bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival in cervical cancer IIb-IVA subjected to postchemo-radiotherapy surgery in Ecuador.
Authors: Reyes José Luís , Morquecho Walter , Argüello Mario , Pulla Fausto Emiliano , Santacruz Mayra , Veliz Elizabeth Graciela , Alarcon Carlos Jose , Plaza Jenniffer Stefania , Rivadeneira Nery Abdon
Published: July 2024

e17517

Background: Cervical cancer (CC) is one of the leading causes of cancer death in the world. The objective of the present study is to determine the overall survival (OS), survival by age group, and histological type in patients with locally advanced CC undergoing salvage surgery after chemo-radiotherapy (CTx-RTx). Methods: A retrospective observational analytical study was carried out on patients with locally advanced CC with stages IIB-IVA who received CTx-RTx treatment from January 2010 to December 2014 with follow-up until August 2023 in SOLCA-Guayaquil. The SPSSv29 statistical program was used to analyze survival curves with the Kaplan-Meier estimator and Log-Rank test. Results: Of a total of 1909 patients, 1581 were excluded because they did not meet eligibility criteria. 328 received CTx-RTx, and 23 underwent rescue surgery. The average survival result is 107 months (m). In survival by histological type, 11 patients presented squamous cell carcinoma (SCC) and 12 adenocarcinoma (AC), with the mean survival for SCC 111 months and for AC 94 months, however in the Log-Rank statistical test (p: 0.672) was not significant, which is why it is estimated that survival is similar in the two histological types (graph 2). In the calculation of survival by age in m (every ten years), in the first group of 30-39 years, it is 98.1 m, 40-49 years 118.8 m, 50-59 years 98.6 m, 60 or more years, it is 56 m; however, in the Log-Rank statistical test (p = 0.317), it is not significant by age group. Conclusions: Of the 23 patients with a mean age of 48 years and a follow-up of 168 months, 13 (56%) are alive. Regarding survival by histological type and age group, there was no significant difference in survival with these results. [Table: see text]
Transcriptomic and epigenetic characterization of mucinous adenocarcinoma of the cervix.
Authors: Duyar-Ayerdi Susan , Abdo Yasmeen , Kumar Roshan , Bishop Erin , Uyar Denise S. , Rader Janet S. , Ojesina Akinyemi I.
Published: July 2024

e17518

Background: Mucinous adenocarcinoma of the cervix (MAC) is a rare and aggressive histologic subtype of cervical cancer with poorer prognosis than its more common counterparts, usual type endocervical adenocarcinoma (UEA) and squamous cell carcinoma (SCC). MAC is also known to be less responsive to standard chemotherapy and radiation approaches used to treat cervical cancer. In this study, we sought to identify transcriptomic and epigenetic features of MAC that distinguish MAC from UEA and SCC, and to identify features that may contribute to poorer prognosis in MAC compared to UEA and SCC. Methods: Clinical data, gene expression, miRNA expression, and methylation data for 17 MAC, 27 UEA, and 247 SCC from The Cancer Genome Atlas Cervical Cancer Project were obtained and analyzed. Clinical data were compared for the histologic groups using Fisher’s Exact, ANOVA, and Kruskal-Wallis statistics where appropriate. Kaplan-Meier curves were used for survival analyses. Gene expression data was analyzed using DESeq2 for differential expression of mRNA. Pathway enrichment analysis of gene expression data was completed using Qiagen IPA Core Analysis software. Comparative marker selection was used to determine differential expression of miRNA, and differential methylation across histologic subtypes. Analyses were completed both by histology and by disease-progression status. Data across all three platforms were integrated to evaluate for potential explanatory relationships of interest. Results: RNAseq analysis revealed a number of genes differentially expressed in MAC as compared to UEA and SCC. Several of these genes were also found to be differentially expressed in samples from patients with disease progression compared to those without known disease progression including increased expression of PPARGC1A, SLC2A1, and ZNF703 and decreased expression of NR4A3. Analysis also revealed hypomethylation at CpG probe sites mapping to SLC2A1 and decreased expression of miRNAs known to target SLC2A1 and PPARGC1A in MAC tumors . Pathways involving translation regulation, EIF2 signaling, and oxidative phosphorylation were downregulated in MAC whereas pathways involving mitochondrial dysfunction, glucose metabolism, and estrogen receptor signaling were upregulated in MAC. Downregulation of immune and inflammatory response pathways and upregulation of tumor-supporting macrophage activation was seen in MAC tumors with disease progression. Conclusions: We identified novel transcriptomic and epigenetic features and altered pathways in MAC, as well as those features and pathways associated with poorer prognosis in this population. These findings may contribute to further confirmatory research and lead to novel therapeutic strategies for this rare cancer.
The efficacy of cumulative cisplatin dose on survival in patients with locally advanced cervical cancer treated with definitive chemoradiotherapy: A multicenter study by the Turkish Oncology Group (TOG).
Authors: Akyildiz Arif , Gultekin Melis , Yigit Ecem , Demir Ecem , Ismayilov Rashad , Ahmed Melin Aydan , Buyukkor Mustafa , Yıldırım Hasan Çağrı , Yildirim Nilgun , Algin Efnan , Orman Seval , Çolak Rumeysa , Özen Engin Esra , Beyaz Havva , Ibis Kamuran , Ergen Şefika Arzu , Sari Sezin Yuce , Tezcan Yilmaz , Yildiz Ferah , Arik Zafer
Published: July 2024

