bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: A real-world study.
Authors: Pavlick Anna C. , Amin Asim , Moser Justin C , Poretta Tayla , Sakkal Leon Alan , Moshyk Andriy , Klink Andrew J. , Schuler Tammy , Feinberg Bruce A.
Published: June 2022

e21534

Background: Nivolumab is approved in the United States and other countries as an adjuvant treatment for patients with completely resected stage III–IV melanoma based on results of the phase 3 CheckMate 238 trial, though the trial enrolled a limited number of patients with stage IIIA disease (AJCC-8). The objective of this real-world study is to describe characteristics, treatment patterns, and outcomes of patients with resected stage IIIA melanoma (AJCC-8) treated with adjuvant nivolumab or monitored with observation. Methods: In this retrospective, chart-review study, physicians from Cardinal Health’s proprietary Oncology Provider Extended Network (OPEN) extracted data from electronic health records of patients who had undergone complete surgical resection of stage IIIA melanoma between Jan. 1, 2018, and Dec. 31, 2019. Recurrence-free survival (RFS) and overall survival (OS) were evaluated from the date of resection and compared between the adjuvant nivolumab and observation cohorts using log-rank tests and adjusted Cox proportional hazards models (covariates included age, sex, race, region, payer type, ECOG PS, and Charlson Comorbidity Index). Discontinuations and deaths due to adjuvant nivolumab toxicity were assessed. Results: This study included 171 patients treated with adjuvant nivolumab and 38 patients monitored with observation. In the adjuvant nivolumab and observation cohorts, respectively, mean age was 57.4 and 68.1 years; most patients were male (59% and 68%) and white (90% and 87%); and median follow-up from resection was 20.7 and 25.0 months. Sentinel lymph node tumor burden of < 1 mm was reported in 12% (n = 20) and 16% (n = 6) of patients in the adjuvant nivolumab and observation cohorts, respectively. The scheduled treatment course with adjuvant nivolumab was completed by 91% of patients (n = 155). RFS and OS rates were numerically higher with adjuvant nivolumab than with observation (Table). There was a trend toward RFS and OS benefit with adjuvant nivolumab versus observation (unadjusted RFS HR 0.53, 95% CI 0.26–1.09; adjusted RFS HR 0.62, 95% CI 0.28–1.40; unadjusted OS HR 0.55, 95% CI 0.19–1.57; adjusted OS HR 0.81, 95% CI 0.25–2.61). Discontinuation of adjuvant nivolumab due to toxicity occurred in 2% of patients (n = 4); no treatment-related deaths were reported. Conclusions: These real-world results confirm that patients with resected stage IIIA melanoma (AJCC-8) have a good prognosis. Treatment with adjuvant nivolumab may provide modest survival benefit over observation in this population, though increased sample size and additional follow-up are warranted.[Table: see text]
Is the BRAF mutation still an unfavorable risk factor in patients with metastatic melanoma in the era of modern therapies?
Authors: Cybulska-Stopa Bozena , Czarnecka Anna Malgorzata , Ostaszewski Krzysztof , Piejko Karolina , Zietek Marcin , Dziura Robert , Rutkowska Ewa , Galus Łukasz , Calik Jacek , Sałek-Zań Agata , Zemelka Tomasz , Kamycka Agnieszka , Bal Wieslaw , Kubiatowski Tomasz , Rogala Pawel , Switaj Tomasz , Kaminska-Winciorek Grazyna , Suwiński Rafał , Mackiewicz Jacek , Rutkowski Piotr
Published: June 2022

