bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined IL-6 and IL-8 inhibition to overcome mesenchymal stem cell (MSC)-induced resistance to antimetastatic drugs in osteosarcoma.
Authors: Baglio S. Rubina , De Schrijver Celine , Massaro Crescenzo , Lagerweij Tonny , Gomez Martin Cristina , Giorgio Cristina , Brandolini Laura , Gavioli Elizabeth Marie , Allegretti Marcello , Pegtel D. Michiel 
Published: June 2022

10037 Background: Mesenchymal stem cells (MSCs) play a key role in the progression of osteosarcoma (OS). In response to tumor-associated signals, including tumor-secreted extracellular vesicles (EVs), MSCs increase the expression of inflammatory cytokines promoting tumor cell aggressiveness. Previous data has demonstrated that IL-6 and IL-8 signaling mediate metastasis in OS. The aim of this study was to evaluate tumor EV-induced alterations of MSCs and identify combination therapies that can counteract MSC-induced resistance to antimetastatic drugs. Methods: Tumor EV-induced alterations of the MSC transcriptome were analyzed by RNA-seq. Gene set enrichment analysis (GSEA) was applied to discriminate TGFβ-dependent and independent pathways. EV RNA-induced expression changes were identified by transfecting purified EV-RNA in MSCs and by using a selective dsRNA antagonist. We selected candidate targets to block MSC-induced drug resistance and evaluated their effect in an orthotopic xenograft model of OS. Ladarixin (an allosteric inhibitor of the CXCL8/IL-8 receptors CXCR1 and CXCR2; 30 mg/kg 6x per week i.p.) and tocilizumab (anti-IL6 receptor antibody; 100 µg/mouse every other day i.p.) were administered starting from day one until the experimental endpoint. Metastasis were quantified by histological examination. This study was funded by the Dutch Cancer Society (KWF), POR FESR Campania 2014‐2020 and Dompé Farmaceutici SpA. Results: EVs from aggressive cancer cell lines induced an inflammatory MSC (iMSC) phenotype, characterized by increased expression of chemokines, including IL-8 as the most upregulated. Apart from IL-6, these alterations were mostly independent from TGFβ signaling and related to pattern recognition receptor (PRR) activation. We demonstrated that tumor EV-associated non-coding RNAs trigger TLR3 signaling in MSCs activating an innate immune response leading to high induction of IL-8 and other chemokines. Ladarixin and tocilizumab combination significantly reduced metastasis formation in a spontaneous metastasis model and overcame iMSC-induced resistance observed with single antimetastatic treatments. No effect was observed on primary tumor growth. Conclusions: EV-associated TGFβ together with EV-RNA induce iMSCs development in OS. Ladarixin in combination with tocilizumab reduced metastasis formation in a xenograft mouse model of OS, and, importantly, may prevent the occurrence of iMSC-induced tumor resistance to antimetastatic drugs.
Long-term medical and functional outcomes of ependymoma survivors: A population-based, matched cohort study.
Authors: Coltin Hallie , Pequeno Priscila , Liu Ning , Tsang Derek S. , Taylor Michael D. , Bouffet Eric , Ramaswamy Vijay , Nathan Paul C. 
Published: June 2022

10054 Background: Ependymoma is the third most common pediatric central nervous system tumour. Treatment approaches are intensive and may include surgery, radiation, and chemotherapy. There are no longitudinal population-based cohort studies evaluating the long-term medical and functional outcomes of survivors of childhood ependymoma. Methods: Using a provincial pediatric cancer registry, all 5+ year ependymoma survivors diagnosed between 1987-2015 in Ontario, Canada were identified and matched to cancer-free population controls based on age, sex, and geographical location. Cases were followed from the index date (5 years from latest of diagnosis, or relapse/subsequent malignancy prior to age 18 years) until December 31, 2020 or censorship (death, or relapse/ new cancer after age 18 years). Clinical data were linked to administrative health databases to estimate the cumulative incidences and cause-specific hazard ratios (HR) of mortality, hospitalizations, strokes, hearing loss requiring a hearing aid, receipt of homecare services, and subsequent malignant neoplasms (SMNs) between cohorts, accounting for matching and competing risks. Results: Of 166 ependymoma diagnoses in the study period, 70 (42.2%) were excluded, most commonly due to early death prior to the index date. Ninety-six cases were matched to 480 controls (Table). The 10-year survival probability after the index date was 92.8% in cases and 99.6% in controls (HR 9.3, 95% CI 2.3-45.2, p=0.002). Compared to controls, cases were at higher risk of hospitalization (HR 3.2, 95% CI 2.2-4.6, p<0.0001), stroke (HR 33.3, 95% CI 5.7-629.1, p<0.0001), and receiving homecare services (HR 4.1, 95% CI 2.5-6.5, p<0.0001). Cases were at high risk of hospitalizations, strokes, hearing loss, and SMNs, with cumulative incidences of 64.7% (95% CI 46.6-78.0), 9.7% (95% CI 3.4-19.9), 13.5% (95% CI 5.3-25.5), and 12.8% (95% CI 4.7-24.9) at 20-years post index date, respectively. Conclusions: As survival of pediatric ependymoma improves, establishing the burden of late morbidity is critical. Dedicated screening programs for late sensory and neurovascular sequelae are warranted, as are interventions during and following treatment to mitigate the risk of developing such complications. [Table: see text]
Targetable genomic mutations in young women with advanced breast cancer.
Authors: Ansari Norin , Gao Lucy , Sokol Ethan , Sivakumar Smruthy , Huang Richard S.P. , Pelletier Maureen , Levy Mia Alyce , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S. , Lustberg Maryam B. , Rozenblit Mariya 
Published: June 2022