e17534

Background: This multicentric study aimed to investigate the impact of cumulative cisplatin dose on clinical outcomes in locally advanced cervical cancer patients undergoing definitive chemoradiotherapy (CRT). Methods: A retrospective analysis was conducted on 654 patients with stage IB3-IVA disease treated with definitive CRT. Radiotherapy (RT) was applied as external beam pelvic with or without para-aortic RT and brachytherapy. Concomitant chemotherapy was in the form of weekly or 3-weekly cisplatin. Data on demographics, treatment protocols, cumulative cisplatin dose, adverse effects, and survival outcomes were collected. Statistical analyses, including univariate and multivariate Cox regression models, were employed to assess factors influencing progression-free survival (PFS) and overall survival (OS). Results: The median cumulative cisplatin dose was 210 mg (range, 40-320 mg), and it was ≥200 mg in 503 (76.9%) patients. Median follow-up was 35 months. The 5-year PFS and OS rates were 66.9% and 77.1%, respectively. Multivariate analysis (MVA) identified poor performance status, non-squamous cell histology, presence of lymph node metastasis and hemoglobin <10 g/dl before CRT were poor prognostic factors for both PFS and OS in the whole group. When stage III cases were evaluated separately, the cumulative cisplatin dose below 200 mg was also found to be a significant poor prognostic factor in OS (HR 1.79, 95% CI, 1.1 to 3.0, p=0.031). Conclusions: The study revealed that a cumulative cisplatin dose exceeding 200 mg, particularly in patients with lymph node metastasis, significantly improved OS. Factors such as anemia, toxicity-related challenges, and comorbidities were identified as critical considerations in treatment planning. These findings emphasize the delicate balance between maximizing therapeutic efficacy and managing toxicity, guiding personalized treatment approaches for locally advanced cervical cancer. [Table: see text]
Measuring COVID-19's impact on diagnosis of cervical cancer by race/ethnicity, age, and region of the United States.
Authors: Stewart Chelsea , Chan Joshua Elbridge , Tran Nathan , Johnson Caitlin Ruth , Darcy Kathleen M. , Tian Chunqiao , Kapp Daniel Stuart , Liao Cheng-I
Published: July 2024

e17535

Background: The COVID-19 pandemic brought to light significant access-to-care issues for patients across the country, which we hypothesized may have disrupted recent trends in incidence for certain screenable diseases. The goal of this study was to evaluate the impact of the COVID-19 pandemic on cervical cancer incidence based on age, race, stage at presentation, and regions of the US. Methods: Data on cervical cancer incidence were obtained from the United States Cancer Statistics (USCS) program from 2001-2020. We employed SEER*Stat 8.4.1.2 and Joinpoint regression program 5.0.2 to calculate estimated and actual incidence rates per 100,000 women. We compared actual cervical cancer incidence rates in the year 2020 to estimated rates based on trends from the years 2001-2019. Results: From 2001-2020, 245,618 cases of cervical cancer were identified. In 2019, prior to the pandemic, the incidence was 7.64 per 100,000 women. From 2001-2019, cervical cancer incidence decreased by 0.96% per year (p=0.023). Based on this trend, we expected the incidence to be 7.57 per 100,000 women in 2020, but the reported incidence was only 6.83 per 100,000, therefore, there were 9.8% less cervical cancer cases (1,189 cases) in 2020 than expected. This was most noticeable at the lower and upper ends of the age distribution, with 17.6% less cases than expected in the year 2020among 25-29 year-olds and 18.4% less cases than expected among 85+ year-olds. This is in comparison to the median age group for cervical cancer (50-54 year-olds) in whom there were 14.5% (193) less cases than expected in 2020. Based on stage of disease, for local, regional, and distant disease there were 16.3%, 2.8%, and 1.9%, less cases than expected in 2020, respectively. Within racial and ethnic groups, we found that Non-Hispanic Black (NHB) and Hispanic patients had 15.0% and 13.9% less cases than expected, versus 8.7% among Non-Hispanic White (NHW) and 5.8% among Non-Hispanic Asian and Pacific Islander (NHAPI) patients. Comparing U.S. regions, the Midwest, Northeast, West, and South had 14.6%, 10.2%, 10.2%, and 9.0% less cases than expected for 2020, respectively. Conclusions: Our data suggest that the reported cervical cancer cases were significantly less than predicted based on past trends during the COVID-19 pandemic.. Older age, NHB and Hispanic patients, and those residing in Midwest states had the greatest number of possible missed diagnoses of cervical cancer during this time. Mitigating strategies are needed to reinstate screening programs, particularly in these at-risk groups to prevent increased rates of advanced stage disease and mortality.
Use of Gynecologic Cancer Intergroup (GCIG) CA125 criteria to evaluate cell cycle checkpoint kinase 1 inhibitor (CHK1i) prexasertib response and disease progression (PD) in recurrent high-grade serous ovarian cancer (HGSOC).
Authors: Ibanez Kristen , Donohue Duncan , Malys Tyler , Lee Jung-Min
Published: July 2024

