bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a geriatric management unit on the outcomes of hospitalized older adults with cancer in Mexico.
Authors: Henriquez Santos Gretell , de la O Murillo Andrea , Soto Perez De Celis Enrique
Published: June 2021

12039

Background: Geriatric assessments and interventions improve the outcomes of hospitalized older adults with cancer, but their implementation in developing countries is limited. We studied the effect of a specialized geriatrician-led inpatient geriatric management unit compared with a conventional internal medicine ward on the outcomes of hospitalized Mexican older adults with cancer. Methods: This retrospective study included patients aged ≥65 with solid tumors who had a cancer-related hospitalization at a public academic center in Mexico City between March 2015 and October 2018. Patients hospitalized in the geriatric management unit (cases) were paired in a 1:2 fashion with those in internal medicine wards (controls). Pairing was done by age (+/- 5 years), tumor type, and admission date (+/- 3 months). We studied the effect of being hospitalized in the geriatric management unit on length of stay (LOS), incidence of delirium, hospital-acquired complications, and in-hospital mortality. Multivariate logistic regression models for each outcome were created using variables which were significant on univariate analysis. Results: 300 patients (100 cases, 200 controls, median age 75) were included. The most common tumors were gastrointestinal (GI) (53%) and genitourinary (25%). Both groups were comparable regarding baseline comorbidities (Charlson index 8.5 vs. 7.7, p = 0.99) and illness severity at admission (NEWS2 score 2.6 vs. 2.3, p = 0.82). No difference in median LOS was found between cases and controls (9.1 vs. 9.5 days, p = 0.34). Diagnosis of a GI tumor (OR 3.4, 95% CI 1.3-5.5), hospital-acquired complications (OR 4.9, 95% CI 2.5-7.3), and delirium (OR 5.5, 95% CI 2.3-8.7) were associated with longer LOS. 14% of patients in both groups had delirium. Hospitalization in the geriatric management unit reduced the risk of delirium (OR 0.35, 95% CI 0.1-0.9), while a higher Charlson index (OR 1.2, 95% CI 1.0-1.4), NEWS2 score (OR 1.2, 95% CI 1.1-1.4), and hospital-acquired complications (OR 7.3, 95% CI 2.9-18.5) increased it. 34% of patients developed hospital-acquired complications. Diagnosis of a GI tumor (OR 1.9, 95% CI 1.1-3.3) and higher NEWS2 score (OR 1.2, 95% CI 1.1-1.4) increased the risk of hospital-acquired complications. No differences in in-hospital mortality were seen between cases and controls (12% vs. 10%, p = 0.59). A higher NEWS2 score at admission (OR 1.4, 95% CI 1.2-1.7) and delirium (OR 10.7, 95% CI 3.2-36.3) increased the risk of death. Conclusions: Among older Mexican adults hospitalized for a cancer-related diagnosis, receiving care in a geriatric management unit led to a significant decrease in the risk of delirium. No improvements were seen in LOS, complications, or in-hospital mortality, which were associated with tumor and patient-related characteristics. Geriatric co-management can lead to improved geriatric outcomes in developing countries with limited resources.
Predictors of early readmission to hospital and mortality in patients with malignant ascites: Analysis of the nationwide readmissions database.
Authors: Yazdanpanah Omid , Mir Tanveer , Kabashneh Sohaip , Azar Ibrahim , Nagasaka Misako , Al Hallak Mohammed Najeeb
Published: June 2021