e21544

Background: BRAF-mutated (MUT) melanoma is characterized by specific clinical features including more aggressive biological behavior than BRAF wild-type (WT) melanoma. BRAF mutations are historically known as negative prognostic factor for to shorter overall survival (OS) in patients with stage IV disease with melanoma. Methods: Consecutive patients with unresectable or metastatic melanoma started treatment with BRAF inhibitors (BRAFi), BRAFi and MEK inhibitors (MEKi) or IT (anti-PD-1 antibody) between 1/Jan/2013 and 31/Dec/2020. Clinical factors including age, gender, primary location of melanoma, ECOG performance status, baseline LDH level, and location of metastases, response to treatment were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2021. Results: In total 1456 patients were enrolled. BRAF mutation was found in 723 (49.7%) patients and 733 (50.3%) patients were BRAF WT. All BRAF WT patients received first-line IT, while BRAF MUT patient received first-line treatment with BRAFi (n = 134/723, 18%), BRAFi and MEKi (n = 426, 58%) or anty-PD-1 (n = 173, 24%). BRAF MUT patients were significantly younger (median 60 vs 69; p < 0.0001), had worse ECOG (p = 0.0008), elevated LDH (p < 0.0001), had higher number of metastatic sites (p < 0.0001) and brain metastases (p < 0.0001). The estimated median OS (mOS) in BRAF WT group was 17.3 month while in BRAF MUT - 14.8 months (p = 0.33; HR = 0.94, Cl 95% 0.8-1.1). mOS in BRAF MUT group treated with BRAFi was - 10.0, while with BRAFi and MEKi combination - 14.9. BRAF WT and BRAF MUT groups treated with IT did not differ significantly in baseline characteristics. BRAF MUT group treated with IT achieved mOS of 26.2 months, while in BRAF WT 17.3 months. Conclusions: The analysis showed no differences in the median OS between BRAF MUT and BRAF WT patients with unresectable or metastatic melanoma treated with novel therapies (BRAFi-MEKi combination or IT), despite unfavorable prognostic factors in the BRAF MUT group. Moreover mOS was significantly prolonged in the BRAF MUT patients treated with IT.
Assessment of tissue and blood tumor mutational burden in patients with melanoma using a 523-gene clinical assay.
Authors: Giardina Tindaro , Humphries Timothy , Reid Anna , MesbahArdakani Nima , Robinson Cleo , Millward Michael , Gray Elin , Amanuel Benhur
Published: June 2022

e21570

Background: High tumor mutation burden (TMB) predicts improved efficacy of immune checkpoint inhibitors (ICIs) across a range of malignancies, including melanoma. Circulating tumor DNA (ctDNA) has emerged as a powerful complement to tumor biopsies for the diagnosis and clinical management of cancer patients. The TruSight Oncology 500 (TSO500) clinical assay interrogates 523 cancer-related genes and has shown good concordance between tissue and ctDNA using a high throughput sequencer such as NovaSeq. There are no studies looking at concordance and utility of this assay using more affordable mid throughput platforms. Here we present a pilot study comparing TSO500 sequencing results from matched tumor and plasma specimens and concordance of selected actionable gene variants investigated by ctDNA digital PCR. Methods: Samples from 18 metastatic cutaneous melanoma patients with matched formalin-fixed, paraffin-embedded (FFPE) tumor tissue and plasma collected in Streck tubes had DNA extracted for library preparation using the Illumina TSO500 NGS assay with inputs of ≥40ng of FFPE DNA and ≥10ng of ctDNA. Libraries were sequenced on a NextSeq2000 P3 flow cell to achieve recommended sequencing depth of 800 million reads per sample. A TMB cut off ≥10 mut/Mb was used as high TMB. Droplet digital PCR (ddPCR) was performed for orthogonal validation of selected clinically significant somatic mutations. Results: Sequencing on the NextSeq2000 achieved an average of 797 million pass filter reads per sample and somatic variant allele frequency (VAF) sensitivity down to 0.12%, which exceeded vendor recommendations. There was 75% concordance on the TMB classification (low and high values, Cohen’s k = 0.714) based on tumor and plasma (r = 0.86, p < 0.01) on 8 paired samples (extended analysis will be presented). Some high TMB cases carried POLE or POLD1 variants. Actionable variants identified by ctTSO500 in 15 cases were confirmed by ddPCR, with an outstanding concordance of their VAF (R2= 0.99, p < 0.0001). Diagnosis of tier I/II actionable variants (21 variants; 81% accuracy) was achieved in 7 matched tumor tissue and blood samples. Some variants found in tumor tissue were not detected in the blood. Conclusions: This pilot study demonstrates the clinical utility of the TSO500 ctDNA panel using an affordable mid throughput sequencing platform to identify actionable variants and TMB from blood specimens with high sensitivity and specificity. Testing of a larger cohort of matched tumor and plasma samples will serve to evaluate the clinical utility of the TSO500 ctDNA panel as a complement or alternative strategy to tissue biopsy for the genomic profiling of melanoma patients.
Clinical and biologic predictors of response to MIBG therapy: A report from the new approaches to neuroblastoma therapy (NANT) consortium.
Authors: Vo Kieuhoa Tran , Matthay Katherine K. , Groshen Susan G. , Chi Yueh-Yun , Granger Meaghan , Park Julie R. , Marachelian Araz , DuBois Steven G.
Published: June 2022