e17536

Background: Data suggest discordance between serum biomarker CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) response and/or PD in chemotherapies and PARP inhibitors. Here, we investigated the impact of CA125 on prognosis and its relationship with RECIST response/PD in HGSOC patients treated with a CHK1i, prexasertib. Methods: All relapsed HGSOC patients in this post-hoc analysis were treated with prexasertib at 105 mg/m2 IV every 14 days in a 28-day cycle until RECIST v1.1 PD, unacceptable toxicity, or consent withdrawal (NCT02203513). CA125 was assessed every cycle and CT scans obtained every two cycles. GCIG CA125 response was defined as >50% reduction confirmed after 28 days and PD as > 2X upper limit of normal (ULN) if baseline was normal or doubling of nadir if baseline was elevated. Patients with baseline CA125 < 2X ULN or nadir > 750 units/mL were not eligible for analysis. Clinical benefit rate (CBR; CR + PR + SD ≥ 6 months) was analyzed by Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves and univariate (UV) and multivariate (MV) hazard ratios by Cox regression models. Positive predictive value (PPV) and negative predictive value (NPV) confidence intervals (CI) were estimated by the Wilson-Brown method. Results: Eighty-one patients received at least two cycles of prexasertib between January 2015 and November 2020, out of which 72 were evaluable by both RECIST and GCIG CA125 response criteria. CBR in the CA125 response (CA125-R) group (24/32; 75%) was significantly higher than the CA125 non-responder (CA125-N) group (12/40; 30%; p<0.001). CA125 response tended to occur prior to RECIST response (median: 28 days; IQR: 28, 30). PFS was improved in CA125-R at 8.0 months vs. CA125-N at 3.5 months (UV HR: 0.34, 95% CI: 0.21-0.56; MV HR: 0.35, 95% CI: 0.20-0.59). OS was improved in CA125-R at 19.8 months vs. CA125-N at 10.3 months (HR: 0.43, 95% CI: 0.26-0.71; MV HR: 0.45, 95% CI: 0.27-0.75). No significant differences in PFS or OS were observed between subgroups by BRCA mutation status, platinum-sensitivity, FIGO stage, baseline CA125 value, or previous PARP inhibitor therapy in MV analysis. Out of 70 patients evaluable by RECIST and CA125 PD criteria, 43 patients had CA125 PD and 24 of those had RECIST PD occur within one cycle of CA125 PD (PPV: 59%; 95% CI: 43-72). Of the 27 patients without a CA125 PD, 9 patients also did not have a RECIST PD (NPV: 33%; 95% CI: 19-52). Conclusions: GCIG CA125 response is an independent predictor of response to CHK1i in HGSOC prior to the first restaging scans and is associated with a higher CBR and improved PFS and OS. However, GCIG CA125 PD has poor PPV and NPV within a one cycle window, indicating that CA125 alone is not sufficient in monitoring for PD in HGSOC treated with CHK1i.
Multiomic analysis in ovarian clear cell carcinoma to gain insight into biology and therapeutic opportunities.
Authors: Kong Ben , Stommel Jayne , Emerson Jenna , Munro Elizabeth G. , Corless Christopher L. , Mills Gordon B. , Pejovic Tanja ,   SMMART Clinical Trial Program
Published: July 2024

e17540

Background: Ovarian clear cell carcinoma (OCCC) is a rare subtype with distinct histologic and molecular features. The prognosis of advanced/recurrent OCCC treated with standard of care surgery and platinum-based chemotherapy remains poor due to inherent chemoresistance. Therefore, there is an urgent need to identify novel biological insights and personalized treatment approaches to improve outcomes. Methods: Participants were referred to the SMMART Program at the OHSU Knight Cancer Institute. Archival or fresh tissue was obtained from metastatic sites and processed through a multiomics platform that included immunohistochemistry (Ki67, HER2, CD4, CD8, PD-L1), fluorescent in-situ hybridization, targeted next-generation sequencing panel (225 genes), whole transcriptomic sequencing, chromosomal microarray, and multiplexed analysis of 67 key cancer proteins and phosphoproteins on the Nanostring GeoMx Digital Spatial Profiler. Results: 5 participants were enrolled with an average age of 62 years (range 52-72). Therapeutically relevant findings included detectable HER2 expression by IHC (2+, N=2; 3+, N=2), HER2 amplification by FISH (N=2), and high HER2 and phospho-HER2 protein expression compared to a breast cancer cohort (phospho-HER2 supports active HER2 signaling in the tumor cells). Additional findings include TMB <10 muts/Mb (N=5), microsatellite stable (N=5), Ki67 40-60% (N=4), mild to moderate CD4 and/or CD8 infiltration (N=4), PD-L1 >1% (N=3), low homologous recombination deficiency score (N=4), chromosomal losses including ATM, SMAD4, RB1, and TP53, and single nucleotide variations in ARID1A (N=4). Two participants with HER2 expression were treated with off-label trastuzumab deruxtecan for 6 or 7 cycles yielding significant clinical benefit. Participant A (HER2 = 3+, FISH negative) had an exceptional response while Participant B (HER2 = 2+, FISH amplified) had stable disease. The toxicity profile was consistent with literature. Conclusions: Our OCCC cohort revealed elevated HER2 expression with or without genomic amplification in 4/5 cases. Two participants experienced clinical benefit when treated with trastuzumab deruxtecan, supporting further exploration of HER2 antibody drug conjugates in this aggressive disease. More study is needed to determine the frequency of HER2 overexpression and amplification in OCCC, the importance of HER2 on OCCC pathophysiology, and the therapeutic benefit of targeting HER2 in this population.
Homologous recombination deficiency score for predicting efficacy of platinum-based chemotherapy and PARPi maintenance therapy in ovarian cancer.
Authors: Wang Jinhua , Shen Jing , Zhang Zhe , Ye Lei , Lu Jin , Xiao Ziyi , Zhang Lihua , Liu Xiaojian , Zhu Chan , Wang Xiaoxuan , Zhang Chao , Zhang Xing , Chen Dong-sheng , Xu Xinyu
Published: July 2024

