bluuebunny/crossref_metadata_2025 huggingface dataset:
Discontinuation of imatinib in patients with oligo-metastatic gastrointestinal stromal tumor who are in complete radiological remission: A prospective multicenter phase II study.
Authors: Hompland Ivar , Boye Kjetil , Papakonstantinou Andri , Røsok Bård , Joensuu Heikki , Bruland Øyvind
Published: June 2022

11535

Background: Life-long tyrosine kinase inhibitor (TKI) treatment is recommended for patients (pts) with metastatic GIST. We investigated whether highly selected pts with metastatic GIST may remain in durable complete remission after imatinib discontinuation. Methods: In this 1-group, prospective, multicenter phase II trial (NTC02924714) selected pts with overtly metastatic GIST discontinued imatinib treatment. Eligible pts had been treated with imatinib > 5 yrs for oligo-metastatic (≤3 metastases) disease, had no GIST progression and had undergone either R0/R1 resection or radiofrequency ablation (RFA) of all metastases, and had no longer detectable metastases on CT/MRI imaging, The primary endpoint was 3-yr progression-free survival (PFS), overall survival was a secondary endpoint. We estimated to achieve an improvement from 15% to 35% in 3-yr PFS compared to pts treated in the BRF-14 trial with a sample size of 31 pts. Results: The trial closed early due to slow accrual. Between January 5, 2017, and June 5, 2019, 12 pts (males, 7) with a median age of 67 yrs (range, 50-85) were enrolled. All pts had their primary tumor surgically removed (stomach, 4; small bowel, 6; large bowel/rectum, 2). Seven pts had KIT exon 11 mutation, 2 KIT exon 9 mutation, 1 PDGFRA exon 12 mutation, 1 had no mutation in KIT/PDGFRA, and 1 pt had unknown GIST mutational status. Eight pts had liver metastases, 3 peritoneal metastases, and 1 had both. Prior to enrollment all pts were in macroscopic complete remission after surgical metastasectomy (n = 7), RFA (n = 2), or both (n = 1), and 1 pt achieved complete radiological response with imatinib. At enrollment, 8 pts had imatinib 400 mg/d and 4 had < 400 mg/d. The median time of imatinib treatment before study entry was 8 yrs (range, 5-17). After imatinib discontinuation 7 (58%) pts progressed; the median time to progression was 10 mos (range, 2-31 mos). Five (42%) patients were progression-free after a median follow-up time of 42 mos (range, 30-59 mos). Median PFS was 23 mos and the estimated 3-year PFS 39%. Patients who progressed all achieved a second remission after restarting imatinib and were alive after a median follow-up time of 48 mos (range, 32 to 61 mos). Conclusions: The findings suggest that discontinuation of imatinib is safe in highly selected patients with oligo-metastatic GIST and that such patients may survive without detectable GIST progression for several years. The findings need to be viewed with caution due to the small pt numbers. Further study on imatinib discontinuation seem warranted. Clinical trial information: NCT02924714.
Second primary malignancies (SPM) in patients with gastrointestinal stromal tumors (GIST): 10-year experience from the Ottawa Hospital (TOH).
Authors: Alfagih Abdulhameed , Alshamsan Bader , AlJassim Abdulaziz , Alqahtani Nasser , Asmis Timothy R.
Published: June 2022

11536

Background: The secondary malignancies in patients with GIST are relatively high. We present our 10-year experience of SPM in patients with GIST from a regional Cancer Centre in Canada. Methods: A retrospective cohort study was performed in all GIST patients treated at TOH between January 2011 and December 2021. Patients were identified using ICD-10 codes and electronic medical records reviewed. Clinicopathological data were analyzed. Logistic regression analysis was used to evaluate associated factors with SPM. Survival analysis was estimated with the use of the Kaplan-Meir method and compared by log-rank test. Results: In total, 248 patients with GIST were identified. Of these patients, 61 (25%) had SPM; synchronous (9, 15%) and metachronous (52, 85%). Nine patients had two additional primary cancers other than GIST, and four patients had three additional primary cancers. The median age at diagnosis was 70 (range 44 – 90) years, and males were (59%). The most common SPMs were skin cancer (14, 17%), melanoma (5), and non-melanoma (9), followed by prostate cancer (13, 16%) and breast cancer (12, 15%). Colorectal cancer and hematological malignancies were found in (5, 11%) patients each, while RCC was found in (4, 6%). Thyroid cancer, lung cancer, neuroendocrine tumor, bladder cancer, thymoma, and other types of cancers were collectively found in 15 patients (24%). The majority (57%) of SPM diagnosed before GIST, 30% after GIST. The most common primary GIST locations were in the stomach (62%), followed by the small bowel (30%), and the most common histology was spindle cell (69%), followed by mixed histology (13%). The majority of GIST were localized (46 patients, 75%). Based on Miettinen risk classes for non-metastatic GIST, 74% had zero to low-risk disease, while 26% had moderate or high-risk disease. There was no association between SPM and GIST primary site (p = 0.4), TNM stage (p = 0.8), histology (p = 0.2), Mitosis (p = 0.5), and Miettinen risk class (p = 0.6). The median follow-up time was 53 months (range 1 – 132), and four patients lost follow-ups. Five years overall survival of SPM group vs. non SPM, 79.8% vs. 94.1%, (p = 0.03). Cox regression did not reveal a significant association with the covariants Conclusions: We observed that one out of four GIST patients have SPM. Skin, prostate, breast cancers were the most common SPM associated with GIST. Molecular studies are needed to explore the association/underlying mechanisms of GIST with these malignancies.
Selective internal radioembolization (SIRT) allows to control liver metastases of gastrointestinal stromal tumors (GIST) failing treatment with tyrosine kinase inhibitors (TKI).
Authors: Hohenberger Peter , Rathmann Nils , Buesing Karen , Menge Franka , Reichardt Peter , Schoenberg Stefan O. , Diehl Steffen
Published: June 2022

