bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel support vector machine to predict sentinel lymph node status in elderly patients with breast cancer.
Authors: Hassan Abbas , Tamirisa Nina , Singh Puneet , Offodile Anaeze Chidiebele , Butler Charles E.
Published: June 2022

1560

Background: Routine sentinel lymph node biopsy in older breast cancer patients with favorable tumor biology is not recommended. However, cases must be evaluated on an individual basis to avoid under or over-treatment. Many nomograms have been developed to calculate the risk of nodal positivity, but machine learning (ML) is a novel tool that may improve the accuracy of nodal prediction. In this study, we developed a support vector machine (SVM) model to delineate factors indicative of sentinel lymph node positivity and refine individualized nodal risk assessment for this heterogeneous patient population. Methods: We conducted a single-institution comprehensive retrospective review of patients 70 years or older diagnosed with unilateral stage I–III primary breast cancer from January 2005 to January 2016. Patient data was partitioned into training and testing sets. A SVM model was developed to predict lymph node status using patients’ demographics, tumor stage, genetic profile, and imaging data. Primary outcome was model performance determined by area under the curve (AUC). Secondary outcomes were accuracy, sensitivity and specificity. Permutation feature importance (PFI) analysis and accumulated local effect (ALE) plots were used to evaluate significant predictors identified by the SVM. Results: We identified 1706 consecutive patients who met the study criteria with a mean age of 76±4.5 years. The plurality of patients were Caucasian (82%), had ER+ (86%), PR+ (70%), HER2- (87%) stage I (72%) breast cancer. Sixteen percent of patients (n = 271) had a positive sentinel lymph node biopsy. The SVM model demonstrated good discriminatory performance for predicting sentinel lymph node positivity with mean AUC of 0.70 (95%CI, 0.62-0.77), mean accuracy of 84% (95%CI, 80-88%), mean sensitivity of 61% (95%CI, 57-66%), and mean specificity of 62% (95%CI, 52-73%). PFI and ALE identified higher disease stage, younger age, family history of breast cancer, margin status, estrogen and progesterone receptor positivity as independently associated with high risk of sentinel lymph node positivity. Conclusions: The proposed ML model accurately identified sentinel lymph node status in older patients with breast cancer. This model holds promise for counselling patients as to the potential risk for node positive disease which may impact surgical and adjuvant therapy recommendations.
Comparative effectiveness of different interventions for cancer-related fatigue delivered digitally by online platforms.
Authors: Kosmidis Paris A. , Deligianni Elena , Kosmidis Thanos
Published: June 2022

1576

Background: As cancer treatments improve, patients’ quality of life becomes even more important. In parallel, supportive care delivery is increasingly challenging, also due to resource pressures and COVID19. The effectiveness of digital and remote patient support tools as a complementary approach to improve patients’ quality of life is under evaluation. Fatigue is considered among the most prevalent and persistent side effects regardless of tumour type; also, despite ongoing research, there is no single approach established. We compare the effectiveness of different self-care interventions delivered by online platforms to cancer patients in several countries. Methods: Patients report side effects (including Fatigue) on the CareAcross online platforms and receive tailored support to help them improve their quality of life. The supportive material encompasses many topics, and patients may receive several combinations. For Fatigue, different topics (nutrition, hydration, rest etc) were analysed to evaluate effectiveness based on prospectively collected patient reported outcomes. Results: 1456 breast, lung, colorectal or prostate cancer patients from 8 countries (mainly UK, Germany, France, Spain, Italy) reported Fatigue at least once. This analysis focuses on persistent fatigue: 1215 patients reported Fatigue more than once, receiving up to 7 permutations of topics (F1-F7; F4-7 consist of F1-3 combinations). All permutations include the “Physical Activity” topic (see Table). Overall, the “Hydration” topic stands out as consistently linked with the most effective material (all except F3). Comparative analysis between similar combinations shows that those with “Anemia warnings” and “Rest” tend to be more effective (F7>F6). Ambiguously, the “Physical activity before & after treatment”, “Relaxation exercises” and “Fatigue diary” topics contribute to effectiveness (F5>F1), but do not counterbalance absence of the previous 3 (F1>F3). Food-related topics have unclear impact, too: “Food types” is absent from the top combination (F2) where “Food timing” is used; however, that topic is linked with a slightly inferior combination (F7>F5). Conclusions: Fatigue is a complex, multifactorial challenge; digitally delivered interventions can lower its incidence. Hydration appears effective, but the nature of these interventions complicates their thorough evaluation. Randomised studies may enhance these findings and enable additional personalisation towards further quality of life improvements. [Table: see text]
Electronic capture of cancer-related distress in a community oncology program.
Authors: Sanyal Amit , Bowen Heather , Janssen Clemens Walter , Weber Alissa Ashley
Published: June 2022

