for LVD was modeled to reduce annual CHF risk by 30%. Quality-adjusted life-years (QALYs) and lifetime costs with and without ECHO screening were calculated. Non-CHF mortality was estimated from the Childhood Cancer Survivor Study and US population rates. Costs and QOL adjustments were obtained from the Healthcare Cost and Utilization Project and medical literature. Screening was considered cost-effective if it resulted in a >6 month delay in onset of CHF and <$50,000/QALY gained. Results: Recommended screening strategies (Table) were cost-effective in: i) CCS exposed to ≥300mg/m² of anthracycline regardless of RT or age; and ii) CCS diagnosed at age 1-4y, exposed to RT and <300mg/m² of anthracycline. Screening was most cost-effective for CCS diagnosed at age 1-4y exposed to RT + ≥300 mg/m² of anthracycline (1.4y delay in CHF onset; $15,821/QALY gained). Screening as currently proposed was not cost-effective for other age/anthracycline/RT combinations. Conclusions: Recommended ECHO screening strategies are cost-effective for all CCS exposed to ≥300 mg/m² of anthracycline; screening was also cost-effective for those 1-4y at diagnosis, exposed to anthracycline <300 mg/m² + RT. Alternate screening strategies are needed for CCS with other exposure conditions. [Table: see text]
In vivo monitoring of JAK/STAT and PI3K/mTOR signal transduction inhibition in pediatric CRLF2-rearranged acute lymphoblastic leukemia (ALL).
Authors: Tasian Sarah Kathleen , Maude Shannon L. , Hall Junior , Vincent Tiffaney , Mullighan Charles Grenfell , Willman Cheryl L. , Hunger Stephen , Loh Mignon L. , Teachey David T. , Grupp Stephan A.
Published: March 2020

9506

Background: Therapy intensification for children with B-precursor ALL with high-risk genetic lesions has improved relapse-free survival. CRLF2 rearrangements and JAK2 and IL7RA mutations occur in 10-15% of adult and pediatric ALL patients, most of whom relapse. We and others identified aberrant kinase signatures and perturbed JAK/STAT and PI3K/mTOR signal transduction via in vitro studies of CRLF2-rearranged (CRLF2r) ALLs, suggesting the therapeutic relevance of signal transduction inhibitors (STIs). Our creation of CRLF2r ALL xenograft models has enabled rapid preclinical testing of STIs and measurement of in vivo target inhibition. We hypothesized that inhibition of JAK/STAT and PI3K/mTOR phosphosignaling correlates with therapeutic responses in these models. Methods: NOD/SCID/γc-null (NSG) mice well-engrafted with pediatric ALL samples were treated with the JAK inhibitor ruxolitinib, the mTOR inhibitor sirolimus, or vehicle for 72 hours (for signaling response) or 4 weeks (for therapeutic response). Splenocytes were briefly stimulated ex vivo with thymic stromal lymphopoietin (ligand for CRLF2) and stained with human-specific surface and intracellular phosphoantibodies for multi-parameter phosphoflow cytometry analysis. Results: Ruxolitinib-induced inhibition of phospho (p)-JAK2 and pSTAT5 was most pronounced in non-CRLF2r ALLs with novel JAK2-activating BCR-JAK2 and IL7RA/LNK mutations. Sirolimus potently inhibited pS6 and other PI3K/mTOR pathway phosphoproteins in the CRLF2r r ALLs. PSTAT5 and pS6 inhibition correlated with longer-term ruxolitinib- and sirolimus-induced decreases in ALL cell burden, demonstrating therapeutic responses to STIs. Conclusions: Ruxolitinib inhibited JAK/STAT phosphosignaling and markedly decreased leukemic burden in the JAK2-activating BCR-JAK2 and IL7RA/LNK mutant ALL xenografts. Sirolimus potently inhibited PI3K/mTOR (as well as some JAK/STAT) phosphosignaling and had greater therapeutic efficacy than ruxolitinib in the CRLF2r ALLs. The safety of ruxolitinib and of temsirolimus with cytotoxic chemotherapy are currently being established in Children’s Oncology Group Phase I trials.
Evaluation of the effect of care at NCI comprehensive cancer centers (NCICCCs) on disparities in outcome within adolescents and young adults (AYAs) with cancer.
Authors: Wolfson Julie Anna , Sun Can-Lan , Kim Heeyoung , Kang Tongjun , Bhatia Smita
Published: March 2020