12057

Background: Malignant ascites accounts for 7 percent of ascites cases in the United States. It is a common manifestation of several solid tumors and is associated with poor prognosis with median survival of 3 months. Moreover, patients with malignant ascites are at risk of recurrent hospitalizations. Hospital readmissions are costly for health-care system and are regarded as a quality of care index. Nevertheless, predictive factors for hospital readmissions and mortality in patients with malignant ascites are limited. Understanding these factors can expedite development of strategies to reduce the readmission and health-care costs. Methods: Utilizing the Nationwide Readmissions Database (NRD), we conducted a retrospective cohort study on patients admitted with malignant ascites between 2016 and 2018 across the United States. We used multivariable logistic regression to determine the predictors of unplanned 30-days readmissions and mortality among patients with malignant ascites. Results: Out of 130,648 patients hospitalized with malignant ascites, 15,756 individuals (12.1%) were readmitted within next 30 days. Predictors of early readmission included pulmonary embolism (OR 2.40; 95% CI 1.55-3.74), complicated diabetes (OR 1.28; 95% CI 1.05-1.56) and having Medicaid insurance (OR 1.34; 95% CI 1.11-1.62). In-hospital mortality for patients with malignant ascites was 14.1%. The comorbidities associated with increased mortality were liver disease (OR 1.87; 95% CI 1.77-1.97), pulmonary embolism (OR 1.60; 95% CI 1.34-1.90), renal failure (OR 1.39; 95% CI 1.27-1.52), and congestive heart failure (OR 1.27; 95% CI 1.16-1.38). Patients with Medicaid insurance also had higher mortality (OR 1.21; 95% CI 1.12-1.32) among the payers. Conclusions: One in eight patients with malignant ascites was readmitted to the hospital within 30 days of discharge. By examining the risk factors leading to readmission, this study helped to identify the subpopulations of patients likely to become more ill. The strong association of pulmonary embolism with readmission and in hospital mortality suggests the benefit of prophylactic anticoagulation. Furthermore, higher readmission and mortality rate within Medicaid insurance population can open a new window in studying health care disparities.
Predictors of falls after starting an exercise program: A secondary analysis in inactive, female cancer survivors participating in the GET FIT trial.
Authors: Tibbitts Deanne , Stoyles Sydnee , Dieckmann Nathan , Horak Fay B. , Luoh Shiuh-Wen , Li Fuzhong , Winters-Stone Kerri M.
Published: June 2021

12075

Background: Women treated for cancer are more likely to fall than women without a cancer history. Exercise is a fall prevention strategy for older adults that we are testing in the GET FIT trial as a fall prevention approach in women cancer survivors. Increasing physical activity, though, could acutely increase the risk of falls in inactive survivors with known fall risk related to treatment. Knowing who might be at risk prior to beginning an exercise program would inform additional safety precautions during exercise. Methods: We conducted a secondary analysis of baseline data from the GET FIT trial that enrolled inactive, older women who had completed chemotherapy for cancer. Women completed objective (muscle strength, static postural control, range of motion, physical functioning) and self-report (fall history, comorbidities, presence of neuropathy symptoms, pain severity, depressive symptoms, cognitive functioning, perceptions of lower extremity functioning, disability, fear of falling, demographic, and clinical characteristics) measures at baseline. Falls were prospectively collected during the 6 month intervention using monthly self report. Potential predictors of falls were included if univariate tests revealed significant differences between fallers and non-fallers. To identify the strongest predictors of falls, we used an automated model selection and multimodel inference approach to perform an exhaustive model search. Results: Baseline data were available for 415 participants with known faller status at the end of the intervention, of whom 31.3% (n = 130) reported at least one fall. The average age of the sample was 62.1±6.4 years and consisted mostly of non-Hispanic white, married, highly educated, overweight or obese women treated for breast cancer. Fallers (1+ falls) and non-fallers significantly differed on measures of fall history, comorbidities, pain, neuropathy, fear of falling, disability, perceived lower extremity functioning, cognitive functioning, depression, and postural control. The best model of faller status (per BIC) included postural control (p = 0.004), perceived lower extremity functioning (p = 0.072), and fear of falling (p = 0.030). Odds of ≥1 fall during the intervention increased by 1.72 (95% CI: 1.05-2.83) times for a 0.1-point decrease in postural control, 1.11 (1.04-1.19) times for a 0.1-point increase in fear of falling, and 1.02 (1.00-1.03) times for a 1-point decrease in perceived lower extremity functioning. Conclusions: Women cancer survivors with poor balance, poor self-rated functioning, and a fear of falling may need to take additional fall precautions when starting an exercise program. Clinical trial information: NCT01635413.
The effectiveness of a provincial symptom assessment program in reaching adolescents and young adults with cancer: A population-based cohort study.
Authors: Gupta Sumit , Sutradhar Rinku , Li Qing , Coburn Natalie G.
Published: June 2021