1577

Background: Cancer related distress can be seen in as many as one in two patients. Many organizations such as the Commission on Cancer require distress screening. National Comprehensive Cancer Network (NCCN) distress thermometer is a common tool used for screening. We studied feasibility of embedding the NCCN thermometer into oncology electronic health record (EHR) for routine patient care. We concurrently studied feasibility of using a mobile health tool for serial evaluation of cancer related distress. Methods: A flowsheet containing NCCN distress thermometer questions was created in Epic EHR (Epic Systems, Verona, WI). Oncology nurses used the flowsheet for routine patient assessment. Patients with distress level ≥ 4 answered additional questions. Ancillary care providers such as palliative care nurses or social workers addressed the identified needs by providing appropriate ‘services’. A field to capture these interventions was created. We also adapted our previously reported web based mobile tool [1] for monitoring cancer distress. Patients rated their distress on a 1-10 scale and highlighted the distress domain (physical, emotional, practical, family). Distress level ≥ 4 generated a color-coded flag for provider review and intervention. Data from both electronic tools was periodically analyzed to inform patient care and quality improvement. Results: Between January and December 2021, Epic EHR based distress flowsheet collected 28,594 distinct responses in 911 patients. 57.4%, 14.9%, 14.1%, 9.4% and 2.3% of the responses were in the physical, emotional, practical, familial and spiritual domains respectively. ‘Other’ responses were 1.4%. Cumulative frequency of non-physical problems was 42.5%. 1819 ‘services’ were provided with 357 emotional, 351 work, 351 housing, 350 transportation and 350 financial need-based interventions. Of 1231 patients who used the distress scale and provided additional comments, 315 (25.5%) had distress levels ≥ 4. The mobile tool captured 849 unique patient responses to the distress question between April 2020 and February 2022. Distress level ≥ 4 was flagged by 281 unique patients (33.09%). Average distress level was 2.7. Emotional domain problems generated the greatest distress level followed by family, physical and practical problems in decreasing order. Conclusions: We demonstrate feasibility of electronic capture of cancer related distress to facilitate holistic patient care in a community-based oncology program. EHR based and mobile tool distress evaluations generated concordant results. Distress caused by emotional, practical and familial domain problems was nearly as frequent and often more severe than distress caused by physical problems, underscoring the need for comprehensive cancer care. References:Sanyal, A. Mobile health tool for monitoring cancer treatment complications. 2020 ASCO Quality Care Symposium: American Society of Clinical Oncology.
Disparity in initiation of checkpoint inhibitors among metastatic melanoma and lung cancer.
Authors: Li Meng , Liao Kai-Ping Eric , Chen Alice , Wehner Mackenzie , Shih Ya-Chen Tina
Published: June 2022

1583

Background: Checkpoint inhibitors are transforming cancer care. However, the high prices of these medicines raise concerns over their affordability and disparity in use. The objective of this study is to describe the disparity in initiating checkpoint inhibitors and examine patient- and area-level factors associated with delayed initiation. Methods: This study is a retrospective cohort study using Optum data. We identified commercially insured patients newly diagnosed with metastatic lung cancer and melanoma since the introduction of checkpoint inhibitors in these cancers (lung cancer cohort: diagnosed between January 2015 and December 2020; melanoma cohort: diagnosed between January 2011 and December 2020). Time from metastatic cancer diagnosis to initiating checkpoint inhibitors was analyzed using Cox proportional hazard models. Independent variables included county-level measures (percentage of black population, percentage of Hispanic population, percentage of other minority, percentage of population living below poverty line, rurality, number of medical oncologist per population, and having a National Cancer Institute designated cancer center) and patient-level characteristics (age, sex, Charlson comorbidity index, any dual eligibility, Medicare Advantage, and year of diagnosis). We clustered standard errors at the county level. Results: The percentage of metastatic lung cancer and metastatic melanoma patients on checkpoint inhibitors increased from 23% to 52% from 2015 to 2020 and from 22% to 58% from 2011 to 2020. Counties with greater percentage of black, Hispanics, and other minorities were high urban with greater density of medical oncologists and NCI-designated cancer centers. However, greater percentage of Hispanic population in a county was associated with significantly slower initiation of checkpoint inhibitors for both the lung cancer and the melanoma cohorts (hazard ratios [HR]: 0.937 and 0.946, respectively; p-values: < 0.001 and 0.014, respectively). Percentage of other minority population in a county was associated with slower initiation for metastatic lung cancer (HR: 0.983; p-value: < 0.001). No other county-level factors had a significant coefficient from the multivariate Cox models. In terms of patient-level characteristics, older age, female, more comorbidities, any dual eligibility, and Medicare Advantage were associated with significantly slower initiation for the lung cancer cohort and older age and female were associated with significantly slower initiation for the melanoma cohort. Conclusions: Commercially insured metastatic lung cancer and melanoma patients who lived in counties with greater percentage of Hispanic population had slower initiation of checkpoint inhibitors after their cancer diagnosis, despite the fact that those counties had greater density of medical oncologists and NCI-designated cancer centers.
Reliability of cancer registry primary payer information and implications for policy research.
Authors: Davidoff Amy J. , Enewold Lindsey , Williams Courtney , Bhattacharya Manami , Sanchez Janeth I.
Published: June 2022

