bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the effects of critical metabolite depletion in pediatric rhabdomyosarcoma (RMS) using a novel inhibitor of nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Collins Victor , McKay-Corkum Grace , Yeung Choh , Issaq Sameer , Heske Christine M 
Published: June 2022

e22004 Background: RMS is the most common pediatric cancer of the soft tissues. Patients who present with metastatic disease or experience recurrence have a poor prognosis; survivors often suffer from long-term systemic effects resulting from cytotoxic chemotherapy. Thus, novel therapies are needed. NAMPT inhibitors are a class of drugs targeting a key metabolic enzyme in the production of NAD+, a coenzyme critical to energy generation in some cancer cells. In this study, we evaluated the mechanism and functional outcomes of treatment with the clinical NAMPT inhibitor, OT-82, in preclinical models of RMS. Methods: Live cell analysis via IncuCyte was used to determine the temporal effects of OT-82 on cell growth in a diverse panel of ten fusion positive and negative RMS cell lines. Analysis of the proposed mechanism of action was performed using NAD/NADH detection assays and rescue experiments with nicotinamide mononucleotide (NMN), the product of NAMPT. Markers of cellular apoptosis and necrosis were quantified with flow cytometric assays. Specific metabolic effects of OT-82 were determined with ATP quantification and real-time extracellular flux analysis of oxidative phosphorylation and glycolysis. In vivo studies were performed in orthotopic RMS models. Tumor dimensions were measured with calipers, and toxicity was assessed by observation and body weight measurement. Results: Treatment of RMS cell lines with OT-82 dosed in the low nanomolar range resulted in time- and dose-dependent decreases in NAD+ levels and proliferation in all cell lines tested. Addition of NMN rescued cell growth, confirming the on-target activity and functional effect of OT-82. Flow cytometric assays revealed cell-line dependent differences in cell fates, with a subset of cell lines staining positive for markers of necrosis, and the other subset staining negative for markers of necrosis and apoptosis. Functional investigation verified that necrotic cell lines did not regrow after withdrawal of OT-82 in culture (durable responders), whereas non-necrotic cell lines recovered growth (transient responders). Additionally, ATP levels in durable responders decreased with OT-82 treatment but remained stable in transient responders. Extracellular flux analysis revealed that both durable and transient responders experienced inhibition of glycolysis, but that oxidative phosphorylation was only reduced in the durable responders. In vivo studies using OT-82 on a clinically-relevant schedule demonstrated that all RMS xenografts underwent complete tumor regression, with durable responder models experiencing a longer tumor-free period following discontinuation of treatment. Conclusions: In vitro and in vivo efficacy of OT-82 suggest that targeting NAD+ metabolism through NAMPT inhibition may be a promising approach for the treatment of RMS.
A bioequivalence study of a novel liquid and ready-to-use temozolomide oral suspension and temozolomide capsules in patients with primary tumors central nervous system malignancies.
Authors: Ducray Francois , Ramirez Carole , Robert Marie , Maxime Fontanilles , Bronnimann Charlotte , Chinot Olivier L. , Estrade Florian , Durando Xavier , Bastid Jeremy , Bienaymé Hugues , Lemarchand Caroline 
Published: June 2022

