bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical evaluation of an engineered oncolytic herpes simplex virus for pediatric osteosarcoma.
Authors: Hutchins Sara , Marayati Raoud , Bownes Laura V. , Quinn Colin H. , Stewart Jerry E. , Friedman Gregory K. , Coleman Jennifer M. , Gillespie G. Yancey , Markert James M. , Beierle Elizabeth A. 
Published: June 2021

10040 Background: Osteosarcoma is the most common primary bone tumor in children. For those with relapsed or metastatic disease, the five-year survival rate is approximately 20%, and survivors often suffer from long-term disability from current therapies. The high morbidity and mortality for these patients highlight a great need for improved therapies. One such novel therapeutic approach is oncolytic herpes simplex virus (oHSV) immunovirotherapy. We previously demonstrated that M002, an engineered oHSV that contains deletions of the neurovirulence gene preventing infection of normal cells, effectively infects and kills neuroblastoma and rhabdomyosarcoma. Currently, similar oHSVs are being evaluated in early phase clinical trials for children and adults with relapsed or refractory brain tumors. To date, there has been limited investigation of oncolytic virotherapy in osteosarcoma. Thus, we sought to examine the ability of oHSV, M002, to infect and kill osteosarcoma cells in vitro. Methods: We evaluated two long-term passaged human osteosarcoma cell lines, U2-OS and MG-63. Flow cytometry was used to assess baseline expression of oHSV viral entry-mediated receptors (CD111, CD112, syndecan, HVEM). Single and multi-step viral recovery experiments measured virus infectivity and replication. Cells were infected with increasing multiplicity of infection (MOI) of M002, and cell viability was measured 72 hours post-infection via alamarBlue assay. Results: Both MG-63 and U2-OS cells expressed HSV entry molecules (Table) including high levels of the primary HSV entry molecule CD111. Single step virus recovery experiments in MG-63 cells infected at a MOI of 10 plaque-forming units (PFU)/cell demonstrated a 3 log-fold increase in virus titer from 12 to 24 hours post-infection. For multi-step experiments, MG-63 cells were infected with a MOI of 0.1 PFU/cell; viral replication significantly increased from 1.1x103 PFU at 6 hours post-infection to 3.8x1010 PFU at 72 hours post-infection. M002 successfully decreased osteosarcoma viability with a lethal dose in 50% of cells (LD50)of 2.82 and0.67 PFU/cell for MG-63 and U2-OS cells, respectively. Notably, at a virus MOI of 5 PFU/cell, viability was decreased by 64% ± 0.1% (p<0.001 vs control) in MG-63 cells and 96% ± 0.1% (p<0.001 vs control) in U2-OS cells. Conclusions: MG-63 and U2-OS osteosarcoma cells express high levels of HSV entry receptors. Virus recovery experiments demonstrated the ability of M002 to infect cells and replicate over time. The viability of osteosarcoma cells significantly decreased following infection with M002. These data suggest M002 may be a promising novel therapeutic option for patients with osteosarcoma and warrant further investigation for translation to the clinical setting.[Table: see text]
Late morbidity and mortality among survivors of neuroblastoma treated with contemporary therapy: A report from the Childhood Cancer Survivor Study.
Authors: Friedman Danielle Novetsky , Goodman Pamela J. , Leisenring Wendy M. , Diller Lisa , Cohn Susan Lerner , Tonorezos Emily S. , Howell Rebecca M. , Smith Susan A. , Wolden Suzanne L. , Neglia Joseph Philip , Ness Kirsten K. , Gibson Todd M. , Nathan Paul C. , Robison Leslie L. , Oeffinger Kevin C. , Armstrong Gregory T. , Sklar Charles A. , Henderson Tara O. 
