bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world comparison of outcomes in the first line treatment of metastatic melanoma according to BRAF mutation status: Nivolumab and ipilimumab therapy vs. nivolumab monotherapy.
Authors: Klein-Brill Avital , Amar-Farkash Shlomit , Fisch Michael Jordan , Aran Dvir 
Published: June 2022

e21519 Background: In metastatic melanoma (MM) patients, nivolumab can be used as monotherapy or in combinations with ipilimumab. The combination therapy has been shown in a randomized clinical trial to provide survival benefit in BRAF mutant patients with an increased toxicity. Using real-world data, we evaluated the impact on overall survival and post-treatment hospitalizations of 1L nivo alone vs nivo+ipi. Methods: We performed a retrospective cohort study of 1L treatment of patients with MM between 1/2016 and 12/2020, utilizing administrative claims data from the Anthem Cancer Care Quality Program. Real-world overall survival (OS) was defined as time from diagnosis to death. A Cox model with inverse probability of treatment weighting (IPTW) was used to adjust for demographic and clinical features. Adjusted hazard ratios (aHR) were estimated using weighted Cox proportional hazards models. Results: Our cohort included 708 1L MM patients, of them 466 (66%) treated with nivo+ipi. There was no difference in BRAF status between the treatment groups. Patients treated with nivo+ipi were younger and had more evidence of brain and lung metastasis. Following adjustment, nivo treated had significant longer OS compared to the nivo+ipi treated (aHR: 1.73 (1.25-2.35), p = 8e-4). This difference mostly stems from increased mortality of the combo treated in the first 6 months. At 24-months, 58% of the combination therapy treated patients were alive compared to 74% in the monotherapy group (p = 0.0006). Survival benefit was only observed in BRAF WT patients. In V600E patients no survival difference was observed (aHR: 0.8 (0.4-1.6), p = 0.5). Patients treated with the combination therapy had 5-fold more hospitalizations during the first 90 days after the treatment start (46% vs 10%, p = 3e-22). Conclusions: Our retrospective cohort study demonstrated improved survival for the monotherapy in BRAF WT patients. Combination therapy was associated with significantly more treatment-related hospitalizations and deaths, mainly in the first 6 months. The increased early morbidity of the combo should be considered in treatment decision.[Table: see text]
Discovery of AMBRA1 and SQSTM1 (p62) as putative biomarkers to identify high risk subsets of patients with cutaneous squamous cell carcinoma.
Authors: Lovat Penny , Alexander Michael , Cousins William , Ewen Tom , Stefanos Niki 
Published: June 2022

e21541 Background: While surgical excision is largely curative, small subsets of patients with cSCC develop metastatic disease for which current AJCC/Brigham and Women’s Hospital staging criteria are unable to reliably identify. There is hence an unmet need for credible prognostic biomarkers to stratify patients based on personalised risk, guide the use of emerging therapeutic intervention for advanced disease and the rationalisation of current/future dermatological healthcare. AMBRA1 and SQSTM1 (p62) play a key role in autophagy and sustained keratinocyte differentiation; two vital processes disrupted in cSCC tumorigenesis, resulting in deregulated cell proliferation and autophagy-mediated tumour cell survival. While AMBRA1 expression is maintained in the normal epidermis its expression is lost in the tumour growth front of cSCCs. Conversely, p62 expression is maintained in basal keratinocytes within the normal epidermis but is lost in the peritumoural epidermis. Collectively these observations suggest tumoural AMBRA1 and peritumoural epidermal p62 expression as biomarkers of cSCC progression. The aim of the present study was to assess the immunohistochemical (IHC) expression of AMBRA1 and p62 in a retrospective cohort of localised or metastatic cSCCs and correlate expression with clinical outcome over 5 years. Methods: Automated IHC analysis of AMBRA1 and p62 expression was performed in a retrospective cohort of well, moderately or poorly differentiated non or metastatic cSCCs. Digital images were annotated prior to H-score expression analysis using optimised cytoplasmic algorithms within Aperio ImageScope software. Results: Receiving Operating Characteristic (ROC) curve analysis revealed an H score of < 20 for peritumoural epidermal p62 and < 60 for expression of AMBRA1 in the cSCC growth front defined cSCCs at high risk of progression while tumours with a p62 H score of ≥ 20 and/or ≥ 60 for AMBRA1 were defined as low risk. Subsequent Kaplan Meier analysis of 51 moderately/poorly differentiated cSCCs demonstrated loss of peritumoural p62 and tumour AMBRA1 expression in 7 tumours correlated with a significantly increased risk of metastasis of 85.7 % compared to 25% for 44 tumours defined as low risk (P < 0.0001, HR 30.07, 95% CI 5.48-165) with an assay specificity of 97%, positive predictive value of 75%, and a negative predictive value of 86%. Conclusions: Overall these data suggest the combined use of tumoural AMBRA1 and peritumoural p62 expression as a putative prognostic biomarker for cSCC metastasis, the future validation of which may provide a valuable stratification tool to guide clinical management, therapeutic intervention and the rationalisation of healthcare resources.
Correlation between homologous recombination repair gene mutation and immunotherapy efficacy in patients with advanced melanoma.
Authors: You Changxuan , Zhou Chengzhi , You Zhixuan , Lv Meng , He Xuanyu , Pan Yingqin , Ge Junfeng , Hu Xue , Zheng Yating , Huang Mengli 
Published: June 2022