9512

Background: AYAs (15-39y at diagnosis) with cancer have not seen the survival improvement evidenced by younger and older age groups with similar diagnoses, leaving an AYA Gap. While treatment on pediatric protocols is associated with superior survival in 15-21 year-olds, the impact of site of care on survival for vulnerable AYA subpopulations (age at diagnosis or race/ ethnicity) between 22-and 39y at diagnosis remains unstudied. Methods: We constructed a cohort of 10,727 patients newly diagnosed between the ages of 22- and 39y with lymphoma, leukemia, brain tumors, melanoma, thyroid and GU cancers, and reported to the LA County cancer registry between 1998 and 2008. Multivariable Cox regression analysis was conducted, and included race/ethnicity, age at diagnosis, SES, insurance status, primary cancer diagnosis and diagnosis year in the model; the analysis was stratified by site of care (NCICCC vs. non-NCICCC). Results: A total of 928 (9%) patients received treatment at the 3 NCICCCs (City of Hope, Jonsson Cancer Center and Norris Cancer Center) in LA County, and 9,799 received care elsewhere. Five-year overall survival (5y OS) was significantly worse for patients treated at non-NCICCC (87%) when compared with those treated at NCICCC (84%, p=0.02). In addition, 5y OS was worse for African Americans (71%) vs. non-Hispanic whites (89%, p<0.0001) and for older patients (31-39yo: 84%, vs. 22-30yo: 86%, p=0.0004). Multivariable analysis adjusting for SES, insurance status, diagnosis and diagnosis year revealed that African Americans (HR=1.4, p=0.0002) and older AYAs (31-39y: HR=1.24, p<0.0001) were at an increased risk of death. Among patients treated at NCICCC, the difference in risk of death due to race (African Americans: HR=0.8, p=0.7) and age (31-39yo: HR=1.1, p=0.6) was abrogated. On the other hand, among patients treated at non-NCICCC, these differences in outcome persisted (African Americans: HR=1.45, p =0.0002; 31-39yo: HR=1.25, p<.0001). Conclusions: Population-based data reveal that receipt of care at an NCICCC abrogates the effects of race and older age on mortality in AYAs with cancer. Barriers to accessing care at NCICCCs are being explored.
Use of whole genome sequencing to identify novel mutations in distinct subgroups of medulloblastoma.
Authors: Robinson Giles W. , Parker Matthew , Kranenburg Tanya , Lu Charles , Chen Xiang , Ding Li , Phoenix Timothy , Huether Robert , Thiruvenkatam Radhika , Wang Jianmin , Easton John , Onar-Thomas Arzu , Gajjar Amar J. , Ellison David W. , Mardis Elaine , Wilson Richard K. , Downing James , Zhang Jinghui , Gilbertson Richard J.
Published: March 2020

9518

Background: Medulloblastoma is a malignant childhood brain tumor comprising four discrete subgroups (SHH-subgroup, WNT-subgroup, subgroup-3 and subgroup-4). The genetic alterations that drive these subgroups and that might serve as treatment targets are largely unknown. Methods: We sequenced entire genomes of 37 tumors and matched normal blood. 136 somatically mutated genes identified in this discovery cohort were sequenced in an additional 56 medulloblastomas. All tumors were classified into the 4 subgroups by expression profiling and immunohistochemistry. All mutations were validated by custom capture, 454, or Sanger sequencing. Results: Recurrent mutations were detected in 49 genes: 41 are not yet implicated in medulloblastoma. Several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumors (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. Conclusions: We have identified several new recurrent somatic mutations that are enriched in specific subgroups of medulloblastoma. Alterations affecting subgroup-3 and 4 tumors appear to disrupt chromatin marking, most notably H3K27me3, potentially preserving a stem cell-like state in tumor cells. Mutations in WNT subgroup tumors affect binding partners of CTNNB1 that regulate WNT-response gene transcription. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
Real-time dynamic and sequential tracking of tumor propagation and associated immune responses in the CNS microenvironment.
Authors: Huang Alex Yee-Chen , Myers Jay T. , Othman Youmna , Barkauskas Deborah Sim , Petrosiute Agne
Published: March 2020