1587

Background: Researchers commonly use “Primary Payer at Diagnosis” measured in cancer registry data to assess the impact of health policy, such as the Affordable Care Act, on insurance, and the impact of insurance on cancer care and outcomes. Measurement error may bias estimated effect size and significance. Little is known about patterns of Medicaid or Medicare misreporting in registry databases commonly used for policy analysis. Methods: We used the National Cancer Institute’s Surveillance, Epidemiology and End Results registry data for adults aged 19-64 years at diagnosis with known cancer stage, linked to most recently available (2007-2011) CMS records on Medicaid and Medicare enrollment at diagnosis month. We recoded the registry Primary Payer variable into 6 categories: private/managed care, Medicare, Medicaid, other government, status unknown, uninsured. State-year policy data regarding Medicaid eligibility and managed care enrollment were also linked. We compared the registry data to Medicaid and/or Medicare enrollment data, and calculated underreporting rates by patient characteristics and state policy. Results: The linked sample (N = 896,031) was 68% non-Hispanic white, 49% male. Overall, the registry data reported 7.8% Medicare and 10.1% Medicaid, while enrollment was 5.5% Medicare, 10.4% Medicaid, and 3.4% dual Medicare-Medicaid. The registry data concordantly identified 61.4% and 57.7% of persons identified per enrollment data to be Medicaid-only and Medicare-only, respectively (Table). Most Medicaid-only enrollees without concordant registry information were reported to have private insurance or be uninsured. Medicaid underreporting (39% overall), was higher for males (43%) vs females (37%), in low (46%) vs high (38%) poverty areas, for Medicaid poverty expansion or waiver enrolled (50%) vs cash assistance related eligibility (33%), and in states with large managed care enrollment, all at p<.001. If Medicaid and Medicare enrollment data were used to edit the registry data, 8% of persons would switch insurance assignment. Conclusions: Primary Payer data reported by cancer registries are subject to measurement error and may result in biased estimates of insurance-related policy impacts. Enhancement with objective Medicaid and Medicare enrollment data will reduce measurement error and may result in unbiased estimates necessary to support policy assessment. [Table: see text]
Responses to telehealth expansion for older adults with cancer during the COVID-19 pandemic.
Authors: Higashi Robin T , Etingen Bella , Cole Suzanne , Mansour John C. , Sweetenham John W. , Lee Jessica L. , Hogan Timothy P.
Published: June 2022

1591

Background: Synchronous video visits (“telehealth”) were rapidly adopted to facilitate provision of cancer care during the COVID-19 pandemic, with little time to comprehensively assess patient and provider needs. Attitudes toward telehealth use during active treatment (vs. survivorship care) were largely unknown, as were perceptions of, experiences with, and needed support for telehealth use among older adults with cancer. Older adults in particular may face increased vulnerability to inequities in access to care due to limited digital literacy. Methods: We conducted surveys and semi-structured interviews with providers, staff, and older patients (age ≥60) from a comprehensive cancer center. Data collection occurred between Dec 2020 - Nov 2021. Results: We completed a total of 106 provider/staff surveys, 128 patient surveys, 20 provider/staff interviews, and 15 patient interviews. A majority of surveyed providers/staff felt that telehealth should “definitely be offered” during treatment-phase encounters (55.9% treatment follow-up; 69.1% results communication; 70.2% discussing treatment side effects). Similarly, most patients indicated they would be willing to have video visits with a member of their care team for: discussing treatment side-effects (73.5%), results communication (69.6%), and treatment follow-up (65.7%). Patients reported experiencing challenges with joining video visits (29%) and understanding the telehealth process (28%). Similarly, less than a third (30.8%) of providers/staff agreed or strongly agreed that the institution did a good job of preparing patients for their first telehealth encounter. Patients felt the institution should do more to communicate the advantages of telehealth to older adults in handouts and videos, which included: engaging multiple family members in critical appointments (e.g., treatment decisions, end-of-life), seeing their doctor when they were too sick to travel, and reducing potential exposure to infectious disease at the clinic. Participants suggested several strategies to assist patients with limited digital literacy: offering video tutorials of the connection process, creating “fake appointments” to practice online connections, and hiring a digital navigator to assist with technical difficulties and setup of the online portal. Despite challenges, a majority of surveyed patients (65.7%) and providers/staff (76.9%) intend to continue using telehealth after the COVID-19 pandemic passes. Conclusions: Use of telehealth for cancer care was received positively by older patients and providers/staff. Taking targeted steps to enhance implementation could reduce barriers to care, including among older adults and other populations with limited digital literacy, thereby promoting greater equity of access to telehealth benefits beyond the pandemic.
Evaluation of a pharmacist-led video consultation to identify drug interactions among patients initiating oral anticancer drugs.
Authors: Lichtenstein Morgan RL , Patel Khilna , Campbell Peter , Nguyen Michelle K. , Harden Erik , Spivack John , Collins Nicole , Faheem Khadija , Beauchemin Melissa Parsons , Crew Katherine D. , Accordino Melissa Kate , Trivedi Meghna S. , Elkin Elena B. , Hershman Dawn L.
Published: June 2022