e21551 Background: Nowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) was a pathway of the DNA damage response (DDR), has been shown to be associated with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy and immunotherapy in variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma. Methods: An independent cohort (Samstein2018) with data from 99 patients with advanced melanoma were used to analyze the correlation with immunogenic marker the prognostic effect of HRR on immunotherapy, and another four cohorts (Miao2018, Allen 2015, Hugo2016, and Synder2014) are used for validation. Immune filtration cells scores analyzed by the TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment. Results: Compared to patients with HRR pathway wild-type (HRRwt), those with HRR mutations (HRRmut) in an independent anti-CTLA-4-treated cohort had higher tumor mutation burden (TMB; median: 29.55Muts/Mb versus 4.46Muts/Mb; P = 0.0003), objective response rates (ORR; P = 0.007), and longer overall survival (OS; median: 58 versus 22 months, hazard ratio (HR) = 2.4, 95%CI 1.17-4.92, P = 0.014). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the ORR and OS. However, there was no correlation between HRRmut and OS in the anti-PD-1-treated cohort. Subgroup analysis showed that although patients with HRRmut received the same benefits from anti-CTLA-4 and anti-PD-1/L1 therapy (p = 0.59), the value of anti-CTLA-4 therapy in the HRRmut group was similar or even better than that in the anti-PD-1/L1 therapy group (24.1 months vs 22.7 months), which unlike it in the HRRwt group (10.8 months vs 32.0 months). In addition, transcriptome profiling analysis revealed that 44 (66.7%) genes mutation of HRR pathway associated with reshaping of the immunological microenvironment in melanoma tumors. Conclusions: HRRmut were associated with a higher TMB level, and immunotherapeutic effect. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.
Melanoma mortality rate trend in an era of effective treatments: A retrospective study, 1975-2019.
Authors: Kahlon Navkirat , Hamouda Danae M. 
Published: June 2022

