bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral motor and sensory neuropathy in survivors of childhood central nervous system (CNS) tumors in the St. Jude Lifetime (SJLIFE) cohort.
Authors: Rodwin Rozalyn L , Lu Lu , Srivastava Deo Kumar , Brinkman Tara M. , Krull Kevin R. , Armstrong Gregory T. , Khan Raja B. , Phillips Nicholas S. , Merchant Thomas E. , Gajjar Amar J. , Robison Leslie L. , Hudson Melissa M. , Kadan-Lottick Nina S. , Ness Kirsten K. 
Published: May 2020

10549 Background: Survivors of CNS tumors are at risk for peripheral motor and sensory neuropathy. Chemotherapy’s contribution to peripheral neuropathy has not been well studied in this population. We aimed to estimate the prevalence of peripheral neuropathy, and determine its association with tumor characteristics and treatment exposures. Methods: Within the SJLIFE cohort, survivors of CNS tumors (n = 363, median [range] age 24 [18-53] years, 43.3% female) ≥10 years from diagnosis and ≥ 18 years at evaluation completed in-person assessments for peripheral motor and sensory neuropathy (defined as abnormal motor or sensory subscales of the Modified Total Neuropathy Score). For comparison, matched community controls (n = 445, median [range] age 34 [18-70] years, 55.7% female) underwent the same assessment. Prevalence of ≥ grade 2 motor or sensory neuropathy was estimated by a modified Common Terminology Criteria for Adverse Events. Multivariable analyses adjusting for age, sex and race were used to identify associated disease and treatment characteristics. Results: Overall, 11.0% of survivors of CNS tumors versus 0.9% of controls had ≥grade 2 motor neuropathy (p < 0.001), and 15.7% of survivors of CNS tumors versus 2.3% of controls had ≥grade 2 sensory neuropathy (p < 0.001). Prevalence of motor and sensory neuropathy varied by diagnosis (Table). Vinca alkaloid exposure (OR 3.5, 95% CI 1.7-7.0) and infratentorial tumor location (OR 2.5, 95% CI 1.1-5.4, reference supratentorial location) were independent risk factors for sensory neuropathy. Infratentorial tumor location was also associated with an increased risk of motor neuropathy (OR 2.4, 95% CI 1.2-4.8). History of radiation and surgery were not significant independent risk factors for motor or sensory neuropathy. Conclusions: Prevalence of peripheral motor and sensory neuropathy was significantly higher in survivors of CNS tumors than in matched community controls. Survivors of CNS tumors would benefit from increased surveillance to identify and treat peripheral neuropathy, especially in those who received vinca alkaloids or had infratentorial tumors. [Table: see text]
Clinical and genetic risk factors for radiation-associated ototoxicity: A report from the childhood cancer survivor study and the St. Jude Lifetime Cohort.
Authors: Trendowski Matthew R. , Baedke Jessica , Sapkota Yadav , El Charif Omar , Wheeler Heather E. , Leisenring Wendy M. , Robison Leslie L. , Hudson Melissa M. , Morton Lindsay M. , Oeffinger Kevin C. , Travis Lois B. , Howell Rebecca M. , Yasui Yutaka , Armstrong Gregory T. , Bhatia Smita , Dolan M. Eileen 
Published: May 2020

10550 Background: Cranial radiation therapy (CRT) for pediatric cancer often results in ototoxicity in the form of hearing loss and tinnitus. We sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with cranial radiation. Methods: Relationships between age at last observation, sex, cumulative CRT dose and self-reported ototoxicity were evaluated for hearing loss and tinnitus among 1,991 (tinnitus) and 2,198 (hearing loss) survivors in the Childhood Cancer Survivor Study who received CRT. Logistic regression evaluated associations with non-genetic risk factors and comorbidities as well as SNP dosages in GWAS of CRT-related tinnitus (cases: 146; controls: 1,845) and hearing loss (cases: 270; controls: 1,928). Results: Males were more likely to report CRT-related tinnitus (9.4% vs. 5.4%; p = 5.81x10−4) and hearing loss (14.0% vs. 10.7%; p = 0.02) than females after adjusting for dose and age at last observation. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: p < 2.00x10−16; hearing loss: p = 6.35x10−9), take antidepressants (tinnitus: p = 0.02; hearing loss: p = 0.01) and report poorer overall health (tinnitus: p = 9.40x10−7; hearing loss: p = 1.30x10−6) compared to survivors without tinnitus or hearing loss after age-adjustment. GWAS of CRT-related tinnitus revealed a prominent signal in chromosome 1 led by rs203248 (p = 1.50x10−9), while GWAS of CRT-related hearing loss identified rs332013 (p = 5.79x10−7) in chromosome 8 and rs67522722 (p = 7.78x10−7) in chromosome 6 as approaching genome-wide significance. Replication analysis in an independent cohort of pediatric cancer survivors (SJLIFE) indicated that rs67522722, intronic to ATXN1, a gene associated with the neurodegenerative disorder spinocerebellar ataxia type 1, was significantly associated with CRT-related hearing loss (p = 0.03). Enrichment analysis and LD score regression with previous GWAS results of cisplatin-related hearing loss and tinnitus in testicular cancer survivors showed no detectable enrichment in genetic architecture with CRT-related hearing loss and tinnitus, respectively. Conclusions: Radiation-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722 that was replicated in an independent cohort of pediatric cancer survivors.