e22003

Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. The clinical and biologic predictors of response to MIBG therapy have not been systematically characterized in a recent era trial. Methods: Patients 1-30 years were enrolled on the randomized phase 2 trial of MIBG vs. MIBG/vincristine/irinotecan vs. MIBG/vorinostat for relapsed/refractory neuroblastoma (NANT2011-01, NCT02035137) between 2014-2019. Data were compared between those who had an objective response (partial response or better using NANT response criteria) to MIBG after the first cycle and those who did not according to clinical features (age at study enrollment; sex; response to prior therapy; prior receipt of MIBG therapy; bone marrow involvement at study enrollment; and measurable disease status at study enrollment) and MYCN status. Univariate analyses were performed using odds ratio and Fisher exact tests. Multivariate logistic regression analysis was used to identify predictors of response to MIBG therapy while controlling for key confounders. Results: 105 response-evaluable patients were included in the analytic cohort. Across the 3 study arms, 20% (21/105) had an objective response to the treatment. Only measurable disease status was statistically significantly associated with response to therapy, with higher rates of response among patients without measurable disease at study enrollment (30% vs. 13%, p = 0.049). Response to prior therapy, sex, MYCN status, and measurable disease status showed univariate odds ratios of 2 or greater (Table). Only measurable disease status remained statistically significant in the multivariate analysis (p = 0.043, Table). Conclusions: Patients without measurable disease have a higher rate of objective responses to MIBG therapy. Understanding these differences based upon predictors of response may help to inform stratification methods for future MIBG clinical trials.[Table: see text]
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.
Comparative effectiveness of systemic treatments in desmoid tumors.
Authors: Costa Philippos Apolinario , Arora Arshia , Tan Heng , Fernandez Yanelys , Campoverde Leticia , Barreto Coelho Priscila , Bialick Steven , Espejo-Freire Andrea P. , Jonczak Emily , D'Amato Gina Z. , Subhawong Ty , Trent Jonathan C.
Published: June 2022

e23534

Background: Many systemic treatment options are described for desmoid tumors, including hormonal therapies, non-steroidal anti-inflammatory drugs, cytotoxic chemotherapeutic agents, and most recently, tyrosine kinase inhibitors. Although many options are described, randomized data is scarce. The lack of comparative studies precludes a definitive sequence of the existing systemic treatments in the management of desmoid tumors. Here we retrospectively compare sorafenib with cytotoxic chemotherapy to generate objective data to guide treatment choice. Methods: We analyzed all patients with desmoid tumors treated with doxorubicin, dacarbazine, vinblastine, vinorelbine, methotrexate, or sorafenib in the first-line setting at a single center from 2000-2021. The primary endpoint was investigator-assessed progression-free survival. The secondary endpoint was the rate of toxic effects recorded accordingly to the Common Terminology Criteria for Adverse Events. We calculated progression-free survival (PFS) using the Kaplan-Meier method with Log-Rank Test to estimate the 95% confidence interval. Results: 79 patients ultimately received systemic therapies. Median follow-up was 5.6 years (0 to 7.9), 69% were women, and median age at diagnosis was 37 (range 5-77). Regarding race and ethnicity, 74% were White, 26%, Black and 45%, Latino. The tumor was in the lower extremity in 21 (27%) cases, trunk in 18 (23%) cases, abdominal wall in 13 (16%), intra-abdomen in 9 (11%), upper extremity in 7 (9%), head-neck in 7 (9%) and breast in 4 (5%). Surgery before systemic treatment was used in 20 (25%) patients. The regiments used were sorafenib (n = 32), doxorubicin with dacarbazine (n = 13), liposomal doxorubicin (n = 11), methotrexate with vinblastine (n = 11), methotrexate with vinorelbine (n = 8) and methotrexate monotherapy (n = 1). The 2-year progression-free survival rate was 80% (95% confidence interval [CI], 0.64 to 0.96) in the cytotoxic chemotherapy group and 66% (95% CI, 0.46 to 0.86) in the sorafenib group (P = 0.06). The most frequently reported adverse events on the cytotoxic group were grade 1 or 2 events of nausea (25%) and rash (15%), and on sorafenib were grade 1 or 2 events of palmar-plantar erythrodysesthesia (40%) and fatigue (25%). There were no treatment-related deaths reported. Conclusions: There was no statistical difference between the analyzed treatments, although there was a trend toward lower progression rates with cytotoxic therapy.
Establishment of PD3D models of sarcomas: A promising preclinical tool for improvement of sarcoma treatment.
Authors: Regenbrecht Manuela , Sauer Rica , Niethard Maya , Regenbrecht Christian RA , Loskutov Jürgen
Published: June 2022