e22008 Background: Oral temozolomide capsule is approved for the treatment of glioma and malignant glioblastoma in adults and in Europe in children over 3-years. As recommended by international pediatric medical associations, temozolomide is also used for the treatment of high-risk relapsed or refractory neuroblastoma, a solid tumor affecting young children. Nevertheless, capsules are not adapted to the pediatric population leading caregivers to handle temozolomide capsules, which bears major risks (i.e. dose inaccuracy, temozolomide instability and exposure to cytotoxic drug). To overcome this situation, a temozolomide oral suspension (Kimozo) was developed. The aim of this phase I study was to demonstrate bioequivalence between the temozolomide oral suspension and the temozolomide capsules (Temodal) and to assess the general and local safety in adult patients. Methods: A randomized, open-label, two-way crossover, single-dose bioequivalence study was performed in 8 centers. Adult patients with primary malignancies and treated with temozolomide 200 mg/m² as monotherapy received a single oral administration of the oral suspension (test) or capsule (reference) on days 1 and 2 of a 5-day cycle, depending on the randomization, and under fasting conditions. Fourteen blood samples were collected over 10-hr in each period for pharmacokinetic purpose. General and buccal safety was assessed along the study. The assessment of bioequivalence was based upon 90% confidence intervals (CI) for the ratio of the population geometric means (test/reference) for maximum plasma concentration (Cmax) and area under the curve (AUC0-t). Results: Among the thirty-six patients enrolled in the study, thirty were assessable for pharmacokinetic primary endpoint. The point estimate and the 90% CI of the ratios of Cmax and AUC0-t were 107.62 (98.07-118.09) and 97.18 (95.05-99.35), respectively. The results obtained satisfy the bioequivalence criteria of the Bioequivalence Guidelines (90% CI between 80.00% and 125.00%). Neither serious adverse events nor adverse events of special interest (i.e. mucositis) were reported. Conclusions: The oral suspension of temozolomide (Kimozo) and capsule of temozolomide (Temodal) are bioequivalent under fasting conditions in patients with CNS primary malignancies, supporting that they are therapeutic equivalent. Clinical trial information: NCT04467346.
Multi-layered measures for mitigating effects of COVID-19 pandemic on national breast cancer screening programme.
Authors: Vrhovec Miloš , Jarm Katja , Hertl Kristijana , Kutnar Veronika , Škrbec Vesna , Kurir Borovcic Mateja 
Published: June 2022

e22501 Background: The beginning of the COVID-19 pandemic caused a major disturbance in the operation of breast cancer screening programmes worldwide with delays in screening examinations. The 2021 Dutch study Effects of cancer screening restart strategies after COVID-19 disruption describes 4 strategies to reduce the impact of the pandemic on 10-year breast cancer mortality, where a full-catch up strategy with increased screening capacities that allow successful reduction of backlog in 6 months after the restart, was recognized as the most effective. In March 2020, the Slovenian Breast Cancer Screening Programme DORA suspended all screening activities and lost 50 working screening days. When planning the restart of the programme, measures for providing a safe environment with a special protocol were implemented nationwide. The capacity of the programme was increased with measures like working during the summer, additional screening terms and extending working hours. Focus was placed on communication activities to promote a safe screening environment. With centralized planning, invitation letters with prefixed appointment are sent, additionally information about safety measures and a questionnaire were included to enable rescheduling of women with risk factors for COVID-19 infection beforehand. The aim of our study was to compare pre-pandemic and pandemic screening programme quality and activity indicators in order to determine, whether the measures for reducing the impact of the pandemic were effective. Material and Methods: Data for the period 2019–2021 was obtained from the programme's screening registry. Regularly controlled indicators for pre-pandemic and pandemic period were compared. Results: With the full catch-up strategy, screening results in the pandemic period reach the pre-pandemic levels. Conclusions: In Slovenian screening programme it was possible to completely reduce the backlog of screening examinations and achieve indicators’ levels that were observed before the pandemic due to robust screening infrastructure. With the successful implementation of a full catch-up strategy it is expected that the COVID-19 pandemic will not have a significant if any effect on breast cancer mortality in the screening population of Slovenia.[Table: see text]
Assessing breast cancer screening results through the lens of COVID-19 pandemic.
Authors: Kaidarova Dilyara , Zhylkaidarova Alma , Saktaganov Muratzhan 
Published: June 2022