1027 Background: Advanced breast cancer in women < 40 years is more aggressive, with worse prognosis and disease-free survival, compared to older women with the disease. With increasing availability of targeted and immune therapies, we aimed to compare genomic alterations (GA) using comprehensive genomic profiling (CGP) of tumor tissue. Methods: We analyzed 2,049 breast cancers submitted to Foundation Medicine for CGP. Hybrid-capture based CGP was performed to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on at least 0.8 Mbp of sequenced DNA and microsatellite instability was determined on at least 95 loci. Tumor cell PD-L1 expression (defined as tumor proportion score >/= 1) was determined by IHC (Dako 22C3). We identified 28 (1.37%) patients <30 years, 159 (7.76%) between 30-39 years, and 1862 (90.87%) >/= 40 years. Breast tissue was used for CGP in 69.5% of cases and remainder of specimens were lymph node, metastatic, or unspecified. Results: Breast tumors were less likely to be estrogen receptor positive in younger women (54% of those <30 years, 60% of those 30-39 years, 69.4% of those >/= 40 years) and more likely to be triple negative (43%, 33%, 26.1% in the same respective groups). There was no clear pattern in HER2+ status by age (0%, 15.1%, 7.2%). Younger women had higher rates of BRCA1 (17.9%, 10.1%, 2.6%), BRCA2 mutations (7.10%, 5.70%, 4.1%), and RB1 mutations (14.3%, 9.4%, 6.1%), and lower rates of CDH1 (7.1%, 5%, 15.4%) and PIK3CA mutations (17.9%, 17.6%, 40.0%). Younger women were more likely to have PD-L1 expression (55.6%, 54.4%, 51.5%) but had lower frequencies of TMB >10 (0.0%, 5.0%, 8.7%). Differences are statistically significant in BRCA1, CDH1, and PIK3CA. Conclusions: These findings confirm that young women with breast cancer have actionable GA. Different mutational profiles may support differential use of targeted and immune therapies. Statistically and clinically significant differences include higher BRCA1 mutations which may lend to PARP inhibitor use and lower PIK3CA mutations which may reduce alpelisib use. Higher RB1 mutations and immunotherapy biomarker differences were not statistically significant. However, these may clinically translate into CDK4/6 resistance and reduced immunotherapy options, respectively. [Table: see text]
Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial.
Authors: Jhaveri Komal L. , Goldman Jonathan W. , Hurvitz Sara A. , Guerrero-Zotano Angel , Unni Nisha , Brufsky Adam , Park Haeseong , Waisman James Ross , Yang Eddy Shih-Hsin , Spanggaard Iben , Reid Sonya A. , Burkard Mark E. , Prat Aleix , Loi Sherene , Crown John , Hanker Ariella , Ma Cynthia X. , Bose Ron , Eli Lisa DeFazio , Wildiers Hans 
Published: June 2022