e17543

Background: Currently, homologous recombination deficiency (HRD) has been confirmed to be a predictive biomarker for poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer, while its effects on the clinical outcomes of platinum-based chemotherapy and PARPi maintenance therapy are not assessed rigorously in ovarian cancer. We developed an HRD assay to evaluate the effect of HRD scores on the platinum-based chemotherapy and PARPi maintenance therapy in Chinese patients with ovarian cancer. Methods: HRD testing was performed on the samples obtained at primary cytoreductive surgery. The progression-free survival (PFS) was observed among the BRCA-mutated/HRD-positive and BRCA wild-type/HRD-negative patients. Univariate and multivariate COX analyses were performed to test the association of PFS with different variables, and hazards ratios (HR) and 95% confidence interval (CI) were calculated. The two-tailed p value less than 0.05 was considered statistically significant. Results: Totally 74 patients who received platinum-based chemotherapy were eligible for the study, among whom 81.1% responded to the initial platinum-based chemotherapy, 33.8% harbored BRCA1/2 mutations and 74.3% were HRD-positive. The median HRD score of platinum-sensitive patients (n=60) was 48.5, significantly higher than the 31 of platinum-resistant patients (n=14, p=0.0035). Analysis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) between platinum-sensitive and platinum-resistant patients showed significant differences in TAI ( p=0.0012) and LST ( p=0.004). Compared with HRD-negative patients, HRD-positive patients had a significantly longer median PFS (10 vs. 15 months, p=0.017), and multivariate analysis further indicated that HRD-positive status (HR, 0.423, 95%CI: 0.191-0.939, p=0.035) was a significant predictor for the improvement of PFS. Conclusions: The HRD assay developed in our study can accurately predict the response to platinum-based chemotherapy and PARPi efficacy in patients with ovarian cancer, providing powerful evidence for implementation of genetic testing and guidance of clinical treatment in ovarian cancer.
Clinical outcomes after adjuvant anti-PD1 therapy for high-risk resectable melanoma and predictors of response.
Authors: Marsiglio John , Bingjian Feng , Kovacsovics Magdalena , Gibson Berit , Zhou Qin , Swami Umang , Russell Jeffery Scott , Erickson-Wayman Alyssa , Asare Elliot Amponsah , Monroe Marcus , Bowles Tawnya Lynn , Nix David , Williams Matthew , Tan Aik-choon , Hyngstrom John Robert , Hu-Lieskovan Siwen
Published: July 2024

e21502

Background: Adjuvant anti-PD1 is the standard of care for high-risk resectable melanoma but many still suffer recurrence. We report a single institution observational study of patients who received adjuvant anti-PD1 with a particular focus on those who recurred. Methods: Through an approved protocol by Huntsman Cancer Institute IRB, patients with resected high-risk melanoma who first received anti-PD1 in the adjuvant setting were consented and followed. Clinical outcomes were assessed per RECIST 1.1, progression free survival (PFS), and overall survival (OS). Results: 186 eligible patients were included, 105 male and 81 females, median age at C1D1 58 (22-93), 12/161/7 at stage II/III/IV and 5 unstageable. Subtypes included 79 (43%) superficial spreading, 50 (27%) nodular, 16 (9%) lentigo/nevoid, 13 (7%) non-acral skin (NOS), 10 (5%) acral, 4 (2%) mucosal, and 14 (7%) others. With median follow up of 708 days (23-9599), 66 (35.5%) had progressive disease (PD), including 33 (50%) early PD and 33 (50%) late PD. Statistically significant predictors of worse outcome included age > 50 (OS p = 0.043), acral subtype (PFS p = 0.023), PD-L1 IHC < = 1% (OS p = 0.052, PFS p = 0.002), duration of treatment < 3 months (OS p = 0.005, PFS p = 1.8E-07), early PD (OS p = 0.003, PFS p = 1.5E-6) and distant recurrence (OS p = 0.002). Trends that were not significant included: male gender (worse OS), BRAF mutation (better PFS), NF1 mutation (better PFS). No correlation between outcomes and TMB, NRAS, TERT mutation, and primary location. In the early/late PD groups, median age was 57/55 (range 28-79 / 25-84), 64/61% male, 1/0, 29/31, 3/2 stage II, III, IV. 17/13 were superficial spreading, 6/10 nodular, 2/5 acral, 2/2 lentigo, 1/0 mucosal and 4/3 other non-acral skin. Primary site was 12/12 head/neck, 9/5 trunk, 4/7 upper limb, 8/9 lower limb. BRAF was 9/11 wildtype, 15/9 mutant and 9/13 unknown. PD-L1 > = 1% by IHC was 4/2. TMB mut/mb > 10 was 6/5. Sites of recurrence included 6/12 local, 7/7 regional LN, 20/14 distal (3/1 in brain) relapses. For unresectable PD (13/13 early/late) response to next line systemic therapy is shown in Table 1. Conclusions: One third of patients developed PD after adjuvant anti-PD1 for high-risk melanoma. PD-L1 negativity and short duration of treatment was associated with worse outcome. Early PD corresponded to more distant metastasis, poorer OS and response to subsequent systemic therapy. Importantly most late PD can still have a favorable response by resuming anti-PD1 therapy. Further molecular study is ongoing to investigate mechanisms of resistance. [Table: see text]
Real world experience of bispecific fusion protein in patients with metastatic uveal melanoma: Can we deliver?
Authors: Joseph Liz , Herbert Christopher , Taylor Hannah , Winter Helen , Howe Adrienne
Published: July 2024