11540

Background: The liver and the peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH (‘wildtype’) or after treatment with 1st/2nd/3rd/4th line therapy, interventional radioembolization with yttrium-90 (90Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients Methods: From 1/2008 to 1/2018, 2^6 pts (12f, 14m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2nd mutation (n = 7), exon 9 (n = 3), exon 9+2ndmut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 33.6 mos (range, 12-108mos) and all patients were followed until death Results:.The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 10.7-23.8 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p < 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in earlier treatment lines.
Serum glycoproteomic signatures and association with survival in patients with bone and soft tissue sarcoma treated with immune-checkpoint inhibitor therapy.
Authors: Serie Danie , Pickering Chad , Rice Rachel , Wong Maurice , Huang Hector , Kansara Maya , Thavaneswaran Subotheni , Ballinger Mandy L. , Sebastian Lucille , Thomas David Morgan , Lindpaintner Klaus
Published: June 2022

11546

Background: Glycosylation is one of the most ubiquitous and functionally important forms of post-translational modification. The role of differential glycosylation in serum proteins has so far been limited by the technical complexity inherent in generating and interpreting this information. InterVenn has built a novel platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine, allowing for highly scalable and reproducible interrogation of glycoproteins with site- and glycan-specificity. Methods: Using this platform, we interrogated 519 glycopeptide (GP) biomarkers derived from 70 serum proteins in pre-treatment samples from a cohort of 103 individuals (56 females, 47 males, age ranging from 18 to 84 years) presenting with one of 20 solid cancer types. All patients were treated with durvalumab and tremelimumab immune checkpoint inhibitor (ICI) therapy. Median follow-up for overall survival (OS) was 11.4 months, with 70 events total observed. OS associations were assessed for individual GPs via Cox regression models and leave-one-out-cross-validation (LOOCV) was employed to generate penalized multivariable prediction scores. Notably, 43 patients had a primary diagnosis of bone and soft tissue sarcoma, and stratified analyses were carried out in this population. Results: We identified 154 biomarkers significantly associated with OS in the full dataset after adjusting for multiple comparisons (FDR < 0.05). Of these, 7 were statistically significant at p < 0.01 in the sarcoma-only subset. LOOCV models built in all cancer types resulted in held-out scores that discriminated those likely to exhibit long-term survival post-ICI therapy from those unlikely to benefit (HR = 4.0, p = 4.91E-08, with 4 GPs included in the final model). Furthermore, LOOCV models including only sarcoma patients demonstrated even stronger predictive attributes (HR = 8.22, p = 2.10E-05, employing 2 glycopeptides). All 9 sarcoma patients with extreme glycosylation signatures for prediction of poor survival displayed quick clinical progression with little benefit from ICI therapy. Relative signal strength and comparative analyses demonstrated strong histotype-specificity inherent in the biomarkers employed for sarcoma vs all cancers. Conclusions: Our results indicate that glycoproteomic liquid biopsy holds potential as a predictive biomarker for identifying sarcoma patients who will derive the greatest benefit from ICI therapy.
Distinct oncogenic signatures in malignant PEComa and leiomyosarcoma identified by integrative RNA-seq and H3K27ac ChIP-seq analysis.
Authors: Giannikou Krinio , Azim Ahmad-Abdel , Adib Elio , Schaefer Inga-Marie , Kesten Nikolas , Taing Len , Zhu Zachary , Hornick Jason , Hirsch Michelle S. , Long Henry , Wagner Andrew J. , Hemming Matthew Louis , Kwiatkowski David J.
Published: June 2022