1028 Background: N is an oral, irreversible pan-HER TKI with activity against HER2 mutations. Genomic analyses from the SUMMIT MBC cohort following N±F suggest that resistance to N may occur via mutant allele amplification or secondary HER2 mutations. Adding T to N+F in SUMMIT showed encouraging durable responses in patients (pts) with HR+, HER2-mutant MBC and prior CDK4/6 inhibitors (CDK4/6i). Methods: SUMMIT (NCT01953926) enrolled pts with HR+, HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6i. Pts received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1&15 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w). During the small, randomized portion of the trial, pts received N+F+T, F+T or F (1:1:1 ratio). Pts randomized to F+T or F could crossover to N+F+T at progression. Efficacy endpoints: investigator-assessed ORR and CBR (RECIST v1.1); DOR; best overall response. Pre-treatment tumor tissue was centrally assessed retrospectively by next-generation sequencing. ctDNA from patient samples was assessed by NGS. Results: SUMMIT has completed enrolment; we report efficacy from 45 pts in the N+F+T cohort, plus 10 pts who progressed on F (n=6) or F+T (n=4) and crossed over to N+F+T (Table). HER2 allelic variants in the 45 N+F+T pts and ORR (%) (pts may have >1 mutation) were: V777L (n=6, 50%), L755S/P (n=15, 40%), S310F (n=4, 50%), exon 20 insertion (n=11, 36%), other KD missense (n=6, 33%), TMD missense (n=2, 0%), exon 19 deletion (n=1, 0%). Conclusions: N+F+T is a promising combination for HR+, HER2-mutated MBC with prior exposure to CDK4/6i, across a range of activating HER2 mutations. Results from the upcoming Apr 2022 data cut, including biomarkers, safety, mechanisms of acquired resistance, and preclinical mechanism of N+T, will be presented. Clinical trial information: NCT01953926. [Table: see text]
HER2-targeted immunoconjugates for breast cancer: Ancestry and dose adjustment for thrombocytopenia.
Authors: Rainone Michael , Behrendt Carolyn E. , Kasparian Saro , Nguyen Tina , Mortimer Joanne E. , Yuan Yuan , Waisman James Ross , Stewart Daphne B. , Lavasani Sayeh Moazami , Sedrak Mina S. , Patel Niki , Pullarkat Vinod A. 
Published: June 2022

1048 Background: Thrombocytopenia (TCP) is a common toxicity of HER2-targeted agents, trastuzumab emtansine (TDM1) and trastuzumab deruxtecan (TDXd). A high incidence of this toxicity was observed in pivotal trials that led to approval of these agents. We investigated whether Asian ancestry increases risk of dose adjustment for TCP on TDM1/TDXd and its impact on dosing in the real-world setting. Methods: Females with HER2+ breast cancer who initiated TDM1/TDXd between 1/16/17-10/26/21 were identified by retrospective review. Primary endpoint was number of chemotherapy cycles until adjustment of TDM1/TDXd dose for TCP; competing endpoints included discontinuation for other toxicity, disease progression, and completion of treatment. Individuals who were switched from TDM1 to TDXd contributed an additional observation post-switch. Recurrent events analysis evaluated Asian ancestry (p<0.05) using a proportional means model, with robust sandwich estimate recognizing correlation between repeated observations per individual. Covariates (age, metastatic disease, drug, prior adjustment) were retained if they improved the model. Results: The study excluded individuals who declined to self-identify (n=23), self-identified as other than Asian or White (n=28), and/or dissented to research (n=24). The study included n=181 individuals (mean age 55.1+12.8 years), of whom n=48 (26.5%) identified as Asian and n=124 (68.5%) had metastatic disease. Overall, 33 individuals received TDXd exclusively, leaving 148 (81.8%) individuals who received TDM1, including 45 individuals who later switched to TDXd after development of TCP while on TDM1 (n=9) or other toxicity (n=36) on TDM1. For n=226 observations (total 2551 cycles), the endpoint was dose adjustment for TCP (n=32), discontinuation for other toxicity or disease progression (n=112), completion of treatment (n=27), or censoring (n=55). Taking into account history of switching drug for TCP, Asian ancestry was associated with increased risk of dose adjustment for TCP (Table). Neither age, metastatic disease, nor specific drug improved the model (data not shown). Conclusions: Among individuals taking TDM1 and/or TDXd for HER2+ breast cancer, we observed that those with Asian ancestry are at greater risk of dose reduction for TCP than their non-Asian counterparts. Upon confirmation in additional individuals with HER2+ cancers of the breast and other sites, this heightened susceptibility to TCP among Asian individuals should be further investigated to elucidate the underlying mechanism and optimize clinical guidelines for prevention and management. [Table: see text]
Trends in stage I lung cancer.
Authors: Singareddy Aashray , Flanagan Mary Ellen , Samson Pamela Parker , Waqar Saiama Naheed , Devarakonda Siddhartha , Ward Jeffrey P. , Herzog Brett , Rohatgi Anjali , Robinson Clifford Grant , Govindan Ramaswamy , Puri Varun , Morgensztern Daniel 
Published: June 2022