Published: June 2021

10044 Background: Survival rates for neuroblastoma vary widely based on risk group. Therapies have evolved over the past four decades to de-intensify treatment for individuals with low/intermediate risk disease and intensify therapy for those with high risk disease. Risk stratification is predicted to result in differential outcomes in late morbidity and mortality; the magnitude of these differences has not been well studied. Methods: We evaluated late mortality, subsequent malignant neoplasms (SMN) and chronic health conditions (CHC) graded according to CTCAE v4.03 among 491 5-year CCSS survivors of neuroblastoma diagnosed 1987-1999 at ≥1 year of age. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n=182]; intermediate [n=70]; high [n=239]). Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) of SMN were calculated using rates from NCHS and SEER, respectively. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings. Results: Among survivors (48% male; median age 22 years, range 7-42; median follow-up 19 years, range 5-29), 80.4% with low risk disease were treated with surgery alone, while 77.8% with high risk disease received surgery, radiation, chemotherapy ± transplant. The 15-year cumulative incidence of all-cause mortality was 9.2% (CI: 7.1-11.4), with a recurrence-related mortality of 7.3% (CI: 5.3-9.3) and SMN-related mortality of 0.3% (CI: 0-0.7). All-cause mortality was significantly higher in all risk groups: (low, SMR=5.8 [CI: 2.6-13.0]; intermediate, SMR=5.7 [CI: 1.4-23.5]; high, SMR=38.6 [CI: 27.9-53.5]). The risk of SMN was elevated among high risk survivors (SIR=25.1, CI: 16.7-37.6), but did not differ from the US population for survivors of low or intermediate risk disease. Table describes the HR of CHCs (grades 1-5 and 3-5) in survivors, by risk group, as compared with siblings, as well as categories of CHCs for which survivors were at increased risk. Conclusions: Long-term survivors of neuroblastoma have a high risk of late morbidity and mortality; risk is particularly pronounced among survivors of high risk disease. Vigilant lifelong medical surveillance will be required for this relatively young population as they age.[Table: see text]
Development and validation of a prediction model for kidney failure in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Wu Natalie Lucy , Chen Yan , Dieffenbach Bryan V. , Li Nan , Ehrhardt Matthew J. , Green Daniel M. , Hingorani Sangeeta , Howell Rebecca M. , Jefferies John L. , Mulrooney Daniel A. , Oeffinger Kevin C. , Robison Leslie L. , Weil Brent R. , Yuan Yan , Yasui Yutaka , Hudson Melissa M. , Leisenring Wendy M. , Armstrong Gregory T. , Chow Eric Jessen 
Published: June 2021

10047 Background: Kidney failure (need for dialysis or kidney transplantation, or death due to kidney disease) is a rare but serious late effect for survivors of childhood cancer. We aimed to develop a model using demographic and treatment characteristics to predict individual risk of kidney failure among five-year survivors of childhood cancer. Methods: CCSS survivors without kidney failure at five years after cancer diagnosis (n = 25,483) were assessed for subsequent kidney failure by age 40. Outcomes were self-reported and corroborated by the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5045) served as a comparator. Piecewise exponential models with backward selection estimated the relationships between potential predictors and kidney failure and were converted to integer risk scores. Additional results from the St. Jude Lifetime Cohort Study (SJLIFE, n = 2490) and the National Wilms Tumor Study (NWTS, n = 6760) validated the models. Results: Among CCSS survivors, 204 developed late kidney failure. We developed a model with sex, race/ethnicity, age at cancer diagnosis, nephrectomy, exposure to specific chemotherapy, any abdominal radiation, presence of genitourinary anomalies, and early-onset hypertension (Table). Risk scores achieved an area under the curve (AUC) and concordance (C) statistic of 0.65 and 0.68 for kidney failure by age 40. Validation cohort AUC and C statistics were 0.83/0.86 for SJLIFE (8 cases) and 0.61/0.63 for NWTS (91 cases). An alternative model with specific chemotherapy doses and kidney-specific radiation dosimetry had similar AUC and C statistic (0.67/0.70). Integer risk scores were collapsed to form statistically distinct low (score <3; 87 cases of 17,326), moderate (score 3-5; 63 cases of 4667), and high (score 6+; 18 cases of 401) risk groups. These groups corresponded to cumulative incidences in CCSS of kidney failure by age 40 of 0.6% (95% CI 0.4-0.7%), 2.3% (95% CI 1.6-3.2%), and 9.4% (95% CI 4.4-16.7%), compared with 0.2% (95% CI 0.1-0.5%) among siblings. Conclusions: Using readily available information, we were able to identify low, moderate, and high risk groups for developing kidney failure following treatment for childhood cancer. These prediction models may help guide screening and interventional strategies for higher risk survivors.[Table: see text]
Safety of trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive locally advanced or metastatic breast cancer (mBC): Final results from KAMILLA Cohorts 1 (global) and 2 (Asia).