11552

Background: Malignant perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two sarcomas with overlapping morphologic and immunophenotypic features which can make their diagnostic distinction challenging. We aimed to characterize the transcriptional and epigenetic landscape of PEComa and LMS to identify distinguishing features. Methods: We performed whole transcriptome RNA-sequencing on 19 PEComas and compared their gene expression profile to 259 sarcomas from The Cancer Genome Atlas (TCGA) including 104 LMS. ChIP-sequencing for H3K27ac, a histone modification associated with activation of nearby genes/open chromatin, was conducted on 9 malignant PEComas and 12 LMS and were compared with publicly available data from 4 other sarcoma subtypes (chordoma; osteosarcoma; undifferentiated pleomorphic sarcoma; rhabdomyosarcoma; n = 29 tumors). Results: Genome-wide epigenetic and transcriptional analyses revealed overlapping patterns between PEComa and LMS, which were distinct from other sarcomas. However, we also identified a set of highly expressed and epigenetically distinct transcripts which may represent diagnostic?biomarkers: e.g., DAPL1, MLANA, SULT1C2, GPR143, and CHI3L1 for PEComa; and MYOCD, WDFC2, DES, MYH11, and CNN1 for LMS; each of which showed >17x fold higher expression for each tumor entity by DESeq2 (FDR<0.0001). Gene Set Enrichment Analyses (GSEA) demonstrated enrichment in the KEGG Lysosome pathway for PEComa (FDR=0.11), whereas myogenesis and smooth muscle contraction pathways were enriched in LMS (FDR=0.09). Integrative transcriptomic and epigenetic analyses revealed a unique set of master core transcription factors for each tumor type including among others MYOCD for LMS; MITF for PEComa, which require further functional investigation. Twelve selected genes including new as well as known and standard diagnostic markers (e.g., DAPL1, MLANA, GPR143, PNL2, CHI3L1, DES, MYH11, ER, CD68, PU.1, pS6 and CNN1) were validated by immunohistochemistry (IHC) in multiple sections from PEComa and LMS (n = 26). The combination of three melanocytic markers (HMB45, MLANA, PNL2) and pS6 can distinguish LMS from PEComas (**** p<0.0001). IHC for CD68 and PU.1 macrophage markers did not show any difference regarding the degree of immune infiltration in PEComa vs. LMS. Conclusions: Our studies revealed novel epigenetic signatures translating into lysosomal and melanocytic proteins for PEComa and myogenic proteins for LMS, which may serve as useful diagnostic biomarkers in the distinction of these two sarcoma subtypes.
Phase 1b study of weekly split-dose selinexor in soft tissue sarcoma (STS).
Authors: Salawu Abdulazeez , Gupta Abha A. , Al-Ezzi Esmail Mutahar , Genta Sofia , Malone Eoghan Ruadh , Vora Tushar Shailesh , Watson Geoffrey Alan , Vornicova Olga , Wang Lisa , Arones Limore , Phillips Madeline J. , Lee Jasmine , Abdul Razak Albiruni Ryan
Published: June 2022

11563

Background: Selinexor has demonstrated clinical activity in a variety of tumors including STS. Selinexor dosing at 60mg twice a week or 80mg once a week in later phase trials was associated with gastrointestinal and hematologic toxicities requiring frequent dose interruption and reduction. Preclinical in vivo studies show that selinexor use in a split-dose regimen or sustained-release formula is associated with less toxicity. This phase 1b study aimed to evaluate the safety and tolerability of split-dose selinexor in patients (pts) with advanced STS. Methods: Eligible pts with advanced STS of any histologic subtype, and ECOG performance status (PS) ≤ 1 were treated with split-dose selinexor (40mg, 20mg, 20mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15 and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. Antiemetic prophylaxis (oral dexamethasone and ondansetron) was given to all pts. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAE) by CTCAE v5.0. The secondary endpoint was assessment of quality of life (QoL) using the EORTC QLQ-c30 tool v3. Descriptive analyses of Global Health Status (GHS) QoL scores at screening (baseline) and cycle 2 day 1 (C2D1) were performed. Radiologic tumor assessments (by RECIST v1.1) were performed every 8 weeks while on treatment. Results: Nineteen pts [12 female and 7 male; ECOG 0/1, 8/11; median age 61 years (range 41 – 83)] were enrolled. The most frequent of 12 STS subtypes was leiomyosarcoma (n = 7, 37%). Among 18 patients evaluable for toxicity, there were no grade ≥ 3 TRAE. The most common grade ≤ 2 TRAE were dysgeusia (n = 11, 61%), nausea (n = 11, 61%), fatigue (n = 10, 56%) and vomiting (n = 10, 56%). Grade ≤ 2 hematologic TRAE were thrombocytopenia (n = 6, 33%), neutropenia (n = 4, 22%) and anemia (n = 1, 6%). Dose reduction was required in 3 pts (17%) due to intolerable grade 2 TRAE (fatigue, nausea, thrombocytopenia). No serious adverse event due to selinexor was noted. QoL scores were evaluable for 15 pts. The mean (± SEM) change in GHS QoL score from baseline to C2D1 was -10.6 (± 4.8). Among 16 pts evaluable for radiologic response, the best response was stable disease (SD) in 10 pts (63%), and progressive disease (PD) in 6 pts (37%). Durable clinical benefit (SD for > 16 weeks) was seen in 5 pts (31%; 95%CI 11.0 – 58.7%) The median PFS was 3.6 months (95%CI 1.7 – 7.3). Conclusions: Split-dose selinexor was well tolerated in this heterogeneous group of pts with advanced STS and warrants further interrogation. Updated toxicity, safety, efficacy and QoL data will be presented at the meeting. Clinical trial information: NCT04811196.
Radiomics of MRI scans enables differentiation of benign from malignant soft tissue sarcoma.
Authors: Li Lin , Kaon William , Viswanathan Vidya Sankar , Kosaraju Vijaya K , Kosmas Christos , Devita Robert , Abboud Salim , Madabhushi Anant , Mangla Ankit
Published: June 2022