Treatment intensity and risk of chronic health conditions and late mortality among long-term survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.
Authors: Weil Brent R , Green Daniel M. , Murphy Andrew J , Liu Qi , Howell Rebecca M. , Weldon Christopher Bertero , Mullen Elizabeth Anne , Madenci Arin L , Leisenring Wendy M. , Neglia Joseph Philip , Oeffinger Kevin C. , Termuhlen Amanda M. , Mostoufi-Moab Sogol , Levine Jennifer , Krull Kevin R. , Yasui Yutaka , Robison Leslie L. , Armstrong Gregory T. , Chow Eric Jessen , Armenian Saro 
Published: May 2020

10553 Background: Refinement in risk stratification has led to intensification of therapy for Wilms tumor (WT) patients with adverse prognostic factors. Chronic health conditions (CHCs) including cardiac conditions, subsequent malignant neoplasms (SMNs), and late mortality are known risks for WT survivors, however the impact of specific treatment regimens on these outcomes is largely unknown. Methods: Late mortality (all-cause and non-recurrence death > 5 years from diagnosis), SMNs, and severity-graded CHCs (2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal) were assessed in 5-year WT survivors in the Childhood Cancer Survivor Study diagnosed from 1970-99. Survivors were categorized according to therapy received (Table). Cumulative incidence of mortality and standard mortality ratios (SMR) were estimated. Piecewise exponential models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 1507 survivors (median age at follow-up 26 yrs; range 6-55), 35-year cumulative incidence of all-cause mortality was 7.9% (SMR 2.9, CI 2.3-3.6) and 5.1% (SMR 1.9, CI 1.4-2.4) for non-recurrence mortality. RRs for developing any grade 2-5 CHC, grade 3-5 SMN, and grade 2-5 cardiac CHCs were higher for survivors compared to sibling controls (2.0, CI 1.8-2.3; 7.4, CI 5.0-10.8; 2.6, CI 2.2-3.1, respectively). Compared with VA and no RT, RR for non-recurrence late mortality and CHCs among survivors were higher for VAD + any RT, and for ≥ 4 drugs + any RT (Table). Conclusions: Administering increased-intensity therapy for WT is associated with increased late health consequences and non-recurrence late mortality, necessitating strategies to monitor and improve long-term health among survivors. [Table: see text]
Integration of the stem cell biology-based genomic tool, StemPrintER, with clinicopathological parameters for the prediction of distant recurrence in ER+/HER2- breast cancer (BC) patients.