e21504

Background: Effective treatments for patients with metastatic uveal melanoma has remained a longstanding unmet need. Poor response rates to checkpoint inhibitors has increased the need for patients to access new ways of targeting this disease. Tebentafusp is a first in class T Cell receptor bispecific fusion protein that has demonstrated an overall survival benefit. However although licensed it has yet to be approved in the UK for wider use. Methods: Prospective data collection on five patients receiving tebentafusp through the Managed Access Programme at a cancer centre that had not taken part in any trials of this therapy before. Patients were permitted with metastatic uveal melanoma; ECOG performance status 0-1 and were HLA-A*02:01 positive. Protocols were disseminated across the wider cancer teams for the management of side effects including cytokine release syndrome. Patients received extended monitoring for at least 16 hours, and vital signs (blood pressure, heart rate, temperature and pulse oximetry) taken every 2-4 hours. Drop in systolic BP < 20mmHg treated with IV fluids. Results: Five patients with advanced uveal melanoma participated in the Access Programme at one cancer site to assess efficacy, tolerability and workforce upskilling and capability with a first in class bispecific fusion protein therapy. All patients were HLA-A*02:01 positive. The patients commenced therapy between November 2021 and July 2023. All were male; median age 66. Four patients developed cytokine release syndrome commencing at cycle one. These patients required intravenous fluids for CRS grade 2, no patients required vasopressors. One patient required IV hydrocortisone. Four patients developed skin toxicity. These were managed with antihistamines and steroids. Three patients stopped due to confirmed disease progression, receiving 2-7 cycles; one made an informed decision to stop due to grade 3 skin toxicity. One patient continues on tebentafusp and has received 32 cycles to date. They recently had treatment paused for ablation and resection of oligometastatic disease that found residual uveal melanoma and have restarted. Conclusions: Real-world data suggests that using a gp100-targeting TCR/anti-CD3 bispecific fusion protein is tolerated and deliverable in new settings. Tebentafusp was delivered without any medical emergencies and CRS was successfully managed with proactive fluid management and steroids. The rate and grading of side effects reflects that described in the large randomised controlled trial. Patients with uveal melanoma can derive ongoing clinical benefit - including one patient who has received 32 cycles and proceeded to surgical resection of oligometastatic disease. Through workplace education and upskilling, the proactive management of the side effects including cytokine release syndrome can be managed in the oncology inpatients and seamlessly moved to outpatient settings.
First-line therapy for metastatic uveal melanoma: Experience from a single reference center.
Authors: Nazarova Valery V. , Magomedova Zakhra R. , Orlova Kristina V. , Unguryan Vladimir , Romanov Denis , Yarovaya Vera , Yarovoy Andrey , Trofimova Oxana , Demidov Lev V.
Published: July 2024

e21514

Background: Metastatic uveal melanoma (mUM) continues to have a poor prognosis with distinct biology from cutaneous melanoma and limited effective treatment options. The main options include immunotherapy (IT, anti-PD-1+/- anti-CTLA-4, tebentafusp), chemotherapy, targeted therapy and local treatment methods for patients with isolated liver metastasis (isolated hepatic perfusion, transarterial chemoembolization, percutaneous hepatic perfusion, radiofrequency ablation). Methods: We conducted a single-center retrospective observation IRB-approved study of first-line therapy for pts age 18 and older with mUM treated at the N.N. Blokhin National Medical Research Center of Oncology from 2020 to 2023. Our objectives were to evaluate clinical outcomes in real-world settings, as well as treatment patterns, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events (AEs). Results: A total of 125 pts included. The mean age was 54 yrs (range: 20-74), and the median time to metastasis from primary tumor was 2 years (range: 0-21). Liver metastases were diagnosed in 92% of patients, lung metastases in 20%, bone metastases in 17%, and soft tissue metastases in 9%. Conclusions: Our data suggest that the combination of systemic and local liver-directed treatment methods may be associated with a survival benefit and higher treatment response to IT in patients with mUM. [Table: see text]
Real-world effectiveness and safety of dabrafenib-trametinib as first-line of treatment for BRAF mutated metastatic melanoma: Results of the study GEM1801.
Authors: Berciano-Guerrero Miguel-Ángel , Perez-Ruiz Elisabeth , Muñoz Couselo Eva , Manzano Jose Luis , Cerezuela-Fuentes Pablo , Ayala de Miguel Pablo , Soria Ainara , García Castaño Almudena , Crespo Guillermo , Puértolas Teresa , Aguado De La Rosa Carlos , Gutiérrez Sanz Lourdes , López Castro Rafael , Espinosa Enrique , Lecumberri Maria José , Majem Margarita , Medina Martinez Javier , Bellido Lorena , Fernández-Morales Luis Antonio , Martin-Algarra Salvador
Published: July 2024