11565

Background: Accounting for >15,000 cases annually, soft tissue sarcomas (STSs) represent a large spectrum of tumors with varying histology and clinical course. However, diagnosis of STSs on MRI is challenging due to its heterogeneous imaging phenotypes, such as surrounding soft tissue edema, vascular lesion characteristics, and specific imaging signs, such as splitting of fat between muscles. The goal of this study was to evaluate the utility of radiomic feature analysis for characterizing subtle heterogeneity patterns on T2-weighted MRI to distinguish benign and malignant STSs. Methods: T2-weighted MRI of N = 176 patients with STS were retrospectively obtained from a single institution. (Table) Tumor regions were manually annotated by a radiologist. The radiomic features included textural features, e.g. gray-level co-occurrence matrix features, which quantify the correlation between textural patterns within annotated regions. Maximum relevance minimum redundancy feature selection was employed to identify top 10 radiomic features that are associated with STS malignancy. Then, the identified features were integrated to generate a radiomic risk score (RRS) via logistic regression on a 10-fold cross validation to differentiate benign and malignant STS. Multivariate analysis and the area under the receiver operating characteristic curve (AUC) were employed to evaluate the association of RRS and clinical parameters, including age, gender, and STS location, with STS malignancy. Results: Multivariate analysis illustrated that age and RRS are independent variables in predicting STS malignancy (p < 0.05). The RRS yielded AUC as 0.76 (confidence interval (CI): 0.69-0.83), age 0.71 (CI: 0.64-0.79) and the combination of the RRS and age 0.84 (CI: 0.78-0.90). Conclusions: The RRS generated by radiomic features was found to be a significant predictor of STS malignancy. Furthermore, RRS could provide complementary information to the clinical parameters in differentiating benign and malignant STSs.[Table: see text]
Genetic abnormalities and aberrant expression of genes involved in chromosome segregation and mitosis in patients with chromosomally unstable malignant soft tissue tumors haboring extensive somatic loss-of-heterozygosity (LOH).
Authors: Takahashi Katsuhito , Miyaji Yasutomo , Higuchi Hajime , Komohara Yoshihiro , Aida Shinsuke , Yashima Jun , Yamamoto Hiromasa , Suzawa Ken , Takahashi Yuko , Toyooka Shinichi , Narahara Hiroyuki , Yotsumoto Junko , Oyama Yu , Ono Yasuo , Teraoka Satoshi
Published: June 2022

11576

Background: Malignant soft tissue tumor is a rare cancer with few therapeutic options. Recent genomic analysis of soft tissue sarcoma (STS) revealed a high degree of chromosomal instability (CIN) including genome-wide copy number alteration, aneuploidy, whole genome doubling and chromothripsis. In STS patients, we observed extensive somatic LOH, a hallmark of CIN, which is haploid of germline mutations/variants in cancer-related genes. CIN of STS genome implicates abnormalities in chromosome segregation and mitosis. So far, studies on this issue, however, have not been reported in STS patients. Methods: We recruited 155 patients with metastatic/recurrent malignant soft tissue tumors (135 female and 20 male, mean age 51 at analysis, 100 LMS, 19 LPS, 4 ESS, 3 UPS, 3 AS, 3 MPT, 3 GIST and others) with information of familial cancer burden. Whole exome sequencing and analysis were performed in both blood and tumor samples as described in 2018ASCO. KIF18A expression was assessed by immunohistochemistry. Results: Patients with tumors harboring less than 33% somatic LOH in a total of somatic and LOH mutations/variants in 595 COSMIC genes (n = 54) have a better prognosis than those (34-66%, n = 49, 67-100%, n = 52) with tumors harboring more LOH genes (5-year OS; 71% vs 52% or 46%, p = 0.0299, p = 0.0117, respectively). Neither TMB nor MSI status was associated with LOH. Of the genes involved in chromosome segregation and mitosis, we found that a family of ARHGAP genes which play a role in the spindle assembly and Aurora A kinase activation was frequently mutated in both tumor and germline genomes (n = 81 in a total of 155). Damaging ARHGAP mutations/variants in tumors are correlated with higher LOH values (54±3.4%, n = 81 vs. 39±3.3%, n = 74. mean±SE, p = 0.0021) and poor prognosis of patients (5-year OS; 58% n = 81 vs. 41% n = 74, p = 0.0098). We also found that elevated and robust expression of a mitotic kinesin KIF18A in tumors harboring higher LOH and/or damaging ARHGAP mutations/variants (n = 12) but not in lower LOH tumors without ARHGAP mutations/variants (n = 4). Conclusions: This study, for the first time, demonstrates that genetic abnormalities and aberrant expression of genes involved in chromosome segregation and mitosis in patients with malignant soft tissue tumors. The results reveal a novel target of drug discovery for incurable STS because CIN tumor cells are shown to be particularly vulnerable to KIF18A inhibition, while somatic, diploid cells are not.
Impact of acetaminophen on the efficacy of immunotherapy in patients with cancer.
Authors: Bessede Alban , Marabelle Aurelien , Guegan Jean-Philippe , Peyraud Florent , Danlos François-Xavier , Cousin Sophie , Chaput Nathalie , Spalato Mariella , Roubaud Guilhem , Cabart Mathilde , Khettab Mohamed , Chaibi Assia , Rey Christophe , Nafia Imane , Mahon François-Xavier , Soria Jean-Charles , Italiano Antoine
Published: June 2022