e22507 Background: In January, 2020 World Health Organization (WHO) declared the COVID-19 outbreak as the first global health emergency. Lockdowns and restrictive procedures with the full and partial cancellation of preventive measures, including breast cancer (BC) screening, took place in Kazakhstan in 2020-2021. Purpose of this study: to determine the impact of the COVID-19 pandemic on BC screening results. Methods: The main screening indicators before (2018-2019) and during the COVID-19 pandemic (2020-2021) were studied: planned coverage and number of examined patients, the proportion of BI-RADS categories (where BI-RADS categories 4-5 are accepted as suspicious for malignancy, additional imaging by ultrasound and/or mammography followed biopsy is recommended), the number of detected cancer cases, the stage of the disease according to the screening database and the Electronic Cancer Registry. Results: 1,624,667 women underwent BC screening in 2018-2019 (96.2% of the planned amount of 1,688,829 women). 1,532,591 (79.4%) women were examined in 2020-2021, though the planned amount was 1,930,515. Before the epidemic, 23,296 patients received BI-RADS categories 4-5 (1.43% from examined women) and were referred for additional ultrasound and mammography examination, in 2020-2021 – 25,008 women (1.63%). 74.2% (1,205,094 women) had BI-RADS category 1 in 2018-2019 and 63.4% (971,754 patients) – during the pandemic. In 2018-2019 - 3,377 BC cases were detected (cancer detection rate was 2.0 per 1000 investigations). In 2020-2021 - 2,474 BC cases were identified (cancer detection rate 1.6 per 1000 investigations). Proportion of screen-detected cancers in stage 0-I was 45.1% in 2018-2019 and 47.5% in 2020-2021. During the pandemic, the number of participants who underwent BC screening significantly decreased (by 20.6% of the planned). The level of cancer detection decreased too (by 22.8%). There was an increase in patients requiring further examination (BI-RADS categories 4-5) and decrease the number women with BI-RADS 1. With an increase in indications for additional ultrasound and radiological examination, the number of revealed cancers reduced by 1.5 times (in 2018-2019, 14.5% patients with BI-RADS categories 4-5 had BC confirmed, in 2020-2021 – only 9.9%). Conclusions: BC screening has been significantly reduced during the COVID-19 pandemic. At the same time, attention should be paid to the increase in overdiagnosis of mammographic pathology, possibly due to an increase in the density of breast tissue on the background of nonspecific inflammation accompanied by lymphadenopathy. The impact of COVID-19 on BC is still unknown. Further research will be needed to confirm the link between COVID-19 and mammography picture and BC.
15 years of experience of an oncogenetics service in the northeast of Brazil.
Authors: Ferreira Thamara Melo , Toralles Maria Betania , Lopes Taisa , Oliveira Pollyanna Carozo , de Oliveira Nascimento Ivana Lucia , Côrtes Juliana , Bomfim-Palma Thais Ferreira , Nascimento Roberto JOSE MEYER , Rodrigues Juliana LIMA GOMES 
Published: June 2022

e22522 Background: The Oncogenetics service at the Federal University of Bahia was implemented in 2007 and since then has been offering pre- and post-test genetic counseling for cancer susceptibility genes, mainly tumors associated with King's syndrome in the population of the state of Bahia. This is a mixed population of about 80% of African ancestry. Methods: Between the years 2007 to 2021, 462 probands and their families have already been evaluated by NGS analysis, Sanger sequencing. Large rearrangements were detected by multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 and BRCA2 genes. Results: The mean age at diagnosis was 41 years. Pathogenic/probably pathogenic mutations were founded in 118 patients: 67 had breast cancer, 09 with ovarian cancer, 26 with more than one tumor, 15 without cancer, and 01 with another tumor type. Most of the pathogenic variants were located in the BRCA1 gene (27 variants), the two most frequent variants being: c.211G > A (13 probands) and c.3331_3334delCAAG (18 probands), both of Iberian origin. Of patients with mutation, 9.8% had large rearrangements in BRCA1 and 11.5% in BRCA2. Bilateral breast cancer appears predominantly in patients with BRCA1 (4) and BRCA2 (1) variants. In this study, only two mutations in BRCA described as of African origin were found in two patients. Other pathogenic mutations appear in ATM, BARD1, BRIP1, CDH1, CHEK2, FAM175A, FANCM, MSH6, NBN, NF2, PALB2, RAD51, SDHB, SLX4, and TP53 genes. Variants of uncertain significance were identified in 71 patients. Conclusions: The population of the state of Bahia has a peculiar mutational profile, containing mutations that are not very frequent in other regions of the country. Despite being a population with high African ancestry, most mutations are of European origin.
Effect of participation in the EGFR resisters research summit on competence, performance, and professional productivity of young researchers.
Authors: Fowler Joan B. , Feldman Jill E. , Sequist Lecia V. , Weaver Rebecca , Trieu Tina , Elkins Ivy Beth 
Published: June 2022