Authors: Wuerstlein Rachel , Ellis Paul , Montemurro Filippo , Antón Torres Antonio , Delaloge Suzette , Zhang Qingyuan , Wang Xiaojia , Wang Shusen , Zhimin Shao , Li Huiping , Rachman Andhika , Vongsaisuwon Mawin , Liu Haiying , Fear Simon , Pena-Murillo Claudia , Barrios Carlos H. 
Published: June 2021

1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enrolled 2185 pts (Cohort 1, n=2003; Cohort 2, n=182), of which 2002 and 181 in each cohort, respectively, received ≥1 study dose and were included in the safety population. Baseline characteristics were generally similar between cohorts. Median (range) T-DM1 exposure was 5.6 mo (0–46) for Cohort 1 and 5.0 mo (0–31) for Cohort 2. The overall G≥3 AEPI rate was higher in Cohort 2 vs Cohort 1 (Table), mostly driven by a higher G≥3 TCP rate in Cohort 2. In Cohort 2, G≥3 TCP (the most frequently reported G≥3 AEPI) did not appear to be associated with G≥3 hemorrhagic events — the majority of G≥3 TCP events (128/138) fully resolved, with a duration of ≤15 days for 98/138 of these events. G≥3 TRAE rates were 18.4% in Cohort 1 and 48.6% in Cohort 2, the latter mainly due to TCP and platelet count decreased; any-grade pneumonitis rates were 1.0% and 2.2%, respectively. No other safety signals were identified. Median progression-free survival and overall survival were similar for both cohorts (Table). Conclusions: These data confirm prior observations in an Asian subgroup of the phase 3 EMILIA trial of T-DM1 in pts with previously treated mBC. Although the G≥3 TCP rate was higher in the Asia cohort, the majority of these events resolved fully. OS and PFS were similar in both cohorts. These data reinforce the favorable T-DM1 benefit-risk profile in mBC. Clinical trial information: NCT01702571 .[Table: see text]
Clinicopathological characteristics of exceptional responders who achieve durable remissions beyond five years (DR5) in HER2+(H+) metastatic breast cancer (MBC).
Authors: Skrobo Darko , Walsh Naomi , Berenguer Jose , Walshe Janice Maria , Higgins Michaela Jane , Fennelly David William , Ballot Jo , Quinn Cecily , Gullo Giuseppe , Crown John 
Published: June 2021

1046 Background: The introduction of anti-H2 targeted therapies has resulted in substantially improved outcomes for patients (pts) with H+MBC, yet despite survival prolongation, most patients so-treated will still ultimately die from MBC. Some patients do however, achieved prolonged remissions. In this report we outline the long-term outcomes of patients with H+MBC who were treated in our institution, with at least five-year follow-up from the diagnosis of MBC. Methods: As part of our larger single-institution “Thousand Patient HER-2 Database”, we conducted a retrospective review of all patients in whom a diagnosis of H+MBC was made prior to December 2015 (range 2000-2015 years). The DR5 category included only those who had never experienced relapse or progression following initial anti-H2 therapy for MBC, and who were alive at 5 years. Patients were designated as (1) DR5, defined as never relapse with an overall survival (OS) > 5 years; (2) nonDR, which included those who had no or shorter remission, but also included nine pts who did achieve a 5 year CR, but who subsequently relapsed. OS was calculated from the date of diagnosis of MBC. The frequency distribution was assessed by Fisher’s Exact Test or Chi-Square Test, as appropriate. OS and PFS were calculated according to Kaplan Meier method, and evaluated by Log-rank test. Univariate and multivariate Cox proportional hazards regression analysis was used to evaluate the effect of clinicopathological features on OS and PFS. Results: A total of 245 patients diagnosed with advanced H+MBC were identified. The median survival was 38 months, (range 0.3 – 248 months). Among these, 85 patients (35%) experienced an OS > 5 years, with 34 designated as DR5. The median OS for DR5 was 117 months, whereas nonDR (n = 211) had median OS of 33 months. The median age was similar between groups (DR5 53 yrs vs nonDR 56 yrs). A higher incidence of visceral disease was present in nonDR compared to DR5 (69% vs 44%). Of all patients diagnosed with de novo H+MBC, 23% achieved DR5. Presence of visceral disease, number of metastases and site of metastases were statistically significant negative predictors of achieving DR5 (P < 0.05). Presence of ER positive disease was not associated with OS. Conclusions: A meaningful subset of patients (14%) with advanced H+MBC achieve prolonged remission beyond five years with H2 targeted therapy. Nearly one quarter of those with de novo H+MBC achieve DR5. As de novo H+MBC now constitutes a higher proportion of all H+MBC than it did in the pre-trastuzumab era, an increasing proportion of H+MBC may now be achieving DR5. Prospective identification of variables to predict DR5 could assist in the stratification of patients for whom additional therapy is needed.