10508 Background: The American Cancer Society has recently reported an increase in the percentage of patients with localized lung cancer from 2004 to 2018 with a corresponding improvement in survival for all patients combined. We analyzed the recent trends in stage distribution for lung cancer including tumor and demographic factors. Methods: We selected patients with lung cancer from the National Cancer Database (NCDB) public benchmark report diagnosed between 2010 and 2017. Patients with unknown stage were excluded. Stage distribution using the AJCC 7th edition of the TNM system was evaluated according to year of diagnosis, histology, age, gender, race, insurance and income. Results: Among the 1,447,470 patients from 1,384 hospitals identified in the database, 56,382 (3.9%) were excluded due to unknown stage or incorrect histology, leaving 1,391,088 patients eligible. The percentage of patients with stage I progressively increased from 23.5% in 2010 to 29.1% in 2017 while stage IV decreased from 45.5% to 43.1% during the same period (Table). The increased in percentages of stage I from 2010 to 2017 were 25.9% to 31.8% in non-small cell lung cancer (NSCLC) and 5.0% to 5.4% in small cell lung cancer (SCLC). Although the increased percentage of stage I lung cancer was observed in all subsets of patients, there were significant imbalances according to demographic and socio-economic factors. In the year 2017, the major gaps in stage I included insurance (31.4% for Medicare, 26.4% for private insurance, and 12.9% for uninsured), income (32.4% for the highest annual income and 25.4% for the lowest) and race (29.9% in whites and 24.3% in blacks). Conclusions: There has been a significant increase in the percentage of stage I lung cancer at diagnosis from 2010 to 2017 which occurred mostly in NSCLC. Disparities in diagnosis and access to treatment may account for the differences in the percentage of patients with stage I among selected demographic populations. The staging trends and recent treatment improvements may lead to better survival for lung cancer. [Table: see text]
Ancestry-specific risk of triple-negative breast cancer (TNBC) associated with germline pathogenic variants (PV) in hereditary cancer (CA) predisposition genes.
Authors: Hall Michael J. , Hughes Elisha , Kucera Matthew , Kidd John , Bernhisel Ryan , Hullinger B , Slavin Thomas Paul , Kurian Allison W. 
Published: June 2022

10517 Background: TNBC represents ̃15% of invasive BC. Ancestry-specific variabilities in TNBC risk are well-described, with African American (AA) women experiencing higher incidence and mortality from TNBC than women of other races/ethnicities. Increased risk of TNBC has been associated with both rarer (e.g. RAD51C/D, BARD1) and more commonly detected (e.g. BRCA1/2, PALB2) germline PV in hereditary CA predisposition genes, but less is known about ancestry-specific TNBC risks for PV carriers. Methods: We examined clinical and genetic records from women referred for multigene CA panel testing (9/2013-5/2020). Multivariable logistic regression was used to test associations of PV in 13 genes with risk of TNBC after accounting for age, ancestry, and personal/family CA history. We analyzed each gene in the full cohort, and in subcohorts defined by self-reported ancestry. Effect sizes are expressed as odds ratios with 95% confidence intervals. Seven genes are not reported in ancestry-stratified analyses due to small numbers of PV carriers with TNBC. Results: From 627,219 individuals referred for multigene panel testing, 115,337 (18.4%) women with personal history of BC were identified, of whom 17,951 (15.6%) reported TNBC. Personal history of TNBC was reported more frequently in women of African ancestry (26.9%) than in women of European (13.9%) or Asian (11.7%) or Latinx ancestry (14.9%). Ancestry-stratified risks of TNBC associated with germline PVs are seen in the Table. Conclusions: While small samples sizes limit some gene-specific analyses, comparable ancestry-specific risks of TNBC were seen across the racial/ethnic groups examined here. [Table: see text]
Comparison of characteristics and outcomes of young onset versus average onset pancreatobiliary adenocarcinoma.
Authors: Jayakrishnan Thejus , Kamath Suneel Deepak , Nair Kanika G. , Wei Wei , Estfan Bassam N. , Krishnamurthi Smitha S. , Khorana Alok A. 
Published: June 2022