12101

Background: Symptom control is prioritized by cancer patients and may improve overall survival. Several jurisdictions have thus launched population-wide initiatives to assess symptoms at regular intervals. In Ontario, Canada, for example, all cancer patients are screened using the Edmonton Symptom Assessment System (ESAS) at every outpatient visit. Few studies have examined symptom burdens in adolescents and young adults (AYA). Previous work suggests that AYA symptoms differ from those in older patients, and that general screening tools may not be appropriate. Despite this, whether current symptom screening initiatives reach AYA with cancer are unknown. We therefore determined 1) Whether AYA with cancer were participating in ESAS screening, and 2) Which AYA were at highest risk of not being screened. Methods: We identified all Ontario AYA diagnosed with cancer at age 15-29 years between 2010-2018 and treated in adult centers. Patients were linked to population-based databases to identify all cancer-related outpatient visits in the year following diagnosis and whether visits involved completion of an ESAS form. Each patient’s first year was divided into two-week periods. For each period, AYA were considered either “unscreened” if they had a cancer-related visit but no ESAS score, or “screened” if they had a cancer-related visit with at least one ESAS score. Periods without cancer-related visits were not considered, given no potential for ESAS screening during such periods. Covariates included age at diagnosis, sex, cancer type, neighbourhood income quintile, and institution type [regional cancer centre (RCC) vs. community]. Multivariable logistic regression models were implemented under a generalized estimating equations approach to account for individual-level correlation. Results: The final cohort included 5,435 AYA. Within any given two-week period, only 36-45% of AYA attending cancer-related outpatient visits were screened. In adjusted analyses, age and sex were not associated with being screened. However, AYA living in the lowest income quintile neighbourhood were less likely to be screened [odds ratio (OR) 0.86, 95th confidence interval (95CI) 0.77-0.97; p = 0.01] compared to those in the highest. Patients with hematologic malignancies were least likely to be screened (OR 0.77, 95CI 0.67-0.88; p < 0.001), as were AYA attending community centers (OR 0.48, 95CI 0.42-0.55; p < 0.001). Conclusions: Despite a population-wide symptom assessment program, only a minority of AYA are screened. Though patients with hematologic cancers suffer from particularly high symptom burdens, they were less likely to be screened. Interventions targeting AYA are required to increase uptake, particularly among those in disadvantaged neighborhoods or attending community hospitals. Studies of AYA-specific symptom assessment tools are also warranted.
Cancer inpatient malnutrition risk, documentation, and ICD-10 coding in an academic medical center.
Authors: Aktas Aynur , Finch Lenna , Boselli Danielle , Walsh Declan , Kadakia Kunal C. , Giamberardino Lauren Dennis , Trufan Sally , Slaughter Daniel , Bose Rupali
Published: June 2021

12107

Background: Malnutrition (MN) is common in hospitalized cancer patients but often underdiagnosed. We evaluated the prevalence of MN risk, dietitian documented MN (DDMN), and physician coded malnutrition (PCMN) in a consecutive cohort of cancer inpatients in an academic, community-based medical center. Methods: Electronic medical records (EMR) were reviewed for inpatients with a solid tumor diagnosis staged I-IV and admitted to Atrium Health Carolinas Medical Center at least once between 1/1/2016 to 5/21/2019. All data were collected from the first admission EMR encounter closest to the cancer diagnosis date. High MN risk was a score ≥2 on the Malnutrition Screening Tool (MST) completed by an RN at admission. Registered Dietitian (RD) assessments were reviewed for DDMN and grade (mild, moderate, severe). PCMN diagnosis was based on MN ICD-10 codes extracted from the medical coder’s discharge summary. Multivariate logistic regression models identified associations between clinic-demographic factors and the prevalence of DDMN and PCMN with stepwise selection. Results: N=5,143; 48% females. Median age 63 (range 18-102) years. 70% White; 24% Black, 3% Latino. Most common cancers: thoracic 19% and digestive system (14% other, 11% colorectal). 28% had known stage IV disease. The MST was completed in 79%. Among those with MST ≥2 (N=1,005; 25%), DDMN and PCMN prevalence was 30% and 22%, respectively. In the entire cohort, 8% had DDMN; 7% PCMN; 4% both. Prevalence of MN risk, DDMN, and PCMN by cancer site are in the Table. DDMN (N=420) was mild 2%, moderate 16%; severe 66%; unspecified 16%. On discharge, PCMN (N=360) was mild 10%; moderate 0%; severe 69%; unspecified 21%. Male gender (OR 1.27 [1.01, 1.59]), Black race (OR 1.57 [1.25, 1.98]), stage IV disease (v. I-III) (OR 3.08 [2.49, 3.82]), and primary site were all independent predictors of DDMN (all p<0.05); Black race (OR 1.46 [1.14, 1.87]), stage IV disease (OR 2.70 [2.15, 3.39]), and primary site were independent predictors of PCMN (all p<0.05). Conclusions: 25% of cancer inpatients were at high risk for MN. Primary site, disease stage, and race were independent predictors of a greater risk. MN appears to be under-diagnosed compared to population studies. This is the first study to report the prevalence of MN in a large cancer inpatient database with a representative population.[Table: see text]
Randomized study of electric hand warmer (EHW) versus observation to avoid discomfort during scalp cooling for chemotherapy-induced alopecia (CIA) prevention.
Authors: Landeiro Luciana Castro G. , Dienstmann Rodrigo , Costa e Silva Matheus , Gonçalves Michele , Viana Priscila , dos Santos Ana Paula , de Castro Adriana , Teixeira Andrea , Costa Maira , da Silva Ceci , Almeida Malta Pamela Souza , Machado Roberto Mathias , Mathias Clarissa
Published: June 2021