1592

Background: The past decade has seen a dramatic increase in the number of oral anti-cancer drug (OACD) approvals in the United States. Though polypharmacy and drug-drug interactions (DDIs) likely contribute to OACD toxicity, the prevalence of these features in patients on OACDs remains largely unknown. We aimed to evaluate a one-time 30-minute pharmacist-led video consultation among metastatic cancer patients initiating OACDs to identify medication list inaccuracies as well as the prevalence, characteristics, and severity of OACD-related potential DDIs. Methods: We conducted a single-arm, prospective telehealth intervention study among 29 patients initiating OACDs to evaluate a one-time 30-minute pharmacist-led video consultation. The video visits focused on identifying and discussing polypharmacy and potential DDIs, and pharmacists then communicated recommendations to each patient's oncologist. We estimated the prevalence, characteristics (QTc prolongation, absorption interactions, etc.), and severity of OACD-related potential DDIs. Lexicomp and Micromedex were used to assess potential DDIs and measure severity on a standardized scale (A – D, X). In addition, we assessed the prevalence of medication list inaccuracies, polypharmacy, and patient satisfaction. Results: Twenty-five patients completed the intervention (86% completion rate) of whom 40% were 75 years of age or older and 60% were men. The majority were white (68%) and non-Hispanic (76%). Sixteen patients (68%) had a solid tumor diagnosis. Nearly half (48%) were insured by Medicare. The median number of medications per patient was 9 with a range of 4 – 21, and 96% of patients had at least 5 prescriptions listed. The median number of medication list errors was 2 with a range of 0 – 16, with at least 1 error for 76% and more than 1 error for 52% of patients. Pharmacists identified potential OACD-related interactions in 9 cases (40%). These included change in drug absorption or metabolism (7), QTc prolongation (1), hypotension (1), and bleeding (1). Interactions were classified as either category C (8) or D (2), requiring close monitoring or a change in treatment, respectively. All patients expressed a high level of satisfaction with the video visit. Conclusions: Polypharmacy, medication list errors, and potential DDIs are prevalent among patients initiating OACDs despite use of an electronic medical record requiring medication reconciliation. Our study suggests that a one-time remote 30-minute pharmacist-led video consultation can effectively identify and address OACD-related potential DDIs, which may decrease medication complexity and improve adherence in this population.
Hematology/oncology outpatient perspectives on telehealth one year into the COVID-19 pandemic.
Authors: Blaes Anne Hudson , Jewett Patricia , Holtan Shernan , Lindgren Bruce , Hui Jane , Boucher Alexander Albert
Published: June 2022

1594

Background: Telehealth use expanded during the COVID-19 pandemic, but few studies have explored patient perspectives on it after the initial months. Using mixed methods, we aimed to understand patient telehealth perspectives and to examine for whom telehealth is less optimal. Methods: A modified Telemedicine Satisfaction and Usefulness Questionnaire (TSUQ) for hematology/oncology outpatient care was sent to patients ≥18 years old within the M Health Fairview Masonic Cancer Clinic with ≥1 prior telehealth visit (phone and/or video). Two focus groups were also conducted. We summarized cohort characteristics and views on telehealth. We dichotomized selected TSUQ items (measured on a 1-5 scale) and evaluated them using logistic regression, adjusted for age (<65 years, ≥65 years), gender, race (White, other), income (<$50,000, $50,000-99,000, ≥$100,000, prefer not to say), education (no college degree, at least college degree), and having cancer (yes, no). Focus group data were analyzed qualitatively. Results: Of 7848 invitations, 588 surveys were completed (7.5% response rate). For respondents, 71% were female, 68.7% married/partnered, 90.6% identified as White, and 36.1% had a graduate/professional degree with an annual salary ≥$150,000 (21%). Most had cancer (73.3%) but were not currently receiving treatment (36.5%); 40% each had employer-based insurance or Medicare. Focus group members (n = 16) were chosen from a demographic mix of 121 volunteers. Most survey respondents found telehealth satisfactory [mean 3.8 ± standard deviation (SD) 0.9] and easy to use (mean 3.4 ± SD 0.9), 72.2% found it convenient, and 82.2% agreed that it saved time. Most (78.6%) would be happy with a combination of telehealth and in-person care going forward, but those with cancer were less likely to prefer future telehealth care (adjusted odds ratio [OR] 0.52, 95% confidence interval [CI] 0.34 - 0.81). Being male and having lower incomes were associated with greater telehealth satisfaction, (male vs. female, OR 1.68, 95% CI 1.00 - 2.83), income <$50,000 vs. ≥$100,000 (OR 2.47, 95% CI 1.16 - 5.28). Focus group members reported between 1 - 30 telehealth visits (overall care range 8 months - 30 years). Views on telehealth mirrored survey results. Time saved and reduced exposure risk were beneficial, especially for those in rural settings and for those seeing genetic counselors or palliative care. However, concerns were voiced about fewer in-person interactions, communication gaps, and provider style variability. Conclusions: Our findings show that oncology patients prefer care in person despite telehealth’s benefits. Additional work is needed to ascertain the optimal, and possibly patient subgroup-specific, combination of in-person and telehealth in ambulatory hematology/oncology care to manage the needs of different populations.
Multi-institutional randomized phase 3 trial comparing cancer stem cell-targeted versus physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135).
Authors: Ranjan Tulika , Sengupta Soma , Glantz Michael J. , Lu-Emerson Christine , Green Richard M. , Howard Candace M. , Yu Alexander , Chen Ricky , Chaudhary Rekha T. , Aregawi Dawit , Glass Jon , Mammoser Aaron Gerald , Moulding Hugh , Jubelirer Steven , Schroeder Jason , Anderson Mark Daniel , Lirette Seth T. , Alberico Anthony , Valluri Jagan , Claudio Pier Paolo
Published: June 2022