12000

Background: Pain is the most common symptom experienced by patients with advanced cancer. Acetaminophen (APAP, commonly known as paracetamol) alone or in combination with a weak opioid, such as codeine or tramadol, is usually considered as the first-line strategy to manage mild-to-moderate pain in this setting. Although generally considered to be safe, several evidences suggest that APAP may have negative immunomodulatory effects. Randomized studies have shown that APAP use is associated with blunted vaccine immune responses. Given its potential to impair vaccine effectiveness, the World Health Organization stated in 2015 that administration of APAP before or at the time of vaccination is not recommended. This study aimed to assess APAP impact on efficacy of immunotherapy in patients with cancer. Methods: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICB): the CheckMate 025 trial, n = 297 (NCT01668784, sponsor: Bristol Myers Squibb), the institutional biomarker program BIP n = 34 (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and the institutional biomarker program PREMIS n = 297 (NCT03984318, sponsor: Gustave Roussy, Villejuif, France). APAP immunomodulatory effects were evaluated on a pre-clinical tumor model (MC38) and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. Results: Detectable plasma APAP levels at treatment onset was associated with a significantly worse clinical outcome in ICB-treated cancer patients (HR for progression-free survival : 1.43, 95% CI 1.07–1.91, p = 0.015; HR for overall survival: 1.78 95% CI 1.18–2.68, p = 0.006), independently of other prognostic factors (age, performance status, number of previous lines of treatment, tumor type, number of metastatic sites, presence of liver metastases, LDH levels). APAP significantly reduced ICB efficacy in the pre-clinical MC38 model, as well as the production of PD1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly upregulated upon treatment with ICB in cancer patients taking APAP. Conclusions: This study provides strong pre-clinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.
Death with dignity utilization among patients with thoracic, head, and neck cancer.
Authors: Uy Natalie F. , Rodriguez Cristina P. , Daum Courtney , Baker Kelsey K. , Singer Jonathan , Hnida James , Lavell Laura , Sofie Katie , Cruz Jourdan , Eaton Keith D. , Santana-Davila Rafael , Loggers Elizabeth Trice
Published: June 2022

12032

Background: Death with Dignity (DWD) legislation, which took effect in 2009 in Washington state, allows terminally ill patients (pts) to self-administer physician-prescribed, life-ending medication. Thoracic, head and neck cancer (THN) pts are among the top cancer types requesting DWD; however, data describing this group are limited. Methods: This retrospective chart review, conducted at Seattle Cancer Care Alliance/University of Washington and Fred Hutch, collected demographics, disease, treatment, support services and steps of the DWD process. We tested the association between disease characteristics of interest and DWD completion using Fisher’s Exact test. Results: Between Jan 2014 and October 2020, 498 pts inquired about DWD, and 108 (22%) were THN pts. Among THN pts, 51 (47%) only initiated the DWD request process, 35 (33%) only completed the DWD request process, and 22 (20%) completed the DWD request and self-administered the medication. Pts were white (n=90, 83%), male (n=64, 59%), primarily English speaking (n=103, 95%), nonreligious (n=69, 64%), single/divorced/non-partnered (n=55, 51%), and insured (n=103, 95%). Median age at request was 68 years (range 35-88). The table details THN DWD utilization. At time of DWD request, the median time from diagnosis was 14 months (range=0.2-242.7), and 62 (57%) had received ≥2 lines of therapy. Among 78 (72%) pts who received systemic therapy, 51 (65%) were ≥30 days from last therapy to time of death. Within 30 days prior to DWD request, 30 (28%), 25 (23%), and 7 (7%) pts saw social work, palliative care, and spiritual health respectively, and 35 (32%) were hospice-enrolled. Stage IV at diagnosis had higher rates of DWD medication use (p=0.05). There was no significant correlation between DWD medication use and primary site, ECOG score at request, insurance type, mental health diagnosis, use of depression/anxiety or pain medications, or hospice enrollment during DWD process. Conclusions: THN pts requesting DWD were predominantly white, nonreligious, insured males. Pts with advanced stage at diagnosis were more likely to use DWD medication. There was a higher proportion of DWD medication use with poorer performance status, and no association between use of depression/anxiety, pain medications, or utilization of supportive care services and DWD medication usage. Future research should investigate DWD utilization among THN pts in multiple centers and states to evaluate these patterns. [Table: see text]
Cancer doesn’t know what day of the week it is: Temporal trends in day of death, 2000-2017.
Authors: Shah Kanan , Tao Anna , Chino Junzo P. , Chino Fumiko
Published: June 2022

12033

Background: Improving end-of-life care is an opportunity to reduce trauma for both patients and caregivers. Studies support the existence of a psychosomatic phenomenon known as the “holiday effect,” allowing critically ill patients to enter a bargaining phase and postpone death until a given event. We hypothesized that there may be a temporal trend as patients with cancer attempt to delay death until the arrival of family on weekends or the passage of a holiday. Methods: All deaths due to malignant neoplasms (ICD C00-C97) from 2000-2017 were collected from the National Center for Health Statistics. Outcomes were the days of week and months of year that death occurred. Weekend mortality was defined as death on Friday, Saturday, or Sunday. Holiday mortality was defined as death in December or January. Chi-squared tests were performed to determine differences in deaths by day or month. Logistic regression examined associations between day or month of death and age, education, race/ethnicity, location of death, marital status, race, and sex. Statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc). Results: 10,305,990 deaths due to cancer were recorded from 2000-2017. Deaths were not uniform across day of week or month of year (p < 0.001 each). Each year, rates of death increased progressively from Monday to Thursday, peaked on Friday and Saturday, and declined on Sunday. There was a relative 3.4% difference in death rate between the peak on Friday and nadir of deaths on Monday. Each year there was a consistent increase in deaths in December and January, with a nadir in February with a relative difference of 10.2%. Multivariate logistic regression assessed associations in weekend and holiday cancer death. Non-hospital death (home, nursing facility, hospice) was more likely to occur on the weekend (aOR from 1.03-1.05, p≤0.01 for all). Hispanic patients (aOR 1.01, p = 0.001) were more likely to die on weekends. Females (aOR 0.99, p = 0.02), those who were divorced (aOR 0.99, p = 0.04) and those with pancreatic cancer (aOR 0.99, p = 0.01) were less likely to die on weekends. Non-hospital death was less likely to occur on Holiday months (aOR from 0.95-0.96, p≤0.01 for all). Those > 75 were more likely to pass away in Holiday months compared to younger age groups (OR 1.02-1.03, p < 0.05 for both). Cancer type was associated with holiday mortality; those with breast or prostate cancer were more likely to pass away (OR 1.01, p < 0.05 for both) during the holidays compared to those with lung cancer. Conclusions: There is a human element to death. The unequal distributions of deaths due to cancer in this study are small but significant; they suggest a non-biological variation that precludes cancer mortality from being strictly date agnostic. Temporal trends in cancer death highlight an opportunity to improve end of life care and demonstrate how care should shift focus to what matters to patients including time with family.
Sociodemographic factors associated with end-of-life palliative care utilization in female breast cancer: A national inpatient database analysis.
Authors: Hsieh Tien-Chan , Wang Yuyao , Zou Guangchen , Zheng Jiayi , Kloss Robert A.
Published: June 2022