12108

Background: CIA has been reported as the most disturbing adverse event of cancer treatment by most women receiving chemotherapy. Many strategies have been tested to minimize CIA, among which scalp cooling has proven high effectiveness. However, discontinuation rates of this technology vary from 3% to 13%, mostly due to headache, cold sensation and pain. EHW could be used to mitigate these side effects, produce heat on demand and a warming sensation. The primary objective of this study is to evaluated the impact of EHW device on the general comfort of breast cancer patients while on scalp cooling during chemotherapy treatment. Methods: Patients were randomly assigned to EHW use or observation. Thermal, sensory and general comfort were measured with pragmatic questionnaires after each chemotherapy infusion: neutral or hot as favorable thermal responses; comfortable and very comfortable as favorable sensory responses; finally, favorable outcomes in both thermal and sensory comfort questionnaires defined a positive result on the general comfort. We evaluated the impact of age (≤ or > 50 years), alopecia (grade 0 or 1/2), chemotherapy regimen (with or without taxanes) and EHW use (yes or no) in the different comfort scales using Logistic Regression (LR) models. Results: Forty women with early or locally advanced breast cancer were assigned to EHW (n = 20) or observation (n = 20) during neo(adjuvant) chemotherapy. Median age was 53 years, 67.5% concluded university education, 52.5% had comorbidities. Most patients had stage II disease (55%), largely ER/PR+ HER2- disease (67.5%), followed by triple negative (22.5%), and HER2+ (10%). Most frequent regimen was ACdd-Tdd (42.5%). Thirty-one patients (77.5%) continued scalp cooling during entire chemotherapy regimen (alopecia < grade 3). A favorable thermal response was seen in 79% of EHW applications as compared to 50% in control arm (odds ratio [OR] 3.79, P <.001). Sensory comfort was satisfactory in 82% of EHW applications as compared to 74% with control (OR 1.62, P =.1). General comfort was favorable in 73% of EHW applications as compared to 44% in control arm (OR 3.4, P <.001). Age, alopecia grade and taxane use did not significantly impact on comfort measures. Conclusions: Our study suggests that an EHW has a consistent favorable impact on thermal and general comfort of breast cancer patients under scalp cooling technology to prevent CIA. This simple device can improve patient´s quality of life and eventually avoid scalp cooling discontinuation due to discomfort.
The impact of the COVID-19 pandemic on African American cancer survivors living in metropolitan Detroit.
Authors: Beebe-Dimmer Jennifer Lynn , Lusk Chrissy , Ruterbusch Julie J. , Baird Tara , Pandolfi Stephanie , Hastert Theresa A. , Harper Felicity W. K. , Thompson Hayley , Schwartz Ann G.
Published: June 2021