e21515

Background: Dabrafenib-Trametinib (DT) is included in the therapeutic arsenal for BRAFV600-mutant metastatic melanoma. However, detailed effectiveness results for dabrafenib and trametinib depending on patient prognostic profile in the real-world are limited. Methods: GEM1801 is a prospective observational study that analyzes the clinical and pathological disease presentation patterns, the different lines of treatment choices and the health outcomes derived from treatments in patients with melanoma in Spain. Here we focus on patients receiving DT as first-line treatment in the metastatic melanoma. Based on previous studies, we defined 3 subgroups: good prognosis (normal LDH and < 3 metastatic sites), poor prognosis (high LDH and ≥3 metastatic sites), and intermediate prognosis (neither of good or poor prognosis). Results: From August 2018 to December 2022, 140 patients receiving DT were enrolled; 45 (32.1%) with good, 42 (30%) with intermediate and 34 (24.3%) with poor prognosis. Subgroup allocation was not possible for 19 patients due to missing info on LDH or metastatic sites. Overall survival (OS) was longer in patients with good versus poor prognosis (median 26.2 vs 10 months; p = 0.024), while those with intermediate prognosis showed a mixed profile with a median OS of 17.4 months. Response to treatment also showed correlation with OS (3-years OS rate: 57.1% vs 23% vs 46.9% vs 26.8% for CR, PR, SD and PD, respectively; p < 0.001). In patients who had a complete response, the 5-year OS rate was 58.3% (95% CI: 31.3-100) while the median overall survival was not reached. In patients with intermediate prognosis, the ECOG-PS was the main prognostic factor in multivariate analysis (hazard ratio: 4.6; 95% CI: 1.8-1.7; p = 0.002). The reported grade 3-5 toxicity was less than 5%. Treatment-related adverse events were reported in 5 (3.6%) patients, consisting of fever, mucositis, pneumonitis, neutropenia, ocular toxicity and retinal detachment. There were no differences across prognostic subgroups ( p = 0.741). Conclusions: DT in the Real-World has an acceptable effectiveness and safety profile. Prognostic groups could help in the selection of patients who could achieve a complete response, since it is the most important prognostic biomarker. Clinical trial information: NCT03605771 . [Table: see text]
Hyperammonemic encephalopathy: An unaccounted side effect of 5FU and capecitabine.
Authors: Sheikh Taha , Watkins Dean , Hamouda Danae M.
Published: July 2024

e24108

Background: Metabolic encephalopathy is a serious but reversible condition that is characterized by a diffuse impairment of cognitive function due to the overabundance of various metabolites or toxins. Hyperammonemia ( > 80 μg/dL or > 47 μmol/L) is a well-known cause of metabolic encephalopathy and also a rare side effect of 5-Fluorouracil (5-FU) chemotherapy. Constipation and renal failure are two known risk factors for developing hyperammonemic encephalopathy with 5-FU use. Capecitabine is a 5-FU prodrug that is commonly used as a more tolerated and more convenient alternative chemotherapy agent. Despite being less common than with 5-FU, cases of hyperammonemic encephalopathy related to capecitabine use may be missed clinically due to under-testing. Additionally, diarrhea may be misinterpreted as a side effect of chemotherapy instead of an effective tool for identifying early disease and accelerating disease resolution. Methods: A search using Pubmed was conducted on January 4th, 2024 to identify cases of hyperammonemia and metabolic encephalopathy related to 5-Fluorouracil and capecitabine. The search strategy was ("metabolic encephalopathy 5-fluorouracil" OR “hyperammonemia 5-fluorouracil”) AND (“metabolic encephalopathy capecitabine” OR “hyperammonemia capecitabine”). Cases were then organized into a table where factors of the cases were stratified. Results: A total of 59 total cases were identified. Every case where 5-FU was used reported a serum ammonia level, while only 5 of the 9 cases (55.55%) where capecitabine was used reported a serum ammonia level. Additionally, only 9 cases (15.25%) reported bowel movement status with 1 patient presenting with diarrhea, and 5 with constipation. The most common methods for managing metabolic encephalopathy in these patients included: branched chain amino acids (66.10%), discontinuing/changing the chemotherapeutic agent (62.71%), lactulose (37.29%), intravenous hydration (32.20%), and hemodialysis/hemofiltration (13.56%). For the 52 cases that reported it, the average duration of symptoms post-treatment was 2.15 days. Conclusions: A goal in managing patients receiving 5-FU or capecitabine with hyperammonemic encephalopathy is the excretion of ammonia without causing dehydration. This management is seen with the use of lactulose to increase bowel movements in patients with decompensated liver cirrhosis. Of note, 5FU and capecitabine have been shown to cause diarrhea as a grade 3 and 4 adverse effect in 12.7% and 16.6% of patients, respectively. Thus it can be theorized that the diarrhea from 5FU/capecitabine may offset the development of hyperammonemia. This principle could potentially be expanded to benefit patients with a history of chronic constipation. The oversight of hyperammonemia from 5-FU and capecitabine use is both dangerous and diminishes the quality of life from patients who are not proactively treated to prevent encephalopathy.
Identifying objective risk factors of financial toxicity in patients with cancer.
Authors: Bazhenov Aleksei , Doro Luiza , O'Sullivan David M. , Menendez Alvaro G.
Published: July 2024