12035

Background: Palliative care (PC) has been shown to improve end-of-life quality in cancer patients. Nevertheless, several studies suggest that PC utilization is associated with socioeconomic factors. Patients with breast cancer, the most common neoplasm in women in the U.S., has lower PC utilization than those with other malignancies. We aim to investigate any sociodemographic barriers that are associated with the inpatient PC utilization in female breast cancer in the U.S. at the end of life. Methods: We used the National Inpatient Sample database of Healthcare Cost and Utilization Project, an all-payer inpatient care database in the United States, with data years 2014-2019. The end-of-life case was defined as hospitalized at least three days and passed away. We included all adult women (age at least 18 years old and female gender in electronic health records). The breast cancer cases were identified with International Classification of Diseases (ICD) 9th or 10th edition within the top three diagnoses. PC consultation could be identified with the ICD procedure code. Comorbidities were controlled with Charlson Comorbidity Index. After univariable analysis, the factors that were statistically associated with PC utilization would subsequently be added to the multivariable logistic regression model. Results: Between the year 2014 to 2019, we identified a total of 2,226 adult female patients who had breast cancer as their top three diagnoses and were hospitalized at least three days before death. 217 (9.7%) cases were 40-49 years old; 441 (19.8%) cases were 50-59 years old; and 1,455 (65.4%) patients were at least age 60 or above. The top three racial groups were Caucasian 1,420 (63.8%), African American 418 (18.8%), and Hispanic 166 (7.5%). 1,267 (56.9%) of all the cases had PC consult. African American (adjusted odds ratio [aOR]: 0.75; p < 0.005) and Hispanic (aOR: 0.62; p < 0.05) were significantly associated with less PC utilization than the Caucasian reference group in multivariable regression model. Lower PC prevalence was also observed at rural hospitals and Midwest region. Higher income group and private insurance no longer showed statistically significant higher PC utilization after adjusted for other variables. Conclusions: In end-of-life hospitalization with breast cancer as primary diagnosis, racial and hospital resource factors were significantly associated with the PC utilization. Cultural difference could be associated with the lower PC prevalence since adjusting income and insurance types could not explain the disparities in PC utilization among different racial groups. Future study should investigate and address the disparities of PC utilization in female terminal breast cancer.
The impact of diabetes on the performance of skeletal muscle density (SMD) in screening for frailty: Findings from the Cancer and Aging Resilience Evaluation (CARE) Registry.
Authors: Thai Sydney T , Lund Jennifer Leigh , Poole Charles , Sturmer Til , Harmon Christian , Al-Obaidi Mustafa , Williams Grant Richard
Published: June 2022

12037

Background: SMD is a marker of myosteatosis that can be obtained from routine computed tomography (CT) imaging and could be used to screen patients for further frailty evaluation. But diabetes (DM) is linked with myosteatosis in men and SMD utility for patients with DM is unknown. We assessed SMD performance as a frailty screening tool in older adults with primarily gastrointestinal cancer and compared performance in patients stratified by sex and DM. Methods: We analyzed CARE Registry patients at baseline, a sample with mostly late-stage, gastrointestinal malignancies. Frailty and DM were captured in the CARE tool, a patient-reported geriatric assessment. SMD was calculated from CT scans at L3 vertebrae. Analyses were run for each sex and by DM status. We used linear regression to assess crude associations of SMD and frailty score. SMD performance in classifying frail status (vs. non-frail) was analyzed with 1) area under the receiver operating characteristic curves (AUC) and confidence intervals (CIs); and 2) sensitivity and specificity for sex-specific SMD quartile cut-offs (Q1, median, Q3). Cut-off performance was compared between patients with DM vs. without using differences in sensitivity and specificity and CIs. CIs were estimated with 2,000 bootstrap replicates. Results: The analytic sample (N=874; 27% DM, 32% frail) was 39% female with median age 68 years. For each sex-DM subset, regression results had negative slopes indicating that low SMD was associated with higher frailty score. AUCs for women with and without DM were 0.57 (95% CI 0.45-0.69) and 0.62 (0.54-0.70). AUCs for men with and without DM were 0.68 (0.59-0.77) and 0.58 (0.52-0.65). Sex-stratified sensitivity and specificity results are below. Median cut-offs had both sensitivity and specificity >0.50; Q3 cut-offs had higher sensitivity but low specificity. Conclusions: SMD could be used to pre-screen older adults with and without DM for further clinical frailty assessment. With high-sensitivity cut-offs (Q3), 13% to 26% of frail patients could be missed. Compared to other groups, SMD pre-screening for men with DM may miss the fewest frail patients but would produce many false-positives. [Table: see text]
Improved overall survival of metastatic cancers in the United States across all age groups in the immunotherapy era: Implications for considering elderly patients (age ≥ 75) for immune checkpoint inhibitors (ICIs).
Authors: Chen Yu-Wei , Tucker Matthew D , Yasin Hesham Abdallah , Guo Xingyi , Shu Xiao-Ou , Rini Brian I.
Published: June 2022