10522 Background: Young-onset gastrointestinal malignancies appear to be increasing in incidence but most investigations have focused on colorectal cancer and there are limited data on young-onset pancreatobiliary cancers (YO-PBA). We evaluated trends and characteristics of YO-PBA in comparison to average-onset disease (AO-PBA). Methods: The study cohort comprised patients with PBA (pancreatic adenocarcinoma, intra- and extra-hepatic cholangiocarcinoma) diagnosed between 2004 and 2017 from the National Cancer Database. YO-PBA was defined as diagnosis at age < 50 years and AO-PBA as >50 years. Logistic regression was used to assess factors associated with YO-PBA status, and cox proportional hazards modeling was performed to associate demographic and clinical factors with overall survival. Results: Of 360,764 patients analyzed, 20,822 (5.8%) were YO-PBA with a median age at diagnosis of 45 years (IQR 42 – 48) vs 70 (62-78) years for AO-PBA. The number of patients with YO-PBA increased by 33.3% during the study period compared to 111.8% for AO-PBA. Characteristics associated with YO-PBA were (p-values<0.001 for all): male sex (6.3% YO-male out of all male patients vs 5.2% YO-female out of all female patients, OR 1.2), Black race (7.9% YO-Black vs 5.0% YO-White, OR 1.4), lower income (6.4% YO-lowest household income based category vs 5.5% highest, OR 1.3), and lower education (6.9% YO-lowest educational status category vs. 4.9% highest, OR 1.4). YO-PBA were more likely to present with stage-IV disease (6.4% YO-Stage IV of all stage IV vs 5.4% YO-Stage I-III, OR 1.2, p-value<0.0001), but more likely to undergo surgery (7.4% YO-surgery patients vs 5.4% YO no-surgery patients). Median OS was YO 11.0 (95% CI 10.8 – 11.3) vs. AO 7.1 months (95% CI 7.0 – 7.1). Effects of patients’ characteristics on OS differed significantly between YO and AO-PBA cohorts (interaction p-values < 0.001), and were analyzed separately (table). Notably, Black patients experienced worse outcomes in both age groups. Conclusions: Young-onset pancreatobiliary cancers (YO-PBA) reported in NCDB have increased over the years. YO-PBA is associated with better survival compared to AO-PBA. Socioeconomic disparities significantly impact incidence and outcomes. More work is needed to help address these health disparities, especially for those with young-onset cancer. [Table: see text]
Renal cell carcinoma in renal transplant recipients: Is there a role for screening?
Authors: Yohannan Binoy , Sridhar Arthi , Kaur Harmanpreet , De Golovine Aleksandra , Maithel Neha 
Published: June 2022

10528 Background: Renal transplant (RT) recipients are at an increased risk of developing renal cell carcinoma (RCC), mainly due to iatrogenic immunosuppression and changes in immune surveillance. Most RCCs in RT recipients arises from the native kidney, but rarely may arise from the allograft. RCC post-RT can adversely affect allograft function and long-term survival. Screening for RCC in RT recipients is controversial and is not routinely done. Methods: We performed a retrospective chart review of RT recipients who underwent transplantation between January 1, 1999, and December 31, 2019. The following data were collected: Baseline demographic variables, cause of end-stage renal disease (ESRD), duration of dialysis prior to RT, type of RT (cadaveric vs. living donor), immunosuppressive regimen, site of RCC (native kidney vs transplanted kidney), time from RT to diagnosis of RCC, stage and Fuhrman grade, tumor histology, RCC treatment, and RCC-related mortality. RCC stage at diagnosis and survival were compared between patients who were screened versus those who were not. Results: Among 1998 RT recipients who underwent transplantation at Memorial Hermann Hospital (MHH) Texas Medical Center (TMC); 16 patients (0.8%) developed RCC. An additional 4 patients with RCC who underwent RT elsewhere but received follow up at MHH TMC were also included. Therefore, a total of 20 patients with post-RT RCC were identified, of whom 75% were men. Subject races included White (20%), Black (50%), Hispanic (20%), and Asian (10%). The median age was 56 years. Median duration of dialysis prior to RT was 36 months (range, 1–120). Median time to RCC diagnosis post-RT was 96 months (range, 16–312). Histologies included clear cell (75%), papillary (20%), and chromophobe (5%) RCC. RCC developed in the native kidney in 60% and in the allograft in 40% of the patients. Post-RT RCC patients were divided into those who underwent regular screening (n = 12) and no screening (n = 8). The regular screening group (n = 12) underwent ultrasound or computerized tomography annually or every 2 years. All of these patients had early-stage disease at presentation: stage I (n = 11) or II (n = 1). All patients who had RCC detected by screening were cured by nephrectomy (n = 10) or cryotherapy (n = 2). In patients who had no screening post RT, 37.5% had stage I, 25% had stage III, and 37.5% had stage IV RCC. Two patients with stage IV RCC died from metastatic disease. The RCC-related mortality was 0% in patients who were screened, compared to 25% in patients who had no screening. Conclusions: All RT recipients who had RCC diagnosed based on screening had an early diagnosis and no RCC-related mortality. Screening for RCC in RT recipients is an effective tool for early diagnosis and to reduce RCC-related mortality. Further research into the cost-effectiveness of screening is imperative.