e21555 Background: Skin cancer is the most common cancer in the US. Among all skin cancer cases, melanoma represents only about 1%, but it causes most of the deaths due to skin cancer. Unfortunately, the incidence of melanoma has increased over the last three decades. In the past decade, new and effective therapies for melanoma have emerged, with FDA-approval of multiple checkpoint inhibitors (such as PD-1 inhibitors and CTLA4 inhibitors), and multiple tyrosine kinase inhibitors (TKIs) targeting v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutated melanoma. The aim of this study is to review mortality trends in melanoma since the FDA-approval of these agents. Methods: Long term age adjusted cutaneous Melanoma Mortality Rate (MMR) trends in the United States were reviewed and evaluated using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program from 1975 to 2019. The Annual Percent Change (APC) with 95% confidence interval (CI) and p-value has been used to report long term trends. APC has been calculated using Joinpoint regression. Results: The MMR was found to be increased during 1975-1988 (APC 1.65%; p < 0.01). No statistically significant change in MMR was seen during 1988-2013 (APC 0.01%; p = 0.85). MMR was significantly decreased during 2013-2017 (APC -6.24%, p < 0.01). No statistically significant decrease has been seen during 2017-2019 (APC -1.56%, p = 0.53); however, there is a downward trend. Conclusions: This SEER database retrospective review of MMR provides the insight into change in long term mortality trends for melanoma in the United States. During 1975-2019, the MMR first increased, then stabilized and then decreased. After introduction of checkpoint inhibitors in 2011 and TKIs in 2013, significant reduction in melanoma mortality rate (MMR) was seen during 2013-2017 in the United States, even in the setting of increasing melanoma incidence. This likely reflects a benefit from the availability of effective therapies in the last decade. These treatment options are now also approved for use in the adjuvant setting, primarily after 2017. It will be interesting to see if a further significant reduction in MMR will be seen. It may also be worthwhile to study real-world population trends in other cancers where similar treatments have been found to be effective in recent years.[Table: see text]
Antimetastatic effect of benzimidazole derivative on the model of melanoma B16 in the experiment.
Authors: Kurbanova L. Z. , Shevchenko Nataliya , Verenikina Ekaterina V. , Komarova Ekaterina Fedorovna , Filatova Elena V. , Khomutenko Irina A. , Goncharova Anna S. , Lukbanova Ekaterina A. , Khodakova D. V. , Galina A. V. , Mindar Maria V. , Zaikina Ekaterina V. , Komarova Elizaveta 
Published: June 2022

e21562 Background: Study of the influence of a pharmacological substance dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a] benzimidazole on the tumor growth on a model of experimental transplantable B16 melanoma in mice. Methods: B16 melanoma strain were transplanted subcutaneously to 80 female C57/Bl6 mice weighing 18-20 g. Intragastric dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a] benzimidazole injections (0.5 ml a day) began 48 h after tumor transplantation once a day for 10 days at single doses of 50, 220 and 500 mg/kg (groups 1, 2 and 3, respectively). Mexidol was used for comparison, and saline as control (injected at similar regimens and doses). Results: Intragastric enoxifol injections did not significantly inhibit the melanoma growth. Only group 2 showed inhibition of the tumor growth by 48.7 % on day 22. Median survival of mice in all experiment groups was similar to that in the control group. The number of metastatic nodes in the lung tissues in groups 1, 2 and 3 decreased by 2.1, 4.8 and 2.5 times, respectively, compared to controls. The average index of metastasis inhibition was 71.3 % in all groups being 1.3 times higher than in the mexidol group (54.2 %). Conclusions: The revealed significant changes in parameters of the metastatic activity of the tumor suppose that dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a] benzimidazole at all studied doses has a greater effect on the development of spontaneous lung metastases and metastasis rates than on the growth of primary B16 melanoma in mice.
Clinical and pathological predictors of micrometastasis in marginal thickness melanoma.
Authors: Yaghi Marita , Bilani Nadeem , Dominguez Barbara , Jabbal Iktej Singh , Rivera Carlos , Liang Hong , Benedetto Paul X , Mrad Chebli , Nahleh Zeina A. , Arteta-Bulos Rafael 
Published: June 2022