Authors: Pece Salvatore , Maisonneuve Patrick , Disalvatore Davide , Freddi Stefano , Veronesi Paolo , Colleoni Marco , Viale Giuseppe , Di Fiore Pier Paolo 
Published: May 2020

1057 Background: The StemPrintER risk score (SPRS) is a 20 gene-based predictor that estimates the “degree of stemness” of the primary tumor and provides additional prognostic information regarding distant metastasis (DM) risk in early stage ER+/HER2- breast cancer (BC) patients beyond that obtained from standard clinicopathological parameters. Here we describe a further refined model, that combines prognostic information from SPRS with tumor size (pT) and nodal status (pN), termed SPARE (SPRS for Personalized Adjuvant therapy in Receptor-Expressing patients). SPARE was compared to the clinical treatment score (CTS) for 10-year risk of DM in a consecutive-retrospective ER+/HER2- BC patient cohort (n=1,827) with 15-year complete follow-up from the European Institute of Oncology (IEO) in Milan. Methods: The SPARE model was developed in patients randomly assigned to a training set (n=609), using the ridge-penalized Cox regression, and tested in an independent validation set (n=1,218). Likelihood χ2 (LRχ2) and Kaplan-Meier survival analysis were used to compare the prognostic information from SPARE and CTS (based on age, pN, pT, endocrine treatment). Comparative analyses were made for the DM risk over the 10-year follow-up, as well as in the early (0-5 years) or late (5-10 years) interval, according to nodal status. Results: SPARE outperformed CTS in providing prognostic information for 10-year DM risk (LRχ2: SPARE = 141.2, P<0.0001; CTS=118.1, P<0.0001), with even greater differences in node-negative patients (LRχ2: SPARE=47.6, P<0.0001; CTS=27.5, P<0.0001) and in 1-3 node-positive patients (LRχ2: SPARE=30.6, P<0.0001; CTS=15.1, P<0.0001). When reciprocally adjusted for each other, SPARE added prognostic information to CTS (ΔLRχ2: CTS+SPARE vs. CTS = 25.2; P<0.0001), while CTS did not provide any statistically significant information to SPARE (SPARE+CTS vs. SPARE = 2.1, P=0.14). Using predefined cut-offs to stratify chemo-naïve patients clinically estimated at low recurrence risk, SPARE identified low, intermediate and high risk patients based on their annual rate of DM in the early (low, 0.2%, intermediate, 0.8%, high, 3.3%) and late (low, 0.3%, intermediate, 0.9%, high, 1.6%) interval. Conclusions: SPARE represents a more refined clinical tool, compared to standard clinicopathological parameters, that could be used for personalized therapeutic decision making in ER+/HER2- BC patients.
A phase II trial of cabozantinib in hormone receptor-positive breast cancer with bone metastases.
Authors: Xu Jing , Higgins Michaela Jane , Tolaney Sara M. , Come Steven E. , Smith Matthew Raymond , Fornier Monica N. , Mahmood Umar , Yeap Beow Y. , Chabner Bruce Allan , Isakoff Steven J. 
Published: May 2020

1062 Background: We assessed the antitumor activity of cabozantinib, a potent multi-receptor oral tyrosine kinase inhibitor with activity against MET, RET, VEGFR2, and AXL, in patients with hormone-receptor positive (HR+) breast cancer with bone metastases. Methods: In this single-arm multicenter phase II study, patients with HR+, HER2- metastatic breast cancer and ≥ 1 prior line of therapy received an initial starting dose of 100 mg cabozantinib, later reduced to 60 mg per day. The primary endpoint was bone scan response rate determined by independent central review and defined as percent change of bone scan area from baseline. The target bone scan response rate was 30% compared to a null response rate of 10%. Secondary endpoints included objective response rate (ORR) by RECIST v1.1, progression free (PFS) and overall survival (OS). Bone scan and CT were obtained every 12 weeks. Results: Among 52 enrolled patients, median age was 55, and 54% and 42% had > 2 lines prior endocrine and chemotherapy, respectively and 18 (35%) had bone-only disease. 20 (38%) experienced a partial bone scan response and 6 (12%) had stable disease (SD). 16 (31%) patients discontinued study prior to week 12 assessment for early clinical progression or toxicity, and three (6%) had missing follow-up scans. Best extra-osseous overall response revealed SD in 26 (50%), but no objective responses. In 25 patients with bone scan disease control at 12 weeks, only 3 (12%) developed extra-osseous progression. Median PFS was 4.3 months (90% CI 2.8 - 5.5) and OS was 19.6 months (90% CI 18.0 – 26.8). In a landmark analysis, patients with bone scan disease control at 12 weeks had longer OS (median 24.2 months, 90% CI 16.4 – 31.7) than those without (median OS 13.3 months, 90% CI 9.5 – 18.2), with a hazard ratio of 0.37 (90% CI 0.21 – 0.65). Most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%) and hypophosphatemia (4%). Dose reduction or delay occurred in 42 (81%) patients. Conclusions: This study met its primary endpoint with bone scans improved in 38% of patients with metastatic HR+ breast cancer and remained stable in an additional 12% with cabozantinib treatment. Bone scan response correlated with improved OS. This is the first reported study in breast cancer to use bone scan response as a primary endpoint. Further studies with cabozantinib in HR+ breast cancer and additional validation of bone scan response as a surrogate for clinical benefit in breast cancer are warranted. Clinical trial information: NCT01441947 .