e23538

Background: Compared to the progress in understanding and treating carcinomas in the past decade, the options and related clinical benefit in terms of response rates and overall survival for sarcoma patients lacks behind. Increasing incidence, low 5-year-survival rates and nearly endless heterogeneity of sarcomas are challenging oncologists every day. The necessity of so far missing representative preclinical models is obvious. PD3D cell culture models have already proven to be a useful tool to reverse clinical engineer patient outcome in carcinomas. Here we report the establishing and refining of PD3D models for the plethora of sarcoma entities. Methods: We obtained viable sarcoma tissue samples from incisional biopsies or tumor resections. We continuously optimized media conditions. For quality control and pathological evaluation, we embedded the cells in FFPE, stained patient-specific models according to original tumor samples and evaluated them pathologically. Upon histopathological evaluation, we performed semi-automated drug response assays on patient-specific models with up to 12 drugs and drug combinations, including standard of care drugs plus a selection of additional drugs. In the fashion of a prospective observatory study, we compared the results from the in vitro screen with the actual clinical outcome. Results: More than 25 patient derived 3D-cell culture models have been established from various subtypes of sarcomas. Optimized media conditions and sampling operation improved the take rates from ca. 10 to 80% irrespective of the tumor subtype. Pathological examination of the models confirmed original diagnoses and revealed that the patient-specific models recapitulate the key properties of the original tumor. Negative predictive value of drug sensitivity testing was close to 100 %, while the positive predictive value was > 80 %. These results in a limited number of cases puts the predictive value en par with recently published data about the predictive value of patient-derived organoids in carcinomas. Conclusions: Patient derived 3D-cell culture models of sarcomas can be routinely established, irrespective of subtype Models can be used for multi-omics analyses including drug sensitivity screenings

Pretherapeutic drug sensitivity screenings could support clinical decision making

Findings need to be confirmed in a prospective observatory trial.
The impact of classic Hodgkin lymphoma (cHL) on informal caregivers: Results from the cHL—Real-world observations from physicians, patients, and caregivers on the disease and its treatment (CONNECT) study.
Authors: Flora Darcy R. , Evens Andrew M. , Liu Nicholas , Yu Kristina S. , Byrd Rachel , Kumar Supriya , Fanale Michelle , Holmes Katie , Flores Avile Carlos , Surinach Andy , Parsons Susan K.
Published: June 2022