2028

Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy selected by ChemoID assay provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. Methods: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. The primary endpoint was overall survival (OS). Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P =.010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P =.008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P <.001). Conclusions: Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group. Clinical trial information: NCT03632135.
Investigating the impact of NGS data availability on clinical decision-making in brain cancer.
Authors: Eckburg Adam , John Jordan , Kumthekar Priya
Published: June 2022

2032

Background: Next-generation sequencing (NGS) of cancer specimens is a valuable diagnostic tool that can provide detailed information regarding specific somatic genetic alterations within a tumor with potential for targeted treatment. Despite the increasing availability of NGS, preliminary data by John et al. from ASCO 2021 suggested that clinical decision making is not frequently impacted by NGS results in the setting of glioblastoma. Herein, we report how NGS data impacts other primary tumor types, including astrocytoma, oligodendroglioma, and various rare subtypes. Methods: A retrospective chart review was performed to assess the proportion of brain cancer patients receiving targeted treatment instead of standard therapeutics after NGS sequencing. Pertinent medical information was ascertained from Epic and the Electronic Data Warehouse. Targeted treatments were defined as those recommended by the Tempus report for NGS-identified potentially actionable mutations. Patients were stratified into one of three categories: astrocytoma, oligodendroglioma, or other rare subtypes (including meningioma, ependymoma, ganglioma, pleomorphic xanthoastrocytoma, atypical teratoid rhabdoid tumors, glioneuronal tumors, and CNS lymphomas). Results: Of 44 Astrocytoma patients with potentially actionable mutations, four (9.1%) were treated with targeted therapy in the form of Enasidenib, ONC201, Nivolumab, and Depatuxizumab, while 40 received NGS agnostic treatment. In 37 Oligodendroglioma patients, three (8.1%) were treated with either targeted Vorasidenib or Ivosidenib, while 34 were started on NGS agnostic therapies. Lastly, four (10.0%) of 40 patients with other rare primary tumor types received either Ibrutinib, Dabrafenib+Trametinib, Vigabatrin, or Vemurafenib as targeted therapy. Avastin and/or standard Temozolomide chemotherapy were the most common NGS agnostic therapies employed by clinicians across all three subclasses. Conclusions: Although a substantial number of potentially actionable mutations were detected by NGS, the presence of this data paired with Tempus targeted recommendations rarely impacted clinician decision-making, ranging from 8.1-10.0% of the time. Despite the availability of resources to prescribe targeted treatment, providers consistently chose NGS agnostic therapies instead. Utilization of targeted treatment may become more frequent over time, as more novel agents come to market and their efficacy is further elucidated.
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway.
Authors: Perreault Sébastien , Sadat Kiaei Dorsa , Dehaes Mathieu , Larouche Valérie , Tabori Uri , Hawkin Cynthia , Lippé Sarah , Ellezam Benjamin , Cantin Edith , Routhier Marie-Ève , Caru Maxime , Vairy Stephanie , Legault Geneviève , Bouffet Eric , Ramaswamy Vijay , Coltin Hallie , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada ,   TRAM-01 Study Team
Published: June 2022