e23010 Background: Recognizing the growing need to support early-career scientists, the EGFR Resisters Research Summit (EGFRRS) strives to identify, cultivate, and prepare young investigators (YIs) for successful careers that advance the field of EGFRm NSCLC. Methods: After a modified-NIH selection process based on submitted abstracts, a selected group of YIs were invited to the multi-day EGFRRS annually from 2019-2021. Each invitee received professional coaching, mentoring, and feedback from senior investigators and patient advocates. Changes in YI competence and performance were measured by self-assessment survey of confidence and professional productivity and analysis of abstract scores before and after receiving mentoring and coaching. Statistical testing was conducted via paired t-tests with a priori significance set at 0.05. Results: The EGFFRS included 52 unique YIs from 2019-2021, 50% female, with 44 (85%) MD/MD-PhD and 8 (15%) PhD researchers. 35 (67%) were fellows/residents and 17 (33%) were junior faculty. The mean abstract score (using a modified NIH score of 1-5 with 1 being best) improved from 2.34 prior to 2.09 post (11% improvement; P < 0.005). The mean confidence score (confidence in presenting to peers; 1-4 with 4 being best) improved from 2.7 prior to 3.29 post (22% improvement; P < 0.005). A follow-up survey sent to all YIs had a 46% response rate and notable findings among respondents include: 92% are still strongly or somewhat involved with EGFR lung cancer research, 96% have incorporated the patient perspective into clinical trials, 38% have collaborated with other EGFRRS participants, 46% have presented EGFR-related data at professional meetings (compared to 17% pre-EGFRRS), 25% have published EGFR-related data (compared to 10% pre-EGFRRS), 17% have obtained major grant funding (compared to 10% pre-EGFRRS), 63% remain connected to EGFRRS faculty mentors, 33% remain involved with EGFR Resisters or other patient advocacy groups. In addition, 63% report increased confidence in grant writing, 96% report increased confidence in public presentation and 100% would encourage colleagues to participate in EGFRRS. Conclusions: A research forum designed for early-career investigators can improve the performance and confidence of YIs, as well as professional productivity that is essential to their career path. These findings highlight the robust, multifaceted impact of the EGFRRS on advancing the professional development of the next generation of lung cancer researchers studying driver mutations and targeted therapies, particularly with the novel inclusion of research patient advocates to provide essential perspective.
Primary site and survival in chondrosarcoma: A National Cancer Database analysis.
Authors: Burdyny Michael , Tupper Connor , Eaton Vincent , McMahon Kevin , Silberstein Peter T. 
Published: June 2022

e23503 Background: Chondrosarcoma is one of the most common primary malignancies of bone, accounting for around a fifth of all primary malignant bone tumors. These tumors typically affect the pelvis, hip, and shoulder but can arise anywhere that there is bone and cartilage (e.g. hands, feet, skull, etc.). To the authors’ knowledge, other primary sites have not been investigated in relation to its effect on survival outcomes. The aim of this study is to investigate this effect and see if there is any difference in survival amongst different primary sites in this patient population. Methods: Using the NCDB, patients diagnosed with chondrosarcoma between 2004-2018 were identified using ICD-O-3 histology codes 9220 and 9221. We analyzed the cohort to investigate survival outcomes in different primary sites. Univariate analysis was performed using SPSS to assess patient length of survival for each primary site. Statistical significance was set at α = 0.05. Results: A total of 7681 patients with known primary site that had survival data were included. The mean survival of the cohort was 140.3 months. The sites with the longest survival were the upper limb and the skull, face, and mandible, each of which had significantly longer survival than all other primary sites (all p < .01). The lower limb and ribs, sternum, and clavicle had the next highest survival which was significantly longer than the vertebral column and pelvis, sacrum, and coccyx (all p < .01). The vertebral column was the primary site with shortest survival with a median of 121 months. Conclusions: This study found significant survival differences between patients diagnosed with chondrosarcoma of different primary sites. Of all sites analyzed, the upper limb had the highest median survival of 187 months and showed statistical significance versus all other primary sites, and the vertebral column had the lowest median survival of 121 months. Future studies could be done regarding primary site to further elicit why there is such a large difference in survival, and can look at different imaging modalities used, time to treatment, and demographic and socioeconomic variables in each cohort.[Table: see text]
Survey of palliative care use in primary malignant bone tumors: An NCDB review.
Authors: McMahon Kevin , Eaton Vincent , Srikanth Kishan , Tupper Connor , Merwin Matthew , Morris Matthew , Silberstein Peter T. 
Published: June 2022