e21585 Background: Sentinel lymph node biopsy (SLNB) remains controversial in patients with localized marginal thickness melanoma (MTM). Nonetheless, micrometastasis (miLN) i.e. the presence of clinically occult lymph node (LN) metastasis, upstages localized tumors to Stage III, indicating the need for more extensive surgical resection and escalated systemic therapy. We aim to identify disease predictors associated with miLN in MTM. Methods: This National Cancer Database (2004-2018) analysis includes patients with T1a/T1b, N0, and M0 (AJCC 8th edition) melanoma (Breslow’s depth: 0.76-1.00 mm). We selected 2 cohorts based on the pathological status of LN metastasis, as per SLNB or elective lymphadenectomy: negative LN versus miLN. Bivariate association of various clinical characteristics and LN status was assessed using Chi-square and Fisher’s exact tests. Significant covariates were integrated into a multivariable logistic regression (MLR) with a backward elimination model to identify the risk factors associated with the presence of miLN. A multivariable Cox regression model with backward elimination compared overall survivor (OS) between both cohorts, adjusting for significantly unbalanced factors. Results: N = 72,945 patients with clinical N0 MTM were identified. N = 68,912 (94.5%) had negative LN and N = 4,033 (5.5%) had miLN on pathology. Ethnicity (p = 0.260), Charlson/Deyo comorbidity score (p = 0.0894) and LDH levels (p = 0.2278) did not significantly vary across cohorts. On MLR analysis, patients with miLN were more likely to be younger and have tumors located outside the head & neck. Tumors with miLN were more likely to show lymphovascular invasion, vertical growth, and a mitotic rate of ≥ 1 but less likely to show positive tumor regression. Ulceration was not an independent risk factor of miLN (p = 0.9305). Multivariable analysis showed that patients with miLN had lower OS rates than those with negative LN (HR = 1.66; 95% CI: 1.45-1.90; p < 0.0001). Conclusions: miLN is associated with a worse prognosis, warranting early recognition and prompt treatment initiation. Despite NCCN guidelines incorporating tumor ulceration into decision-making regarding the need for SLNB in clinical N0 MTM, we show that tumor ulceration was not significantly associated with miLN in MTM. However, patient age, tumor location, tumor mitotic rate, lymphovascular invasion, and vertical growth phase were associated with miLN and thus need to be assessed when considering SLNB.[Table: see text]
Nodal surveillance and adjuvant therapy in sentinel lymph node-positive melanoma patients.
Authors: Brunsgaard Elise Kornreich , Asare Elliot Amponsah , Bowles Tawnya Lynn , Hyngstrom John Robert 
Published: June 2022

e21586 Background: Since the publication of the Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) in 2017, completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive patients has mainly been deferred for ultrasound surveillance of the nodal basin. Additionally, there is now widespread use of adjuvant therapy in these patients. However, CLND was required for the major adjuvant therapy trials, therefore information on recurrence patterns in SLN-positive patients receiving adjuvant therapy without CLND is limited. Methods: In this retrospective cohort study of patients with SLN-positive melanoma identified from 2017 to 2021 at a single institution, the primary aim was to evaluate the incidence of local, nodal, in-transit, and distant recurrence in patients receiving adjuvant therapy with nodal surveillance compared to nodal surveillance alone. Method of detection of recurrence, compliance with ultrasound surveillance, and clinicopathologic risk factors were also assessed. Chi-square tests were used to evaluate for any associations between clinicopathologic characteristics, initial location of recurrence, and receipt of adjuvant therapy. Results: Of 157 SLN-positive melanoma patients identified, 21 (13%) received CLND and 13 (8%) had insufficient follow-up information for inclusion. Among 123 eligible patients (mean 55 years, 54% male), the median follow-up time was 24.5 months during which 33 (27%) patients recurred. Of 13 patients with isolated nodal recurrence, three were detected by ultrasound alone, five were detect by CT alone, and five were detected by both CT and ultrasound (Table). 90 (73%) patients in the cohort received adjuvant therapy (92% anti-PD1, 6% BRAF/MEK, 2% anti-CTLA4). The main reasons for exclusion of adjuvant systemic therapy were minimal nodal disease or patient refusal. The average time to recurrence was 13.4 months. There were no significant differences in recurrence rates (p = 0.49) or location of initial recurrence (p = 0.64) by receipt of adjuvant therapy. 29 (24%) patients missed more than one ultrasound. Ultrasound surveillance was most frequently missed due to clinician omittance or patient distance to clinic. Conclusions: In our cohort of SLN-positive melanoma patients, the majority received adjuvant anti-PD1 immunotherapy and were followed in surveillance without CLND. There was no significant difference in recurrence patterns based on receipt of adjuvant therapy and a quarter of nodal recurrences were detected by ultrasound alone. Our results support the use of ultrasound surveillance in addition to cross-sectional imaging to monitor for recurrence in these high-risk patients.[Table: see text]
VEGFR-C mutation serves as a potential negative predictor for immunotherapy in metastatic melanoma.
Authors: Du Zhenguang , He Qianru , Xing Xiaodan , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang 
Published: June 2022