Pazopanib (PZ) plus endocrine therapy as treatment for hormone resistant advanced breast cancer (ABC).
Authors: Gumusay Ozge , Majure Melanie Catherine , Deal Travis , Renslo Jonathan R. , Wabl Chiara A. , Melisko Michelle E. , Chien Amy Jo , Goga Andrei , Moasser Mark , Park John , Hwang Jimmy , Rugo Hope S. 
Published: May 2020

1068 Background: A major limitation of endocrine therapy in hormone receptor positive (HR+) ABC is the development of resistance. Preclinical data suggests that higher levels of vascular endothelial growth factor (VEGF) are associated with endocrine therapy resistance. We conducted a phase II trial to evaluate the clinical benefit (CB) of PZ, a VEGF receptor tyrosine kinase inhibitor (TKI) combined with nonsteroidal aromatase inhibitors (NSAIs) in pts with ABC resistant to NSAIs. Methods: Eligibility included postmenopausal women with HR+ ABC and progressive disease (PD) after at least one month of NSAIs. Treatment was PZ 800 mg/day plus either letrozole or anastrozole. The primary endpoint was clinical benefit rate at 12 weeks (CBR12, wks). Secondary endpoints were PFS and safety. A CBR of 20% was considered a clinically meaningful comparison to the expected CBR of < 5% with continued NSAIs after PD. Using a 2-stage design, stable disease in at least 1 of the first 13 pts allowed continued enrollment to a planned 28. Results: 32 pts were enrolled; 28 are evaluable for study endpoints and all patients completed the study. The median age was 58 years (range: 41-77). Pts were heavily pre-treated, with a median of 2 prior hormone therapies (range 1-6) and 1 prior chemotherapy (range 0-8). 8 pts (28.6%) stopped treatment due to adverse events (AE) including hypertension (HTN), fever, transaminitis, nausea, vomiting, rash, hand foot syndrome and pulmonary embolism (PE); 6 pts progressed before wk 12. CBR12 was 46.4% (12 SD, 1 PR); CBR24 was 25% (5 SD, 2 PR). Median PFS was 20 wks (95% CI 11-48, and median PFS for pts with CBR12 was 24 wks. 7 pts had PFS > 6 months (24, 32, 36, 36, 48, 184 and 274 wks); 2 pts had PFS > 3 years (184 and 274 weeks). The most common grade 1/2 AE were nausea (48.2%), fatigue (33.3%), diarrhea (29.6%), back pain (22.2%), and arthralgias (22.2%). Grade 3/4 AEs included HTN (3/28; 11.1), transaminitis (3/28; 11.1%), headache (2/28; 7.4), heart failure, vertigo, nausea, oral pain, vomiting, fever, fatigue, and hypokalemia (one patient each: 3.7%). Conclusions: The addition of PZ to NSAIs resulted in a CBR12 of 46.4%, and a CBR24 of 25% in pts with heavily pre-treated ABC resistant to NSAIs. These results support clinical efficacy of antiangiogenic TKI in HR+ ABC, and suggest benefit in hormone resistant disease. Expected toxicities resulted in early discontinuation in 28.6%, which limited drug exposure. Clinical trial information: NCT 01466972 .
Frequency of brain metastases in patients with locally advanced triple negative breast cancer after neoadjuvant platinum-based chemotherapy: Impact of BRCA1/2 mutations.