e24116

Background: Current financial toxicity (FT) screening tools rely on patient-reported risk factors (RF)1. Underrepresented populations may not be forthcoming about FT fears due to cultural concerns of treatment withholding or migratory repercussions, if applicable1–4. Identifying objective RF, such as social determinants of health (SDH) and disease-specific factors (DSF), could reduce FT in cancer patients and healthcare systems. Methods: This was a multi-center retrospective study evaluating SDH and DSF associated with FT (defined as ≥$15,000 owed) related to cancer treatment. Inferential statistics were used to evaluate differences between the FT cohort and those who owed < $15,000. Continuous data were compared with a Student’s t or Mann-Whitney U test, depending on distribution. Categorical outcomes were compared with a chi square test. A logistic regression model was used to evaluate multivariate associations with FT, using p < 0.05 to define significant results. Results: The sample comprised 162 records, 81 in each group. Univariate analyses demonstrated differences in age, lack of PCP, non-US country of origin, lack of insurance, lower education levels, need for an English interpreter, stage 4 at diagnosis, recurrent or metastatic disease, use of immune checkpoint inhibitors (ICI), and use of targeted molecular therapy (TMT) (Table 1). Employment status and marital status were not statistically different. The logistic regression model showed that lack of insurance and stage 4 at diagnosis were significantly associated with FT (p = 0.001 and p = 0.0495, resp.). Conclusions: Objective FT screening can minimize response bias and incidence in those at increased risk. Non-US country of origin and lack of English proficiency suggests that first-generation Hispanics may not be appropriately navigated for FT. These findings identify specific subpopulations at risk for FT and will guide prospective interventions looking to minimize FT. Healthcare systems should analyze objective measures of FT while considering loco-regional and subcultural SDH/DSF in order to overcome response bias. Ref. Witte J et al. Methods for measuring financial toxicity after cancer diagnosis and treatment. Annals of Oncology. 2019;30(7) Strasser-Weippl K et al. Progress and remaining challenges for cancer control in Latin America and the Caribbean. Lancet Oncol. 2015;16(14) Zhu Z et al. Cancer survivors’ experiences with financial toxicity. Psychooncology. 2020;29(6) Chebli P et al. Multilevel determinants of financial toxicity in breast cancer care. Supportive Care in Cancer. 2020;28(7). [Table: see text]
LOOP: An observational, prospective, multicenter study of patients with non-small cell lung cancer in the US receiving standard-of-care and initiating an approved therapy with risk of pneumonitis/ILD.
Authors: Piault-Louis Elisabeth C , Marvel Melissa , Newton Michael David , Haddad Vincent , Hutchison Emmette R , Hughes Joseph T , Campbell Alicyn K , Basch Ethan
Published: July 2024

TPS12157

Background: A wide range of oncology treatments are associated with a risk of pneumonitis or ILD, which is an uncommon but serious side effect with potential for significant morbidity and mortality (Conte et al 2022). The development of pneumonitis/ILD remains unpredictable and relatively uncommon in a single practice or hospital setting. Risk of drug-induced pneumonitis/ILD remains a limiting factor to prescribing life-saving treatments. A non-invasive, patient-centric multimodal solution for remote data capture could support recognition and tracking of pulmonary symptoms in addition to providing insight for the clinical team to personalize the monitoring of patients according to their medical history or specific physiological markers. Methods: LOOP is an observational, prospective, multicenter study conducted in the US. Stage III and IV NSCLC patients receiving SoC and initiating treatment with an FDA-approved ICI (alone or in combination with other agents), ADC, or small molecule EGFR inhibitor are eligible to participate. The primary objective is to enable the development and refinement of an algorithm including documentation of its performance (specificity, sensitivity and odd ratio to inform risk of pulmonary/respiratory/thoracic-related events including ILD). A secondary objective proposes to characterize the risk factors, signs, and symptoms leading to onset, diagnosis, and treatment of pneumonitis/ILD in patients receiving SoC. The study will collect patient-generated data outside of point-of-care for six months, using questionnaires and a medical pulse-oximeter device . Clinical data available per SoC in the medical records will be collected. Approximately 600 patients will be enrolled over 13 months to accrue approximately 100 pneumonitis/ILD events. Events will include all grades of pneumonitis, including ILD and radiation pneumonitis, as determined by the Investigator. Qualitative interviews will be conducted to inform a more granular understanding of the patient specific experience of developing ILD. Logistic regression, area under curve, descriptive statistics and relevant visualizations will map the relationship between pneumonitis/ILD and patient’s health status. The study is currently enrolling; the protocol was approved by a central IRB. Clinical trial information: NCT06192004 .
Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Authors: Serzan Michael Thomas , Jegede Opeyemi , Alter Robert S. , Bilen Mehmet Asim , Braun David A. , Einstein David Johnson , Haas Naomi B. , Herchenhorn Daniel , King Jennifer , Runcie Karie , Sosman Jeffrey A. , Sternberg Cora N. , Yang Yuanquan (Aaron) , Signoretti Sabina , CHOUEIRI Toni K. , Atkins Michael B.
Published: July 2024