2042

Background: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children and the majority of PLGG have activation of the MAPK/ERK pathway. Plexiform neurofibromas (PN) are found in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PLGG and PN, but no clinical trial has reported its efficacy. Methods: This multicenter phase II trial includes patients aged ≥ 1 month to ≤ 25 years with progressing/refractory PLGG groups or PN. The primary objective was to evaluate the overall response rate after daily oral trametinib administration for eighteen 28-day cycles. Results: As of January 31st, 2022, 60 patients with PLGG and 45 patients with PN have been enrolled. Median age is 9.5 years (range 1.8-25.4) for PLGG and 11 years (range 0.7-19.8) for PN. Median follow-up is 18 months (range 0.1-38.1). Fifty-three patients with PLGG were evaluable. The overall response includes: 1 complete response (CR) (1.9%), 7 partial response PR (13.2%), 17 minor response MR (32.1%), 23 stable disease (SD) (43.4%) and 5 progressive disease (PD) (9.4%). Twenty-eight patients with a total of 32 PN were available for volumetric analysis. Volumetric assessment demonstrated an overall response rate of 60.7% compared to 24.1% when using RECIST 1.1 and 62.5% of PN showed a decrease of more than 20% in volume. Median volume change was a decrease of 30% (range -93.5 to 14.3). A total of 59 (69.4%) patients discontinued treatment as planned after 18 cycles and 9 (10.6%) patients had to stop trametinib due to adverse events. Conclusions: Response rates observed in our study suggest that trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG and PN. Treatment was overall well tolerated. This trial will continue to gather data on duration of response and long-term outcome for PLGG and PN treated with trametinib. Clinical trial information: NCT03363217.
Prognostic significance of therapy-induced myelosuppression in newly diagnosed glioblastoma.
Authors: Weller Michael , Oppong Felix Boakye , Vanlancker Maureen , Stupp Roger , Nabors Louis B. , Chinot Olivier L. , Wick Wolfgang , Preusser Matthias , Gorlia Thierry , Le Rhun Emilie
Published: June 2022

2055

Background: Myelosuppression is the major toxicity encountered during temozolomide chemoradiotherapy for newly diagnosed glioblastoma. Methods: We assessed the association of myelosuppression (neutropenia, thrombocytopenia, anemia, lymphopenia) during temozolomide chemoradiotherapy alone or in combination with experimental agents with progression-free survival (PFS) or overall survival (OS) in 2073 patients with newly diagnosed glioblastoma enrolled into five clinical trials: CENTRIC, CORE, EORTC 26082, AVAglio, and EORTC 26981. A landmark analysis approached was used. For each primary association analysis, a significance level of 1.7% was used. Results: Lower neutrophil counts at baseline were associated with better PFS (p = 0.011) and OS (p < 0.001), independently of steroid intake. Females experienced uniformly more myelotoxicity than males. Lymphopenia during concomitant chemoradiotherapy was associated with OS (p = 0.009): low-grade (1-2) lymphopenia might be associated with superior OS (HR 0.78, 98.3% CI 0.58-1.06) whereas high-grade (3-4) lymphopenia might be associated with inferior OS (HR 1.08, 98.3% CI 0.75-1.54). There were no associations of altered hematological parameters during concomitant chemoradiotherapy with PFS. During maintenance chemoradiotherapy, no significant association was found between any parameter of myelosuppression and PFS or OS, although exploratory analysis at 5% significance level indicated that either mild-to-moderate (HR 0.76, 95% CI 0.62-0.93) or high-grade lymphopenia (HR 0.65, 95% CI 0.46-0.92) were associated with superior OS (p = 0.013), but not PFS. Conclusions: The association of higher neutrophil counts at baseline with inferior PFS and OS requires further prospective evaluation. The link of therapy-induced lymphopenia to better outcome may guide the design for immunotherapy trials in newly diagnosed glioblastoma.
Phase 1 trial of ruxolitinib, temozolomide, and radiation in high-grade gliomas.
Authors: Ahluwalia Manmeet Singh , Rauf Yasmeen , Stevens Glen , Peereboom David M.
Published: June 2022

2061

Background: Ruxolitinib is a novel, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Preclinical evidence supports inhibition of JAJK STAT pathway arrogated glioma growth. Methods: Ruxolitinib is a novel, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Preclinical evidence supports inhibition of JAJK STAT pathway arrogated glioma growth. Results: 60 patients were treated on the study and there were no dose limiting toxicity seen on the protocol. Survival data was calculated for GBM. The OS for arm 1 was 18.17 (10.15, NA) and was not reached for arm 2. The 1 year OS was 0.62 for arm 1 and 0.93 for arm 2. Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Conclusions: Dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical benchmarks and randomized phase 2 trial is planned. Clinical trial information: NCT03514069. [Table: see text]
Characterizing malignant transformation in patients with IDH-mutant glioma.
Authors: Liu Vicki , Eldred Blaine S.C. , Wetzel Ethan , Zapanta Rinonos Serendipity , Khanlou Negar , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy Francis , Ellingson Benjamin M. , Lai Albert
Published: June 2022