e21593 Background: Immune checkpoint blockade has shown significant promise as an anticancer treatment and anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. Vascular endothelial growth factor-C (VEGF-C), a member of the VEGF gene family, has been characterised as a prime mediator of lymphangiogenesis and angiogenic growth factors that promote the growth and metastasis of neoplasms. Previous studies provided evidence that VEGF-C correlated with poorer survival in melanoma. We aimed to determine the association of VEGF-C mutations with melanoma survival to immune checkpoint inhibitors (ICI). Methods: Data from Allen study (n = 110, anti- CTLA-4 therapy) was obtained and analyzed. Meanwhile, we extracted skin cutaneous melanoma (SKCM) RNA data from The Cancer Genome Atlas (TCGA). In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm, the relative proportions of 22 types of infiltrating immune cells were determined in TCGA cohort. Results: In Allen cohort, the frequency of VEGFR-C mutation was 5.45% (6 in 110). Meanwhile, the frequency of VEGFR-C mutation in TCGA cohort was 7.37% (33 in 448). VEGFR-C-mutant (VEGFR-C-mut) group showed a poorer progression-free survival (PFS) (HR, 2.34; 95%CI, 1.01 to 5.4, p = 0.041) and overall survival (OS) (HR, 2.84, 95%CI, 1.22 to 6.62, p = 0.012) than the VEGFR-C-wild (VEGFR-C-wt) group, based on results of the log-rank test and Kaplan-Meier analysis. Moreover, COX proportional hazards model analysis showed VEGFR-C mutation was associated with poorer PFS (HR, 2.54; 95%CI, 1.04-6.25, p = 0.0042;) and OS (HR, 3.25; 95%CI, 1.30-8.12, p = 0.0117) compared with VEGFR-C-wt. In addition, we identified that the levels of naive B cells and resting CD4+ memory T cells were more abundant in VEGFR-C-mut group according to CIBERSORT algorithm. Conclusions: In our study, the frequency of VEGFR-C mutation in melanoma was investigated in Allen and TCGA cohorts, which might provide useful information to guide precision medicine. VEGFR-C mutation may serve as a potential negative predictor of response to anti-CTL4 treatment in melanoma via higher levels of naive B cells and resting CD4+ memory T cells.
AYA rhabdomyosarcoma: Evolving changes in regional service delivery impacting on outcomes and meningeal disease.
Authors: Hatcher Helen , Wong Han , Harrington Jenny , Prewett Sarah , Horan Gail 
Published: June 2022

e22006 Background: Rhabdomyosarcoma (RMS) is a rare and aggressive sarcoma with a variable prognosis dependent upon age, histology, PAX-FOXO1 translocation status, site, stage of disease and treatment. RMS has a peak age of incidence in adolescents and young adults (AYA). Centralisation of care in the UK has impacted on treatments given and outcome. With extended outcomes in an age associated with poor prognosis we have seen increased rates of meningeal disease as a late event. We examined factors predisposing to meningeal involvement and associated outcomes in changing treatments. Methods: Retrospective review of AYA with RMS, treated between 2004 and 2022 at a regional AYA center serving a population of 2.5 million. Results: 17 patients (9 males, 8 females) were identified (median age 18). At diagnosis, 5 patients had locally advanced disease and 11 had metastases. Meningeal disease developed in 11/17 after a median of 11 months (range 6-87) from diagnosis. Overall survival was 14 months (range 14-87) for those who developed meningeal disease versus 54 months (range 6-167, not reached in 3) in those who did not. Following meningeal involvement, survival ranged from 0-7+ months. Histology of those with meningeal disease: embryonal (5) alveolar (6). 5/6 patients with alveolar RMS (ARMS) had FOXO1 gene rearrangement. Presentation of meningeal disease included: headaches (7), visual phenomena (3), nausea/vomiting (2), unusual chest or back pain (5). Risk factors included bone marrow infiltration (2/2), para-meningeal/orbital primary (4/4), and widespread metastatic or locally advanced primary disease 10/11. 10/11 received treatment with radiotherapy and/or chemotherapy with symptomatic benefit. Conclusions: Meningeal disease in RMS occurs more frequently in those with a primary close to the brain and with bone marrow involvement. Site and extent of primary disease was more predictive than histology for meningeal disease, but not of survival. Adaptation to longer initial treatments with maintenance therapy has increased survival in AYA RMS. Early recognition of key warning symptoms is important to guide prognostication and symptom control.