TPS4614

Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter investigator initiated trial evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .
Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies
Authors: Papusha Ludmila , Zaytseva Margarita , Panferova Agnesa , Salnikova Ekaterina , Samarin Alexey , Vilesova Irina , Voronin Kirill , Protsvetkina Anastasia , Podlipaeva Svetlana , Zakharov Ilya , Usman Natalia , Hwang Eugene , Karachunskiy Alexander , Packer Roger J. , Novichkova Galina , Druy Alexander
Published: July 2024

PURPOSE

Midline low-grade gliomas (mLGGs) of early childhood have a poorer prognosis compared with tumors of other localizations and in older patients. LGGs are associated with aberrant activation of RAS-RAF-MEK pathway, and pharmacological inhibition of the pathway has therapeutic promise. The aim of this study was clinical and molecular characterization of infantile mLGGs, with emphasis on the efficacy of targeted kinase inhibition.

PATIENTS AND METHODS

This study enrolled 40 patients with mLGG age <3 years. The majority of the patients (30/40) received first-line chemotherapy (CT) as per International Society of Paediatric Oncology LGG 2004 guidelines. In all patients, molecular genetic investigation of tumor tissue by polymerase chain reaction and RNA sequencing was performed. The median follow-up was 3.5 years.

RESULTS

First-line CT failed in 24 of 30 recipients. The identified molecular profiles included KIAA1549::BRAF fusions in 26 patients, BRAF V600E in six patients, FGFR1::TACC1 fusions in two patients, and rare fusion transcripts in four patients. At disease progression, targeted therapy (TT) was initiated in 27 patients (22 patients received trametinib) on the basis of molecular findings. TT was administered for a median of 16 months, with partial response achieved in 12 of 26 (46%) patients in which response was evaluated. Severe adverse events were detected only on trametinib monotherapy: acute damage of GI or urinary mucosa complicated by hemorrhage and development of transfusion-dependent anemia in four patients and grade 3 skin toxicity in three patients.

CONCLUSION

mLGGs of early childhood are often aggressive tumors, resistant to CT, and frequently require alternative treatment. The majority of patients harbor druggable molecular targets and respond to molecular TT.
Clonal Hematopoiesis in Patients With Neuroendocrine Tumor Treated With Lutetium-177 and the Risk of Thrombocytopenia: A Prospective Study
Authors: Kusne Yael , Lasho Terra , Finke Christy , Elsabbagh Zaid , McCue Shaylene , Hobday Timothy , Starr Jason , Bekaii-Saab Tanios , Halfdanarson Thorvardur R. , Patnaik Mrinal M. , Ou Fang-Shu , Sonbol Mohamad Bassam
Published: July 2024

PURPOSE

Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT.

MATERIALS AND METHODS

Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter.

RESULTS

Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes ( DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two.

CONCLUSION

CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.
Εγκληματικότητα και μέσα μαζικής ενημέρωσης
Authors: Θεολόγη Βασιλική
Published: July 2024

Πρόκειται για μία μελέτη η οποία παρουσιάζει εγκληματολογικό και ποινικό ενδιαφέρον. Εγκληματολογικό ενδιαφέρον, διότι η μελέτη της προβολής της εγκληματικότητας προσεγγίζεται μέσα από θεωρίες που σχετίζονται με το έγκλημα και τις αιτίες που το προκαλούν (βιολογικές, ψυχολογικές, κοινωνιολογικές) και συνεπώς συμβάλλουν στην εγκληματογένεση. Ακολουθεί τους δρόμους και της Εγκληματολογίας της Κοινωνικής Αντίδρασης προκειμένου να καταδείξει τον τρόπο κατασκευής της κοινωνικής πραγματικότητας από τα ΜΜΕ. Παράλληλα, εξετάζει τα κριτήρια με τα οποία οι δημοσιογράφοι επιλέγουν και παρουσιάζουν τις ειδήσεις για το έγκλημα και την εγκληματικότητα. Η εργασία παρουσιάζει επίσης ποινικό ενδιαφέρον, ως προς τη νομοτυπική μορφή των εγκλημάτων που τελούνται δια του τύπου και ως προς τα μέτρα που προτείνονται για την αντιμετώπισή τους. Κατά την εκπόνηση του θέματος έχει λάβει χώρα η συνταγματική προσέγγιση και οι αντίστοιχες δικονομικές διατάξεις. Η τεκμηρίωση των θεωρητικών ζητημάτων εμπλουτίζεται από την επεξεργασία των ευρημάτων της εμπειρικής έρευνας που εκτείνεται στον περιφερειακό τύπο και την περιφερειακή τηλεόραση.