Breast cancer screening for carriers of ATM, CHEK2, and PALB2 pathogenic variants: A comparative modeling analysis.
Authors: Lowry Kathryn P. , Geuzinge H. Amarens , Stout Natasha K. , Alagoz Oguzhan , Hampton John M. , Kerlikowske Karla , Miglioretti Diana L. , Schecter Clyde , Sprague Brian L. , Trentham-Dietz Amy , Tosteson Anna N.A. , Van Ravesteyn Nicolien , Yaffe Martin , Yeh Jennifer , Couch Fergus , Kraft Peter , Polley Eric , Mandelblatt Jeanne S. , Kurian Allison W. , Robson Mark E. ,   Cancer Intervention and Surveillance Modeling Network (CISNET); Breast Cancer Surveillance Consortium (BCSC); Cancer Risk Estimates Related to Susceptibility (CARRIERS)
Published: June 2021

10500 Background: Inherited pathogenic variants in ATM, CHEK2, and PALB2 confer moderate to high risks of breast cancer. The optimal approach to screening in these women has not been established. Methods: We used two simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) and data from the Cancer Risk Estimates Related to Susceptibility consortium (CARRIERS) to project lifetime breast cancer incidence and mortality in ATM, CHEK2, and PALB2 carriers. We simulated screening with annual mammography from ages 40-74 alone and with annual magnetic resonance imaging (MRI) starting at ages 40, 35, 30, and 25. Joint and separate mammography and MRI screening performance was based on published literature. Lifetime outcomes per 1,000 women were reported as means and ranges across both models. Results: Estimated risk of breast cancer by age 80 was 22% (21-23%) for ATM, 28% (26-30%) for CHEK2, and 40% (38-42%) for PALB2. Screening with MRI and mammography reduced breast cancer mortality by 52-60% across variants (Table). Compared to no screening, starting MRI at age 30 increased life years (LY)/1000 women by 501 (478-523) in ATM, 620 (587-652) in CHEK2, and 1,025 (998-1,051) in PALB2. Starting MRI at age 25 versus 30 gained 9-12 LY/1000 women with 517-518 additional false positive screens and 197-198 benign biopsies. Conclusions: For women with ATM, CHEK2, and PALB2 pathogenic variants, breast cancer screening with MRI and mammography halves breast cancer mortality. These mortality benefits are similar to those for MRI screening for BRCA1/2 mutation carriers and should inform practice guidelines.[Table: see text]
Nearly half of TP53 variants are misattributed to Li-Fraumeni syndrome: A clinical evaluation of individuals with TP53 variants detected by hereditary cancer panel assays on blood or saliva.