Authors: Glazkova Elena , Stenina Marina , Frolova Mona A. , Ignatova Ekaterina , Rumyantsev Alexey , Petrovsky Alexander , Tjulandin Sergei 
Published: May 2020

1079 Background: patients with triple negative breast cancer has poor survival outcomes. Achievement of pathological complete response (pCR) after neoadjuvant chemotherapy can significantly improve survival of these patients, however some patients will relapse even after pCR. Methods: we reviewed prospectively-maintained outcomes database of N.N. Blokhin NMRCO. We extracted information about patients with locally advanced non-metastatic (stage IIIA-IIIC) triple negative breast cancer who were treated with neoadjuvant platinum based chemotherapy in 2014-2018 years. All included patients were tested for the presence of BRCA1/2 mutation with whole-exome next-generation sequencing or for “founder” hot-spot mutations. Results: we identified 80 patients who received neoadjuvant treatment with various platinum-based regimens. Pathological complete response rate was 62.5%. BRCA-mutations was found at 22 (27.5%) patients. Median follow-up time was 35.6 months (17.0 – 61.3). 2-year DFS was 77.3%, and 3-year DFS was 70.0%, there was significant differences in DFS in patients, who achieved and patients with residual tumor – 85,2% vs 64,3% (p=0,028). 2-year OS was 91%, 3-year OS was 78,5%. 18 patient had disease progression, the most common sites of disease progression were brain (9 [50.0%]), lungs (5 [27.8%]), 3 (16.7%) patients had locoregional relapses and 1 (5,6%) liver metastases. We separately analysed characteristics of patients with brain metastases (table). There were no significant differences in tumour pathologic response and patient age. All patients, who relapced after pCR, had brain metastases. We also found, that 7 of 9 patients with brain metastases had different BRCA mutations. Brain metastases developed in 40,9% (9/22) of patients with BRCA1 mutations and 3,4% (2/58) of patients with wild type BRCA1 (p<0,00001). Conclusions: BRCA1 mutation is significant prognostic factor for brain metastases development in locally advanced triple negative breast cancer. [Table: see text]
FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
Authors: Goyal Lipika , Meric-Bernstam Funda , Hollebecque Antoine , Valle Juan W. , Morizane Chigusa , Karasic Thomas Benjamin , Abrams Thomas Adam , Furuse Junji , He Yaohua , Soni Nital , Benhadji Karim A. , Bridgewater John A. 
Published: May 2020

108 Background: Patients (pts) with intrahepatic cholangiocarcinoma (iCCA) have a 5-year survival rate of 24%. There is no standard treatment for advanced disease after first-line chemotherapy. Fibroblast growth factor receptor-2 ( FGFR2) gene fusions occur in 10% to 20% of pts with iCCA, offering a promising therapeutic avenue for this disease. Futibatinib is a highly selective irreversible FGFR1-4 inhibitor given as a continuous once-daily (QD) oral regimen. This phase 2 registrational trial was initiated because of results from a phase 1 dose escalation/expansion study showing tolerability and preliminary efficacy of futibatinib in pts with iCCA with FGFR2 fusions. Methods: FOENIX-CCA2 (NCT02052778), a single-arm multicenter phase 2 study, enrolled pts with locally advanced/metastatic unresectable iCCA harboring FGFR2 gene fusions or other rearrangements, disease progression after ≥1 line of systemic therapy (including gemcitabine plus platinum-based chemotherapy), no prior FGFR inhibitor treatment, and an ECOG performance status of 0 or 1. Pts received futibatinib 20 mg QD until disease progression/unacceptable toxicity. The primary endpoint is objective response rate (ORR) based on independent central radiology review. Secondary endpoints include disease control rate (DCR), duration of response (DOR), and safety. Results: A total of 103 pts were enrolled. For this interim analysis, data are reported for the 67 pts (65%) with ≥6 months of follow-up. Of these, 82.1% of pts had tumors harboring an FGFR2 fusion. One, 2, or ≥3 prior therapies were received by 44.8%, 28.4%, and 26.9% of pts, respectively. ORR was 34.3% (all partial response, n = 23), and DCR was 76.1%; assessment was pending for 8 pts. Median time to response was 1.6 months (range, 1.0-4.9), and median DOR was 6.2 months (range, 2.1-14.2). The most common treatment-related adverse events (AEs; all grade, grade ≥3) were hyperphosphatemia (79.1%, 25.4%), diarrhea (37.3%, 0%), and dry mouth (32.8%, 0%). Any-cause grade ≥3 AEs were reported in 73.1% of pts. Dose delay or dose reduction was required in 65.7% and 53.7% of pts, respectively; 6.0% of pts discontinued treatment because of AEs. Conclusions: Preliminary assessment of these phase 2 data indicate efficacy and tolerability of futibatinib for treatment of pts with iCCA harboring FGFR2 fusions or other rearrangements who have progressed after chemotherapy. Continued analysis of the study population is underway. Clinical trial information: NCT02052778.