e24004

Background: The health and work productivity burden informal cHL patient (pt) caregivers face is unknown. As part of the US-based CONNECT study, we evaluated caregivers’ burden and role in treatment (tx) decisions by relation to the pt: spouse/partner (SP) vs other (parent, child, friend, other relative). Methods: The CONNECT caregiver survey was an IRB-approved online survey administered from Dec 2020-Mar 2021 to self-identified current or former adult cHL pt caregivers. Health-related quality of life (HRQoL, PROMIS-Global), work impact (WPAI), decision-making, tx selection, and physician communication were assessed. Statistical significance was at the 95% confidence level. Results: 209 caregivers (58% women; median age 47 yrs; 54% employed; 53% SP) completed the survey. At completion, 69% cared for pts diagnosed in the past 1-2 yrs; 48% of pts cared for had stage III/IV cHL and 58% were in remission/not receiving active tx. While caregiver HRQoL was similar to that of the general population on the PROMIS-Global, employed caregivers had work impairment (29%) from caregiving activities (Table) which was higher when the pt was on vs off tx. Caregiving began at pt symptom onset for more SP vs other caregivers (61 vs 27%), and after the pt’s first tx for more other vs SP caregivers (34 vs 5%). 88% of caregivers discussed tx options with the pt. Cure, caregivers’ top tx goal (49%), was rated higher by SP vs other caregivers (56 vs 42%). Tx decisions with the pt (54 vs 23%) and tx option discussions with the doctor (52 vs 28%) were more common for SP vs other caregivers. More SP vs other caregivers had extensive tx option discussions with the pt (88 vs 68%), said it was important the doctor discussed managing side effects (94 vs 84%), felt the doctor provided adequate information about side effects (91 vs 71%), and felt aligned with the pt’s tx goals (93 vs 79%). Caregivers noted COVID-19 impacts like limiting daily activities to reduce COVID-19 risks (72%). Conclusions: Although cHL pt caregivers reported good HRQoL, caregiving impacted their work productivity regardless of relation to the pt. Cure was caregivers’ top tx goal. SP vs other caregivers were more involved and earlier, reporting alignment with pt tx goals and decision-making.[Table: see text]
The analgesic compound palmitoylethanolamide reduces inflammation in human cardiomyocytes and vascular endothelial cells exposed to doxorubicin and anti-HER2 monoclonal antibody through PPAR-α and NLRP3-related pathways.
Authors: Iovine Martina , Quagliariello Vincenzo , Buccolo Simona , Paccone Andrea , De Laurentiis Michelino , Maurea Nicola
Published: June 2022

e24054

Background: Palmitoylethanolamide (PEA) is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. It is a new analgesic drug with anti-inflammatory effects through the induction of PPAR-related pathways. We aimed to assess whether palmitoylethanolamide co-incubated during doxorubicin and trastuzumab, reduces anticancer drugs-related cardiotoxicity in cellular models. Methods: Human vascular endothelial cells and cardiomyocytes were exposed to subclinical concentration of doxorubicin (at 100 and 200 nM) combined to trastuzumab (at 100 and 200 nM) alone or in combination with a formulation composed by palmitoylethanolamide 500 nM for 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Palmitoylethanolamide co-incubated with doxorubicin exerts vasculoprotective and cardioprotective effects, enhancing cell viability of 56.3-78.7 % compared to untreated cells (p < 0,001 for all). Notably, PEA reduced significantly the cardiotoxicity through peroxisome proliferator-activated receptor-α –related pathways and NLRP3 inflammasome but without the involvement of calcium homeostasis. Several cytokines and chemokines were also reduced confirming its anti-inflammatory effect. Conclusions: The present study demonstrates that palmitoylethanolamide protects against vasculotoxicity and cardiotoxicity of doxorubicin and trastuzumab by promoting an anti-inflammatory phenotype, representing a new therapeutic approach to resolve doxorubicin-induced vasculo-cardio toxicity and inflammation.
Breast cancer survivors: Main physical and psychosocial problems after completion of treatment at a Brazilian cancer center.
Authors: Vidal Brito Thiago , Reboucas Camilla Vieira de , Alves Rafaela de Brito , Magalhaes Trindade D. Yamada Alayne , do Nascimento Martins Adriana , Cruz Felipe Melo
Published: June 2022

e24057

Background: The number of breast cancer survivors has grown worldwide in recent years due to advances in treatments, however, increased survival lead to the appearance of signs and symptoms after the end of treatment that affect the quality of life of these patients in the long term. Methods: Women aged 20-60 years with a diagnosis of breast cancer and primary treatment for at least 1 year were selected. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was used and sociodemographic data, life habits and clinical conditions of the participants were collected. The primary end point was to identify the main repercussions of breast cancer and its treatments. Results: A total of 87 women were enrolled for this study. The mean age was 48.5 years. The main symptoms identified were pain (15.48%), nausea (13.10%), fatigue (11.90%), hot flashes (9.52%) and insomnia (5.95%). The total FACT-B+4 score was 110.75 (SD 20.02). No statistically significant variables were identified as predictors of worsening quality of life. Conclusions: The main residual problems in breast cancer survivors 1 year after curative treatment at Hospital São Camilo Oncologia were identified, however, it was not possible to establish significant predictors of worsening quality of life. We will conduct a new interview in 1 year using others quality of life assessment instruments.