e23514 Background: Palliative care has been associated with reduced patient symptom burden, improved physician satisfaction, and reduced cost of care. However, its use in primary bone tumors has not been well classified. Methods: This study retrospectively evaluated the use of palliative care in patients with primary malignant bone tumors (osteosarcoma, chondrosarcoma, Ewing sarcoma & chordoma) diagnosed and recorded in the National Cancer Database (NCDB) between 2004 and 2018. Patients were identified by ICD-O-3 coding and patients with other malignancies were excluded. Cross Tabulations with Chi-square analysis was performed to evaluate frequencies of different patient and tumor characteristics. Multivariable logistic binary logistic regression was performed to evaluate relationships between patient and tumor characteristics and the use of palliative care. Results: 24,401 patients with primary malignant bone tumors were identified. Overall, only 2.52% had any form of palliative care utilization. Of those receiving palliative care, 55.5-65.1% were treated with only non-curative surgery, radiation, chemotherapy, or any combination of these modalities. Odds of palliative care were decreased for patients with chordomas, patients living more than 24 miles from the treatment facility, patients living in west-south-central or pacific states, or patients with private insurance, medicare, or unknown insurance status. Odds of palliative care were increased in patients with greater tumor diameter or unknown tumor size, tumors in the midline, increased tumor grade, stage 4 tumors, or patients living in urban areas. Conclusions: Palliative care use in patients with primary bone tumors increases with tumor stage, tumor grade, tumor size, midline tumors, or in patients living in urban areas, but overall utilization remains markedly low. Future studies should be done to investigate these patterns of care and help expand the utilization of palliative care.
Impact of histopathological revision and molecular pathology in the diagnosis of sarcomas in a reference center in Brazil.
Authors: Lopes Carlos Diego Holanda , Queiroz Marcello Moro , Sampaio Luana Alencar Fernandes , Perina Andre , Akaishi Eduardo Hiroshi , Teixeira Frederico Ribeiro , Ferreira Fabio Oliveira , Hanna Samir Abdallah , da Silva Joao Luis , De Lima Luiz Guilherme C. A. , De Oliveira Claudia Regina G. C. M. , Munhoz Rodrigo Ramella 
Published: June 2022

e23533 Background: The accurate classification of sarcomas remains a major challenge due to the diversity and rarity of this group of mesenchymal tumors. In addition to standard microscopy and immunohistochemical techniques, molecular analyses are often required to achieve an appropriate diagnosis. The limited availability of specialized pathology centers, multidisciplinary teams, and diagnostic tools may directly affect the initial evaluation and subsequent treatment plan. Therefore, we sought to characterize the impact of diagnostic review by reference pathologists and molecular assessments in a reference center in Brazil. Methods: We conducted a retrospective analysis of sarcoma samples initially analyzed at outside laboratories and subsequently revised in a reference center by two dedicated pathologists between 01/2014-12/2020. After extracting demographic and tumor characteristics, we assessed the presence of complete discordance (benign versus malignant, sarcoma versus other malignancy), partial concordance (similar diagnosis of connective tumor, but different grade/histological subtype/differentiation), and complete concordance. The concordance for histology or grade, as well as the role of molecular assessments supporting the diagnosis, were also independently determined. Statistical analyses were conducted through the kappa coefficient of agreement, adherence by χ2 test, χ2 test by Person, and Fisher's exact test. Results: A total of 197 cases were included, with a predominance of male patients (57.9%), localized tumors (86.8%), and the median age at diagnosis of 46.3 years. The most common primary sites were lower extremities (34.6%) and retroperitoneum (11.3%). Following the revision, the most frequent histologies were undifferentiated pleomorphic sarcoma (20.3%), liposarcomas (13.1%), and leiomyosarcoma (6.6%). Complete discordance was present in 13.2%, partial discordance in 45.2%, and complete concordance in 41.6% of reviews (p < 0.001). We found a concordance for histology or grade of 53.5% (p < 0.001) and 51.8% (p < 0.001) respectively. Molecular assessments, comprising NGS panels (79.5%) and FISH (20.5%), were performed in 44 (22.3%) cases, with findings of diagnostic relevance in 31.8% of those. Conclusions: In almost 60% of the cases, the initial diagnosis was at least partially modified when revised in a reference center, with a relevant impact of molecular assessments. These findings highlight the importance of managing sarcoma patients in reference centers and justify the assembly of referral networks in countries with limited healthcare resources.