12039

Background: ICIs have changed the treatment paradigm in many cancer histologies. Population-level data regarding the impact of ICIs on the contemporary US cancer patients is scarce. In addition, elderly patients were underrepresented in the landmark trials. Methods: Metastatic cancers (melanoma, lung cancer, kidney cancer, head and neck cancer, Hodgkin’s lymphoma, and urothelial cancer) diagnosed between 2004-2018 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The year of the first FDA approved ICI in each cancer site was considered the commencement of the ICI era. The impact of metastatic cancers diagnosed in the ICI era was assessed in each age group (<65, 65-75, and ≥75) using multivariable Cox regression after adjustment for age, sex, race, household income and residence status (metropolitan vs non-metropolitan) Results: There were 363,191 patients with metastatic cancers included in the analysis [lung cancer: 68%, head and neck cancer: 14%, Hodgkin Lymphoma: 7%, kidney cancer: 7%, urothelial cancer: 3%, and melanoma: 2%): 60% were male and 73% were non-Hispanic White. The median age was 66 (interquartile range: 57-75). After baseline adjustments for sociodemographic factors, metastatic cancers diagnosed in the ICI era had improved overall survival except urothelial cancer (Table). Results of overall survival and cancer-specific survival were consistent across all age groups (<65, 65-75, and ≥75). Among patients with age ≥75, metastatic cancers diagnosed in the ICI era had improved overall survival in melanoma (AHR: 0.81, p-value<.0001), lung cancer (AHR:0.91, p-value<.0001), kidney cancer (AHR: 0.89, p-value: 0.0004), head and neck cancer (AHR:0.82, p-value<.0001), Hodgkin lymphoma (AHR: 0.75, p-value:0.003) but not in urothelial cancer. Conclusions: Metastatic cancers diagnosed in the ICI era had improved overall survival and cancer-specific survival including the subgroup of age ≥ 75. ICIs should not be withheld in elderly patients solely due to chronological age. [Table: see text]
Locoregional therapy trends by frailty and life expectancy in older adults with T1N0 hormone receptor-positive breast cancer.
Authors: Minami Christina Ahn , Jin Ginger , Freedman Rachel A. , Schonberg Mara A. , King Tari A. , Mittendorf Elizabeth A.
Published: June 2022

12047

Background: Women >70 years old with T1N0 hormone receptor-positive (HR+) breast cancer face complex locoregional therapy decisions, as breast surgery type, and omission of axillary surgery or radiation therapy (RT), do not impact overall survival. Although frailty status and life expectancy (LE) ideally factor into therapy decisions, their impact on decision-making is unclear. We sought to identify trends in, and factors associated with locoregional therapy type by frailty and LE, and to determine if therapy type was associated with cause of death. Methods: Women >70 years old with T1N0 HR+/HER2-negative breast cancer diagnosed 2010-2015 were identified in SEER-Medicare. Stratified by validated claims-based frailty (Kim et al) and LE (Tan et al) measures, trends in therapy (lumpectomy, lumpectomy + axillary surgery, lumpectomy + RT, mastectomy, lumpectomy + axillary surgery + RT, and mastectomy + axillary surgery, with the last two combinations deemed “more intense” therapy) were analyzed. Generalized linear mixed models were used to identify factors associated with therapy receipt (breast surgery type, axillary surgery, and RT) and, among the women who died in this cohort, to explore potential associations between local therapy received and cause of death. Results: Of the 16,188 women included, 21.8% were frail, 22.2% had a LE<5 years, but only 12.3% were both frail and had a LE<5 years. In frail women who had a LE < 5 years, more intense therapy regimens decreased significantly (lumpectomy + axillary surgery + RT: 27.5% to 17.3%, p<0.001; mastectomy + axillary surgery: 20.8% to 13.9%, p=0.02) over the study period. However, in 2015, 30% of frail women with a LE<5 years still underwent a more intense regimen. On multivariable analysis, frailty and LE<5 years were associated with a lower likelihood of axillary surgery (frailty: OR 0.65, 95% CI [0.57-0.73]; LE<5 years: OR 0.67, 95% CI [0.59-0.76]) and RT (frailty: OR 0.77, 95% CI [0.69-0.86]; LE<5 years: OR 0.73, 95% CI [0.65-0.83]), but not with breast surgery type. Of the 1868 women who died, 306 (16.4%) died of breast cancer and those undergoing more intense therapy were as likely to die of breast cancer vs other causes (Table). Conclusions: In older women with T1N0 HR+ disease, rates of more intense therapy are decreasing but 30% of frail women with a limited LE still underwent more intense therapy in the final study year. As therapy intensity does not affect breast cancer-specific mortality, appropriate de-escalation of locoregional therapy is needed. [Table: see text]
Remote geriatric assessment program for older patients starting new chemotherapy treatment in Brazil.
Authors: Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Razavi Marianne , Lakhdari Sabri , Philip Errol James , Franca Marcos V S , Molina Lorena Nascimento Manrique , Freitas Alici Natalia de Sousa , Taveira Mariane Cunha , Azeredo Andressa Cardoso , Fuzita William Hiromi , Fernandes Cristiano Menezes , Pio Raquel Baptista , Filho Romildo De Araujo Periera , Couto Milena Macedo , Vasconcellos Vitor Fiorin de , Matos Neto Joao Nunes , Buso Marco Murilo , Soto Pérez de Celis Enrique , Dale William
Published: June 2022