12129

Background: COVID-19 has had profound direct and indirect effects on population health to date and long-term effects are anticipated. Vulnerabilities to the most serious consequences of infection include older age, obesity, African American race and the presence of comorbid conditions. African American cancer survivors represent a particularly high-risk group, therefore understanding the impact of the virus and our strategies to prevent its spread on this patient population is important. Methods: The Detroit Research on Cancer Survivors (ROCS) cohort is a unique effort to understand the determinants of poor outcomes in African American cancer survivors. Eligible participants were diagnosed with breast, prostate, colorectal, or lung cancer on or after 1/1/2013, or with endometrial or any other cancer before age 50 on or after 01/01/2016 and were identified through the Metropolitan Detroit Cancer Surveillance System cancer registry. To date, we have enrolled 4173 survivors. Full participation includes completion of a baseline survey, and collection of biospecimens, medical records and tumor tissue, if available. Participants are also followed annually for outcomes and changes in history. A supplemental survey focused on the impact of COVID-19 was offered to enrolled participants beginning in the spring of 2020. The results presented here include data from 890 survivors who also completed the ROCS COVID survey. Results: Nearly all ( > 99%) survivors reported some change in their daily activities in an effort to reduce the risk of infection. At the time of survey, just over 1/3 of participants reported being tested for the virus and among those, 12% reported positive results. More than 40% of survivors reported some disruption in their access to medical care. A substantial ( > 40%) proportion of survivors reported feeling anxious, depressed and/or isolated during the COVID-19 pandemic. Approximately 40% of patients reported changes in health behaviors as a direct result of the pandemic that are known to negatively affect survivorship outcomes (physical inactivity, smoking, alcohol use). Notably, 30% of survivors reported declines in physical activity and these declines were significantly associated with increased anxiety (p = 0.008), depression (p = 0.005) and poorer health-related quality of life (p < 0.001). Conclusions: The influence of the COVID-19 pandemic on African American cancer survivors has been substantial, affecting both their physical and mental health and access to needed medical care. Coupled with changes in health behaviors as a direct result of the pandemic, these factors will likely affect outcomes in this high-risk patient population making further study and interventions necessary to mitigate the long-term impact of the pandemic on cancer outcomes.
Association between Medicaid expansion under the Affordable Care Act and survival among newly diagnosed cancer patients.
Authors: Han Xuesong , Zhao Jingxuan , Yabroff Robin Robin , Johnson Christopher J. , Jemal Ahmedin
Published: June 2021

1502

Background: Medicaid expansion under the Affordable Care Act (ACA) is associated with increased insurance coverage and early stage at diagnosis among patients with cancer. Whether these gains translate to improved survival is largely unknown, however. This study examines changes in one-year survival rates among persons newly diagnosed with cancer following the ACA Medicaid expansion. Methods: Patients aged 18-62 years from 41 population-based state cancer registries diagnosed pre-(2010-2012) and post-(2014-2016) ACA Medicaid expansion were followed through October 1, 2013 and December 31, 2016, respectively. Difference-in-differences (DD) analysis was conducted to estimate changes in one-year overall and cause-specific survival rates associated with Medicaid expansion, adjusting for age group, sex, race/ethnicity, area-level poverty, urban/rural status and region. Stratified analysis was conducted by cancer type, sex and area-level poverty. Results: A total of 2,537,818 patients diagnosed with cancer were included from Medicaid expansion (N = 1,492,729) and non-expansion (N = 1,045,089) states. During follow-up, 291,854 patients died including 246,660 deaths from cancer. The one-year overall survival rate (%) increased from 88.1 pre-ACA to 89.1 post-ACA in Medicaid expansion states and from 85.6 to 86.4 in non-expansion states for both sexes combined, resulting in a net increase of 0.4 (95%CI = 0.3-0.6) in expansion states after adjusting for sociodemographic factors. By cancer site and for both sexes combined, the increase in adjusted one-year overall survival in expansion states versus non-expansion states was greater for cancers of lung (DD = 1.6; 95%CI = 0.8-2.5), pancreas (DD = 2.2; 95%CI = 0.5-3.9) and liver (DD = 3.4; 95%CI = 1.7-5.1); as were the increases for cervix (DD = 1.3; 95%CI = 0.1-2.5), melanoma (DD = 0.4;95%CI = 0.04-0.9), non-Hodgkin lymphoma (DD = 1.2; 95%CI = 0.1-2.2) and esophagus (DD = 7.1; 95%CI = 0.5-13.7) among women. The improvement in one-year overall survival was larger among patients residing in the poorest areas (DD = 0.7; 95%CI = 0.3-1.1) compared to those in the richest areas (DD = 0.2; 95%CI = -0.2 to 0.5), leading to a narrowing survival disparity by area-level poverty. Patterns in one-year cause-specific survival were similar. Conclusions: Medicaid expansion was associated with greater increase in one-year overall survival rates, largely driven by the improvements in survival for cancer types with poor prognosis, suggesting improved access to timely and effective treatments. Furthermore, the increase was largest in poorest areas, highlighting the promising role of Medicaid expansion in reducing health disparities. Future studies should monitor changes in longer-term health outcomes following the ACA.
Extracting non-small cell lung cancer (NSCLC) diagnosis and diagnosis dates from electronic health record (EHR) text using a deep learning algorithm.
Authors: Rich Alexander S. , Leybovich Barry , Estevez Melissa , Irvine Jamie , Singh Nisha , Cohen Aaron B. , Birnbaum Ben
Published: June 2021