9520

Background: Ex vivo experimental systems are often unable to fully capture complex intercellular communication between tumor cells and surrounding tissues - a critical feature in understanding cancer development and immune evasion. Imaging modality such as bioluminescence lacks the resolution necessary to discern subtle structural differences and heterogeneity in the tumor niche. Microscopic examination of fixed specimens is devoid of the 3-dimensional context or evolution of tumor progression within the same host. Methods: New insights have come from studies involving the use of intravital 2-photon laser scanning microscopy (2P-LSM), which allows deep visualization (>300um) with single-cell resolution (<1um), thus enables direct observation of cellular behavior in intact tissues at a suitable dynamic spatial-time resolution. We study the role of tumor niche in shaping immune repertoire and develop strategies to modify tumor niche to enhance anti-tumor immunity. Results: One example is our study of glioblastoma multiforme (GBM), which contains a cellular hierarchy with a CD133+ sub-population representing self-renewing and tumorigenic GBM stem cells (GSCs). In a xeno-transplant model, GSC was capable of tumor initiation in the mouse brain. To directly test the relative tumorigenic potential of GSCs (CD133+) and non-GSCs (CD133-), we inoculated paired tumor populations from the same primary GBM tumor cells and monitored tumor competition by serial 2P-LSM through implanted cranial windows. Serial 2P-LSM imaging shows that after 35 days, GBM formation was driven exclusively by GSCs but not non-GSCs. To interrogate tumor-associated immune responses, we inoculated syngeneic mouse glioma tumors into C57BL/6 mice. Using this and CNS-inflammatory models, we have begun to undercover the role of perivascular antigen-presenting cells and microglia in guiding the recruitment of CNS-bound lymphocytes. Conclusions: Our data provide the first direct functional evidence that CSCs are responsible for tumor propagation in GBM, and represent an in vivo experimental platform to monitor immunotherapeutic interventions.
Genome-based outcome prediction in MYCN nonamplified high-risk neuroblastoma.
Authors: Morales La Madrid Andres Eduardo , Stricker Thomas , Pytel Peter , Gosiengfiao Yasmin C. , Shohet Jason , Shimada Hiroyuki , Furman Wayne Lee , Zage Peter E. , Park Julie R. , Perlman Elizabeth , Guerrero Lisa , Salwen Helen , Chlenski Alexandre , London Wendy B. , Cohn Susan Lerner
Published: March 2020

9534

Background: Less than 40% of children with high-risk neuroblastoma achieve long-term survival, and at diagnosis, it is not possible to identify patients who will be cured. Microarray studies have proposed expression signatures associated with outcome within high-risk cohorts. However, integrating this technology as a clinical test has been difficult, in part due to the lack of available frozen tissue and high quality RNA. The nCounter overcomes this obstacle, using formalin-fixed paraffin embedded tissue (FFPE). Our objective is to test the correlation of a previously published “ultra high-risk” microarray gene signature developed in the MYCN nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 2006) with the gene expression signature obtained with the nCounter (NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified high-risk neuroblastoma samples. Methods: FFPE tumor samples linked to clinical outcome data were obtained from 6 collaborative institutions. Tumor content of each sample was assessed morphologically. RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding to the candidate genes were designed by NanoString. Hybridization reactions were performed in duplicate using 100 ng of RNA. Positive and negative control probes and housekeeping probes were included in every reaction and were used to normalize data for differences in purification, hybridization, and capture efficiencies Results: Forty-two MYCN nonamplified high-risk neuroblastoma samples were analyzed by the nCounter. The cohort 5-year event-free survival and overall survival were 44.6 +/- 8.0% and 53.8 +/- 8.4% respectively. Highly degraded RNA (RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle components analysis on normalized expression data showed differential expression of most of the genes with clustering of cases depending upon outcome (FDR = 0.05). Conclusions: Our results demonstrate that the nCounter can yield gene expression profiles that are similar to microarray gene signatures. Further investigation of the clinical utility the nCounter technology to prognosticate outcome in patients with high-risk neuroblastoma is warranted.