2065

Background: Gliomas, which constitute the majority of primary brain cancers in adults, are assigned to a particular grade based on histological and molecular criteria set forth by the World Health Organization (WHO). A subset of initially low grade glioma patients transition to a higher grade at recurrence through a process known as malignant transformation (MT). Despite its significant implications on clinical prognosis, MT remains a poorly understood phenomenon in regards to its incidence rates, effects on survival, and potential prognostic factors. Our study aims to elucidate MT in patients that possess a mutation in the isocitrate dehydrogenase ( IDH) gene, one of the most common genetic alterations in gliomas. Methods: All known IDH mutant glioma patients, seen at UCLA between 1986 and 2022, who received at least 1 repeat resection for presumed recurrent disease were included. Based on surgical pathology reports, patients were categorized into MT and non-transforming progression groups, and further stratified by diagnosis in compliance with the 2016 WHO Classification of Tumors of the Central Nervous System. Relevant clinical information, including patient demographics, survival data, tumor microscopic descriptions, and magnetic resonance imaging, was accessed via electronic medical records. Kaplan Meier analyses were conducted to evaluate the predictive power of various clinical, pathological, and radiological markers. Results: Of 724 total IDH mutant patients screened, 253 received a second surgery and were thus incorporated in this study. Among the 196 patients with lower grade pathologies capable of MT, 129 (65.8%) progressed to a higher grade at recurrence while 71 (36.2%) did not. By diagnosis, the incidence rates of MT for initial grade 2 astrocytomas, grade 3 astrocytomas, and grade 2 oligodendrogliomas were determined to be 74.7%, 48.9%, and 66.1%, respectively. MT was associated with worse overall survival and post-recurrence survival compared to non-transformation in astrocytomas, a trend not seen in oligodendrogliomas. Across all relevant diagnoses, a subset of 36 MT patients did not receive treatment in the interval between initial and recurrent surgery, demonstrating the existence of spontaneously occurring MT. Furthermore, consolidating data from pathology and MRI reports revealed that a greater extent of abnormal molecular characteristics at initial diagnosis and earlier post-operative contrast enhancement may predict MT. Conclusions: These results highlight the distinct nature of gliomas that undergo MT, particularly in tumors of astrocytic differentiation. Considering its adverse impact on clinical outcome, understanding and anticipating this phenomenon is instrumental for the determination of optimal treatment among glioma patients.
Spatiotemporal multiomic landscape of human medulloblastoma at single cell resolution.
Authors: Liu Hailong , Jiang Tao , Qiu Xiaoguang
Published: June 2022

2069

Background: Medulloblastoma is the most common malignant childhood tumor type with distinct molecular subgroups. While advances in the comprehensive treatment have been made, the mortality in the high-risk group is still very high, driven by an incomplete understanding of cellular diversity. Methods: We use single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling to generate an integrative multi-omic map in 40 human medulloblastomas spanning all molecular subgroups and human postnatal cerebella, which is supplemented by the bulk whole genome and RNA sequences across 300 cases. Results: This approach provides spatially resolved insights into the medulloblastoma and cerebellum transcriptome and epigenome with identification of distinct cell-type in the tumor microenvironment. Medulloblastoma exhibited three tumor subpopulations including the quiescent, the differentiated, and a stem-like (proliferating) population unique to cancer, which localized to an immunosuppressive-vascular niche. We identified and validated mechanisms of stem-like to differentiated process among the malignant cells that drive tumor progression. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing stem-like malignant cells as a hub for intercellular communication. Multiple features of potential immunosuppression and angiogenesis were observed, including Treg cells and endothelial cells co-localization in compartmentalized tumor stroma. Conclusions: Our study provides an integrative molecular landscape of human medulloblastoma and represents a reference to advance mechanistic and therapeutic studies of pediatric neuro-oncological disease.
Customized autoantibodies (autoAbs) profiling to predict and monitor immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICI).
Authors: Genta Sofia , Keshavarzi Sareh , Yee Noelle , Heirali Alya , Hansen Aaron Richard , Siu Lillian L. , Saibil Samuel , Stayner Lee-Anne , Yanekina Maryia , Sauder Maxwell , Salawu Abdulazeez , Spiliopoulou Pavlina , Vornicova Olga , Vilbert Maysa Tamara Silveira , Butler Marcus O. , Bedard Philippe L. , Abdul Razak Albiruni Ryan , Coburn Bryan , Chruscinski Andrzej , Spreafico Anna
Published: June 2022