1556

Background: Identifying patients with a particular cancer and determining the date of that diagnosis from EHR data is important for selecting real world research cohorts and conducting downstream analyses. However, cancer diagnoses and their dates are often not accurately recorded in the EHR in a structured form. We developed a unified deep learning model for identifying patients with NSCLC and their initial and advanced diagnosis date(s). Methods: The study used a cohort of 52,834 patients with lung cancer ICD codes from the nationwide deidentified Flatiron Health EHR-derived database. For all patients in the cohort, abstractors used an in-house technology-enabled platform to identify an NSCLC diagnosis, advanced disease, and relevant diagnosis date(s) via chart review. Advanced NSCLC was defined as stage IIIB or IV disease at diagnosis or early stage disease that recurred or progressed. The deep learning model was trained on 38,517 patients, with a separate 14,317 patient test cohort. The model input was a set of sentences containing keywords related to (a)NSCLC, extracted from a patient’s EHR documents. Each sentence was associated with a date, using the document timestamp or, if present, a date mentioned explicitly in the sentence. The sentences were processed by a GRU network, followed by an attentional network that integrated across sentences, outputting a prediction of whether the patient had been diagnosed with (a)NSCLC and the diagnosis date(s) if so. We measured sensitivity and positive predictive value (PPV) of extracting the presence of initial and advanced diagnoses in the test cohort. Among patients with both model-extracted and abstracted diagnosis dates, we also measured 30-day accuracy, defined as the proportion of patients where the dates match to within 30 days. Real world overall survival (rwOS) for patients abstracted vs. model-extracted as advanced was calculated using Kaplan-Meier methods (index date: abstracted vs. model-extracted advanced diagnosis date). Results: Results in the Table show the sensitivity, PPV, and accuracy of the model extracted diagnoses and dates. RwOS was similar using model extracted aNSCLC diagnosis dates (median = 13.7) versus abstracted diagnosis dates (median = 13.3), with a difference of 0.4 months (95% CI = [0.0, 0.8]). Conclusions: Initial and advanced diagnosis of NSCLC and dates of diagnosis can be accurately extracted from unstructured clinical text using a deep learning algorithm. This can further enable the use of EHR data for research on real-world treatment patterns and outcomes analysis, and other applications such as clinical trials matching. Future work should aim to understand the impact of model errors on downstream analyses.[Table: see text]
EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.
Authors: Roth Patrick , Gorlia Thierry , Reijneveld Jaap C. , De Vos Filip Yves Francine Leon , Idbaih Ahmed , Frenel Jean-Sebastien , Le Rhun Emilie , Sepulveda Sánchez José Manuel , Perry James R. , Masucci Laura , Freres Pierre , Hirte Hal W. , Seidel Clemens , Walenkamp Anna Maria Elisabeth , Dhermain Frederic , Van Den Bent Martin J. , O'Callaghan Christopher J. , Vanlancker Maureen , Mason Warren P. , Weller Michael
Published: June 2021

2004

Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 study arms. No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR = 0.99). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.
Long-term results of the GEINO 1401 TRIAL: Randomizing patients to stop or to continue temozolomide until 12 cycles.
Authors: Domenech Marta , Fabregat-Franco Carles , Mesia Carlos , Esteve Anna , Berron Sonia Del Barco , Pineda Estela , Gironés Sarrió Regina , De las peñas Ramon , Fuster Jose , Navarro L Miguel , Alonso Miriam , Olier Clara , Perez Pedro , Berrocal Alfonso , Covela Rúa Marta , Hernandez Gonzalez Ainhoa , Carrato Cristina , Sanz Carolina , Sepulveda Sánchez José Manuel , Balana Carmen
Published: June 2021