12052

Background: Older cancer patients in developing countries face considerable challenges in obtaining access to specialized medical attention, often due to a lack of human resources and healthcare infrastructure. This study sought to explore the benefit of a remote, validated geriatric assessment (GA) program for older patients starting chemotherapy in Brazil. Methods: Older adults (65+ years) beginning a new chemotherapy treatment regimen in Brazil were recruited. Through telehealth, patients were assessed with GA before starting chemotherapy treatment for any type of solid cancer and at a follow-up visit (3 months after enrollment). GA results were discussed by a multidisciplinary team (e.g., geriatrician, psychologist, nutritionist) and recommendations were determined. Outcome measures included chemo toxicity scores (CARG, scale 0-19), physical symptoms (FACT-G, scale 0-108) and activities of daily living (IADL, scale 0-5 for men and 0-8 for women, or scale 0-1 for IADL ratio). Descriptive statistics were generated, and paired t-tests were used to evaluate the change in these measures over time. Results: A total of 51 older patients from 5 different Brazilian states (Amazonas, Distrito Federal, Espirito Santo, Pernambuco and Rio Grande do Sul) have been enrolled to date. The mean distance from a patients’ home to their place of cancer treatment was 21 miles (range: 3-101 miles). Participants had a mean age of 76.5 years (SD = 7.6) and were predominantly female (57%), white (57%), married (61%), and had a high school degree or more (65%). Patients were mostly diagnosed with gastrointestinal (39%) or gynecological (20%) cancers; 55% of patients were diagnosed with a stage IV disease. The majority of patients (80%) were referred to appropriate remote services based on the GA; including geriatricians (41%), nutritionists (39%) and/or psychologist (16%). At the time of abstract submission, data from 34 complete cases were available for longitudinal analysis, in which we observed a decrease in chemo toxicity scores (M1= 6.65, M2= 5.88, p = 0.035) and an improvement in FACTG (M1= 92.94, M2= 98.53, p < 0.001). The improvement in IADL ratio was not significant (M1= 0.79, M2= 0.85, p = 0.069). Conclusions: This novel, ongoing study is, to our knowledge, the first to implement a remote GA program in Brazil. Our preliminary findings suggest that a remote GA program, with appropriate referrals to specialists, may increase the reach of supportive services and improve cancer care in developing countries.
Using CT-based body composition metrics and frailty index in predicting survival among older adults with cancer.
Authors: Giri Smith , Feliciano Elizabeth , Harmon Christian , Kenzik Kelly , Al-Obaidi Mustafa , Anyene Ijeamaka , Beg Mirza Faisal , Chow Vincent Tze Yang , Popuri Karteek , Lenchik Leon , Caan Bette Jane , Williams Grant Richard
Published: June 2022

12057

Background: Older adults with cancer are at an increased risk of treatment related toxicities and excess mortality during cancer treatment. While altered body composition and frailty are associated with worse survival among older adults with cancer, no prior study has examined their combined influence on survival prediction. Methods: Prospective study of older adults (≥60 years) undergoing geriatric assessment (GA) at initial visit with a medical oncologist at UAB from 9/2017-07/2021 with available abdominal computed tomography (CT) within 60 days of GA. Using multi-slice CT images from T12 to L5 level, volumetric skeletal muscle (SMV), visceral (VATV) and subcutaneous (SATV) adipose tissues, and skeletal muscle density (SMD), were derived. Sex-specific z-scores for each measure were determined. A 44-item frailty index was obtained, using the deficit accumulation model. Overall survival (OS) was defined as time from GA to death or last follow-up (11/8/2021). Kaplan-Meier estimates of survival rates were compared using log-rank statistics. Multivariable cox regression models were used to predict OS in a random sub-sample (1:1 split of training:validation set), sequentially adding frailty and each body composition measure and assessing improvement with likelihood ratio tests and Harrel’s C statistic. Results: 815 patients were included (median age 68 years, 61% men, and 75% non-Hispanic Whites. 73% had gastrointestinal malignancies (stage III, 25%, stage, IV 48%). 32% were frail, 31% pre-frail. There was a weak negative correlation between height-adjusted SMV and frailty (r = -0.16), particularly among men (r -0.24). Over a median follow-up of 25.7 months (range 0.3-49.6 months), 268 patients (33%) died. The 2-year survival rate was 75.9%, 68.5% and 52.2% among robust, pre-frail and frail (log-rank p <.001), respectively. In multivariable models adjusted for age, sex, race, cancer type and cancer stage, being frail (vs robust) (Hazards Ratio, HR = 2.32; 95%CI: 1.69-3.2; p <.001) and higher skeletal muscle volume (HR = 0.85; 95%CI: 0.72-0.99; p= 0.04, per SD increment) were independently associated with OS. Adding body composition and frailty to clinical variables led to significant improvement in prediction (Harrel’s C increased from 0.69 to 0.74). In the validation set, discrimination was similar (Harrel’s C = 0.72) and plots suggested good model calibration. Conclusions: CT-based body composition metrics and frailty are independent predictors of OS among older adults with cancer and improve survival prediction compared to routine clinical risk factors.