2528

Background: Using a customized microarray, we previously reported that patients (pts) who develop irAEs grade (G)≥2 and those who do not, have different median fluorescent intensity (MFI) levels of specific autoAbs at baseline (pre-ICI). Leveraging a larger dataset, we evaluated whether overall baseline autoAbs elevation and early increases in autoAbs after ICI can predict irAEs as well as if steroid treatment can reduce autoAbs. Methods: Plasma was obtained from pts receiving ICI in two clinical trials (MET4-IO, NCT03686202 and INSPIRE, NCT02644369) and from healthy controls (hc). Collection time points in MET4-IO and INSPIRE studies included: baseline, 3-4 weeks (w), 6-8 w, 24 w and at the end of treatment and baseline and 6 w respectively. Arrays with 162 autoAg customized for frequent irAEs were incubated with plasma and probed with Abs to detect IgG and IgM reactivity. AutoAbs with MFI >500 per individual were compared between hc and pts with and without irAEs G≥2 by the Student-t test. Results: Samples from 114 pts and 14 hc were analyzed (pts characteristics are summarized in the Table). G≥2 irAEs included: hypothyroidism (13), pneumonitis (10), colitis (7), hepatitis (4), skin toxicity (7), infusion reaction (2), pancreatitis (2), meningitis (1), hypophysitis (1), corneal ulcer (1), high creatinine (1), myocarditis (1), myositis (1), diabetes (1), mucositis (1), myasthenia (1) and adrenal failure (1). Hc had less autoAbs with MFI >500 as compared to pts at baseline (median 32 vs 62 p<0.001). IgG with MFI >500 were higher at baseline in pts who developed G≥2 irAEs vs those without G≥2 irAEs (median 39 vs 33, p=0.03). In 23 pts with plasma collected at the time of irAEs, we observed a significant increase of autoAbs with MFI>500 from baseline (median 84 vs 77 p= 0.009). Paired samples at the time of irAEs and after steroids were available for 9/23 pts, showing lower autoAbs after steroid treatment (54 vs 79 p=0.006). No differences in autoAbs with MFI>500 pre and post ICI were seen in pts without G≥2 irAEs (baseline vs first post ICI collection median 58 vs 60, p=0.13). Conclusions: We observed a higher number of IgG with MFI >500 at baseline and a greater increase after ICI administration in individuals with irAEs compared to those without irAEs. Steroid treatment resulted in a decrease in autoAbs. A prospective study is ongoing to validate the potential role of autoAbs for risk stratification and monitoring of irAEs. [Table: see text]
In-vivo reprogramming macrophages and dendritic cells with Allocetra-OTS: Successful mono- and combination-antitumor therapy.
Authors: Mevorach Dror , Shabat Yehudit , Regev Eshchar , Yalon Eran , Karbian Netanel , Reicher Barak
Published: June 2022

2532

Background: Chimeric antigen receptor (CAR) T cells can activate an immune response to a cancer-specific antigen but is less effective in solid tumors. Immune check point inhibitors (ICI) revolutionized the treatment of solid tumors, however, in many tumors only partial response is achieved. Here we questioned the role of synergistic effect of Allocetra-OTS (cellular therapy for in-vivo reprogramming macrophages and dendritic cells, Enlivex Therap.) on solid tumor progression. Methods: To follow tumor growth in vivo, HeLa-CD19 cells were stably transduced with pLenti-PGK-V5-Luc-Neo. For CAR preparation, fresh mononuclear cells (MNC) were transfected with CD19-CAR plasmids. For the intraperitoneal solid tumor model, SCID-Bg mice were injected intraperitoneally (IP) with human HeLa-CD19 or HeLa-CD19-luciferase cells, 10×106 allocetra-OTS or vehicle, and 10×106 CD19-CAR T cells or mock T cells. In an immune-competent model, Balb/c mice were treated IP with AB12 (mesothelioma) with pLenti-PGK-V5-Luc-Neo and treated with anti-CTLA4 with or without Allocetra-OTS. Mice were monitored daily for clinical signs and peritoneal fluid accumulation and weekly for tumor growth. Kaplan-Meier log rank test was done for survival. Peritoneal cells were evaluated using single cell analysis and flow cytometry. Tumors were examined for bacterial presence by immunohistochemistry staining with antilipoteichoic acid (LTA) and antilipopolysaccharide (LPS). For allocetra-OTS preparation, enriched mononuclear fractions were collected by leukapheresis from healthy eligible human donors and induced to undergo early apoptosis. Results: SCID mice survived 30±5 days (range 27–37) and were sacrificed or died from solid tumor in the peritoneal cavity after accumulation of bloody peritoneal fluid and clinical deterioration. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly ameliorated survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further ameliorated survival to 75±10 (p < 0.001) with 20-40% complete remission. In AB12 model, anti CTLA4 therapy significantly ameliorated survival from 26±5 to 38 ±9 days (p < 0.05). However, Allocetra-OTS monotherapy ameliorated survival to 45 ±12 days (p < 0.02) and combinational therapy to 75±9 days (p < 0.0001) with complete remission in 60-75% of mice. Single cell analysis revealed that restoration of large peritoneal macrophages (LPM), were associated with antitumor activity. Conclusions: During intraperitoneal tumor progression, allocetra-OTS as monotherapy or combinational therapy with CAR or anti-CTLA4 significantly reduced tumor size and enable complete remission in up to 75% treated mice. Based on excellent safety profile in > 30 patients treated for sepsis and Covid19, human phase I/II of allocetra-OTS plus ICI, for peritoneal metastases, is planned for 2022.