2013

Background: We previously presented our results of the GEINO 1401 trial that randomized patients diagnosed with glioblastoma and treated with chemoradiotherapy and adjuvant temozolomide (TMZ) followed by six cycles of TMZ, to receive an extended use of TMZ up to 12 cycles or to control. We found no differences in 6-months neither progression free survival (PFS) nor overall survival (OS). In this report we actualize our results and analyse long-term survivor patients (LTSP). Methods: The trial NCT02209948 randomized (ratio 1:1) 159 patients diagnosed with glioblastoma who had been treated with standard therapy to stop treatment or to continue up to 12 cycles of TMZ. Patients were stratified based on their O6-methylguanine-DNA-methyltransferasa (MGMT) methylation status and presence or absence of measurable disease at inclusion. We update here OS outcomes and analyse the data of LTSP defined as an OS over 30 months from diagnosis. Results: At a median follow-up of 20 months, 82.4% of the patients had died and 89.9% had progressed. The median OS from randomization was 22.0 months for the control arm and 18.2 for the experimental arm: HR 0.957 (95%CI 0.806-1.136, p = 0.615). At 2 years from randomization there were a 61% of survivors in the TMZ group and 62% in the control group. There were a 49.7% of LTSP showing no differences between TMZ and control group. We found a higher prevalence of methylated MGMT in LTSP, but no differences were shown in patients with or without measurable disease at inclusion, status of IDH and the use of bevacizumab after progression. Conclusions: Adding 6 cycles of TMZ after the first 6 adjuvant cycles confers no additional benefit in OS. Nearly 50% of the patients included in GEINO 1401 who had been previously treated with TMZ 6 cycles without progressing were LTSP. Clinical trial information: NCT02209948.
Randomized phase 2 study of nivolumab (nivo) plus either standard or reduced dose bevacizumab (bev) in recurrent glioblastoma (rGBM).
Authors: Ahluwalia Manmeet Singh , Rauf Yasmeen , Li Hong , Wen Patrick Y. , Peereboom David M. , Reardon David A.
Published: June 2021

2015

Background: Trials with anti-PD1 in rGBM have shown limited efficacy. VEGF is highly up regulated proangiogenic growth factor in GBM contributing to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. Methods: 90 patients with first-recurrent GBM were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Single cell RNA sequencing with CITE-seq was used to analyze blood samples from pre- and 8 weeks post-treatment among 8 responders and 8 non-responders. Progression-free survival (PFS) and overall survival (OS) were compared between two arms. Results: 90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 of 88 patients were MGMT methylated (2 indeterminate). Overall OS was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p = 0.14), while OS was better for arm A in age > 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P = 0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P = 0.90). Single cell RNA sequencing with CITE-seq was used to analyze blood samples from 16 patients, baseline and 8 weeks post treatment. Standard dose bevacizumab treated patients had decreased myeloid derived suppressor cells and an inflammatory response gene signature at 8 weeks. Most frequent toxicities ( > 20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. Conclusions: Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab may benefit older but not younger patients. Ongoing response evaluation and immunocorrelative data will be presented. Clinical trial information: NCT03452579.
Presentation and management of patients with brain metastases of primary melanoma, non-small cell lung cancer, and breast cancer origin.
Authors: Kawahara Yuki , Mills Matthew , Potluri Thrisha , Fahey Matthew , Figura Nicholas B , Soyano Aixa , Washington Iman , Diaz Roberto , Oliver Daniel Eli , Yu Hsiang-Hsuan Michael , Etame Arnold B. , Vogelbaum Michael A. , Czerniecki Brian J. , Arrington John , Sahebjam Solmaz , Soliman Hatem Hussein , Forsyth Peter A. J. , Han Hyo S. , Ahmed Kamran A.
Published: June 2021