Authors: Schwartz Alison , Hyman Sophie , Stokes Samantha , Castillo Danielle , Weitzel Jeffrey N. , Rana Huma Q. , Garber Judy Ellen 
Published: June 2021

10501 Background: Multigene panel testing (MGPT) has identified TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes from no cancer to classic Li-Fraumeni syndrome (LFS). There is increasing recognition of variants at low allelic fraction (VAF) for TP53 in particular, which can be suggestive of post-zygotic mosaicism or aberrant clonal expansion (ACE), comprising clonal hematopoiesis of indeterminate potential (CHIP) or occult hematologic neoplasia. Distinguishing among these categories is essential because of widely different cancer risk and management implications for patients and their relatives. We report an evaluation of TP53 positive probands to determine germline versus somatic status from a cancer genetics clinic. Methods: We reviewed probands with TP53 P/LP variants by MGPT on blood (N = 83) or saliva (N = 1) samples from 2012-2019. Available VAFs were collected from commercial testing laboratories. Probands positive for a known familial variant, who met LFS testing criteria without indication of low VAF, or who carried the Brazil founder p.R337H variant were considered germline. For those with uncertain germline status, data was obtained from ancillary testing of family members, cultured skin fibroblasts, and other somatic benign or tumor tissues. TP53 variants were further categorized based on all available data. Results: Of the 84 probands, 28 (33%) had germline TP53 P/LP variants determined by above initial criteria; 18 (21%) were confirmed germline through ancillary testing. Seven (8%) individuals were classified as having constitutional mosaicism. In eleven (13%) individuals, the TP53 variants were consistent with ACE, in 9 (11%) with CHIP and in 2 (2%) with a hematologic malignancy (1 CLL, 1 NHL). Five (6%) cases could not be categorized despite ancillary testing. Fifteen (18%) probands declined any further workup. Conclusions: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, only 54% of patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism (8%) require intensified surveillance. Assessment of VAF, family member testing, and analysis of TP53 in cultured fibroblasts or other tissue samples may distinguish germline and constitutional mosaic variants from the ACE spectrum. Expanding use of MGPT will increase this clinical challenge, which may motivate the modification of lab reports to include VAF and possible non-germline explanations. The findings of this study support a framework of multiple strategies to discern true constitutional status of a TP53 P/LP variant.
Development of AI-powered imaging biomarker for breast cancer risk assessment on the basis of mammography alone.
Authors: Kim Ki Hwan , Nam Hyeonseob , Lim Eunji , Ock Chan-Young 
Published: June 2021

10519 Background: There is increasing interest in early detection of breast cancer by utilizing MRI in high-risk populations. However, it is still challenging to define and enrich the high-risk population. In this study, we developed an artificial intelligence (AI)-powered Imaging Biomarker in Mammography (IBM) to discover unique mammographic patterns, beyond simple density evaluations, that are related to breast cancer. Methods: A total of 49,577 mammography exams were collected to develop the AI-powered IBM, in which 6,218 were cancers. First, we evaluated the hypothesis that the unaffected breast of cancer patients would have a different pattern than that of non-cancer patients, by training AI (IBM-A) with unaffected breast in cancer patients and breasts of non-cancer patients. We then utilized further images of the cancer patients to train AI (IBM-B). This time we used both affected and unaffected breasts of cancer patients and breasts of non-cancer patients, allowing IBM-B to additionally learn patterns related to breast cancer. The IBMs were evaluated using the internal data (n = 2,058) that included 719 cancers. To demonstrate the feasibility of early detection by using IBM-B, it was tested with external data (n = 4,158) from an independent institution. This included pre-index exams (n = 292) taken prior to index exams acquired at the time of cancer diagnosis. Results: With the internal data, IBM-A showed AUC of 0.842, suggesting that AI could learn the difference between the normal breast of cancer patients and non-cancer patients. With IBM-B, which used additional cancer images to train, AUC was improved to 0.852. Based on the internal validation, IBM-B was chosen for the external validation, in which pre-index examinations were used only. IBM-B showed AUC of 0.777 in discriminating the pre-index exams of cancer patients and those of non-cancer patients. The radiologists excluded the apparent missed cancers (n = 87) by reviewing the pre-index exams retrospectively. After, the recalculated AUC of IBM-B was 0.770, suggesting that IBM-B can distinguish between mammograms of patients who will develop breast cancer in the future and those who will not. The mean IBM-B scores in pre-index exams of cancer group (0.580) were significantly higher than those in the normal (0.258, P < 0.001) and benign (0.258, P < 0.001) groups. Conclusions: AI-powered IBM could detect the unique parenchymal pattern associated with high breast cancer risks, and we show the potential of the AI-powered IBM to be used as an independent biomarker to select high-risk populations based on mammography alone.[Table: see text]