2033

Background: As systemic therapy improves; the prevalence of brain metastases is increasing. Screening brain MRIs are currently recommended for all stage ≥ II non-small cell lung cancer (NSCLC) and stage IIIB–IV melanoma patients, but only when neurologic symptoms arise in stage IV or recurrent breast cancer (BC) patients. This study assessed the presentation and institutional outcomes treating brain metastases (BM) of BC, NSCLC, and melanoma origin. Methods: Patients with BM treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Characteristics of initial BM diagnoses were retrieved from clinical chart review. Kruskal-Wallis and Pearson’s chi-square tests were used to test differences between groups. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan–Meier method. Results: A total of 959 patients were identified (BC 18%, NSCLC 51%, melanoma 31%). BC patients were younger at initial presentation (BC median age: 57, NSCLC 65, melanoma 62, p< 0.0001). At BM diagnosis, BC patients were more likely to have concurrent systemic metastasis (BC 77%, NSCLC 42%, melanoma 69%, p< 0.0001), at least 5 BM (BC 27%, NSCLC 14%, melanoma 13%, p= 0.0004), and leptomeningeal disease (BC 23%, NSCLC 6%, melanoma 6%, p< 0.0001). Patients with BC were significantly more likely to receive whole brain radiation therapy (WBRT) (BC 58%, NSCLC 37%, melanoma 22%, p< 0.0001) and less likely to receive stereotactic radiation (BC 26%, NSCLC 48%, melanoma 58%, p< 0.0001) following initial BM diagnosis. There were no significant differences in surgical resection between cancer types (BC 24%, NSCLC 24%, melanoma 29%, p =0.166). Median OS was shorter for BC (BC 9.9 months, NSCLC 10.3 months, melanoma 13.7 months, p= 0.0006) following BM diagnosis. Conclusions: Our institutional analysis found BC patients were more likely to be younger, present with more advanced brain disease, require WBRT, and have poorer OS than NSCLC and melanoma patients following initial brain metastasis diagnosis. This may be due in part to a lack of brain MRI screening recommendations in BC. Further investigation is needed to determine which BC patients are at sufficient risk to warrant brain MRI screening.
Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.
Authors: Lickliter Jason D. , Jennens Ross , Lemech Charlotte Rose , Kichenadasse Ganessan , Cai Dongpo , Su Steven Yung-Chang
Published: June 2021

2037

Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.
Gene fusions in glioblastoma: Results of Gliocat project.
Authors: Hernandez Gonzalez Ainhoa , Esteve-Codina Anna , Carrato Cristina , Munoz Ana , Pineda Estela , Gallego Rubio Oscar , Arpi Oriol , Gut Marta , Martinez Garcia Maria , Lopez Raquel , Mesia Carlos , Barco Berron Sonia DEL , Sanz Carolina , Chen Sun , Domenech Marta , Alameda Francesc , Balana Carmen
Published: June 2021

2042

Background: Malignant gliomas are heterogeneous diseases in genetic basis. The development of sequencing techniques, such as RNA-Sequencing, has identified many gene rearrangements encoding novel oncogenic fusions. Gene fusion discovery can potentially lead to the development of novel treatments, however studies of gene fusions in glioma remain limited. Methods: The GLIOCAT project studied 139 patient samples of newly diagnosed glioblastoma who had received the standard first-line treatment from 2004 to 2015, to identify gene fusion events from glioblastoma transcriptome data (RNA-Seq). The molecular subtype could be studied in 124 cases. RNA-Seq reads were mapped against the reference human genome with STAR-fusion version 0.7.0, specifically, with FusionInspector validate ( http://star-fusion.github.io ). Two other platforms, FusionHub ( https://fusionhub.persistent.co.in ) and Oncofuse ( www.unav.es/genetica/oncofuse.html ), were applied to eliminate false positives or previously described in healthy tissue and to predict of the oncogenic potential each fusion. Results: A total of61 patients showed 103 different fusions, a median of two fusions by sample. The majority of gene fusions were intrachromosomal and most frequently implied chromosome was 12 followed by 7. In addition, fusions were more common in patients with MGMT promoter methylation, TCGA classical subtype and 18 IGS subtype. There were no differences in age, sex, type of surgery or long survivors ( > 30 months). Ten fusions were already described in cancer, including three in gliomas (FRS2-KIF5A, EGFR-SEPT14 and FGFR3-TACC3). From the detected fusions, 22 of them included an oncogene or protooncogene. Conclusions: In our study, we report the landscape of gene fusions from a large data set of glioblastomas analyzed by RNA-seq. The majority of the fusions were private fusions. A minority of these recur in a low frequency but as many as a quarter of them included an oncogene or protooncogene. RNA-seq of GBM patient samples it is an important tool for the identification of patient-specific fusions that could drive personalized therapy. Furtherless, we will plan to validate this gene fusions.
BDB001, an intravenously administered toll-like receptor 7 and 8 (TLR7/8) agonist, in combination with pembrolizumab in advanced solid tumors: Phase 1 safety and efficacy results.
Authors: Patel Manish R. , Tolcher Anthony W. , Rasco Drew W. , Johnson Melissa Lynne , Alistar Angela Tatiana , Li Lixin , Chung Alexander H. , Andtbacka Robert H.I.
Published: June 2021

2512

Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.