bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular profiling by NGS upon progression disease in advanced stage NSCLC patients.
Authors: Serna Roberto , Sanchez Alfredo , De Julian Maria , García Girón Carlos , Domine Manuel , Blasco Ana , Sanchez Torres Jose Miguel , Oramas Juana , Bosch-Barrera Joaquim , Sala Maria Angeles , Sereno Maria , Ortega Ana Laura , Chara Velarde Luis Enrique , Hernandez Berta , Padilla Airam , Coves Juan , Jantus Lewintre Eloisa , Molina-Vila Miguel Angel , Romero Atocha , Provencio-Pulla Mariano 
Published: June 2021

e21196 Background: Non-small cells lung cancer (NSCLC) patients treated with Tyrosine Kinase Inhibitors (TKI) at first-line ultimately develop disease progression after 10 to 14 months. Mechanisms underlying TKI-resistance are not complete understood. Tumor re-biopsy is often unfeasible for NSCLC patients and liquid biopsy is a suitable alternative in identify mechanism by which tumors progress. Methods: 113 plasma samples were collected from advanced stage EGFR positive NSCLC patients upon disease progression according to RECIST V1.1. cfDNA NGS profiling was carried out using the Oncomine™ Pan-Cancer Cell-Free Assay and sequenced on an Ion GeneStudio S5 Plus System. Variant calling and annotation were performed with Torrent Suite and Ion Reporter (v5.16) software, respectively. In addition, we developed a bioinformatic pipeline, using RStudio for variant filtering. Results: Overall, 344 somatic variants were detected with an average number of variants per patient of 2.32 and a median Mutant Allele Frequency (MAF) of 0.83%. Most mutated genes were EGFR (63.72%), TP53 (60.18%), APC (16.81%), MAP2K1 (11.50%), PIK3CA (10.62%), FGFR3 (7.08%), KRAS (7.08%) and BRAF (6.19%). As expected, SNPs were the most frequent mutation type (72.67%), following by INDELs (24.41%) and CNVs (2.91%). We found high co-occurrence between MYC-GNA11, MYC-CCND2, HRAS-AR and EGFR-TP53 genes using Jaccard’s score (0.5, 0.5, 0.5 and 0.46, respectively). Within EGFR-mutated patients, 40% had T790M resistance mutation. Finally, we found KRAS mutations and missense PIK3CA mutations were mutually exclusive. Conclusions: Molecular profiling of liquid biopsies collected upon disease progression using NGS help to identify molecular mechanisms underlying treatment failure.
Prognostic value of systemic inflammatory markers in first- and subsequent-line immunotherapy and durability of response in NSCLC.
Authors: Basher Fahmin , Saravia Diana , Lopes Gilberto 
Published: June 2021

e21210 Background: Treatment of advanced non-small cell lung cancer with immune checkpoint inhibitors (ICI) has been shown to yield durable responses. High neutrophil-to-lymphocyte ratios (NLR), low lymphocyte-to-monocyte ratios (LMR) and high platelet-to-lymphocyte ratios (PLRs) have been used as surrogates for increased levels of inflammation in the tumor microenvironment that can predict cancer progression and response to therapy. However, the comparative prognostic role of these markers account for when immunotherapy is utilized has not been explicitly determined. Methods: We performed a retrospective review of 233 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who received ICI either as first-line (1L) or second-line (2L) therapy and for whom laboratory data, in particular absolute neutrophil, lymphocyte, monocyte, and platelet counts, were available pre-treatment and 4 weeks after initiation of immunotherapy. Results: Using receiver operating characteristic (ROC) curves, we identified cutoff values with optimal prognostic value for NLR (4), LMR (2), and PLR (200). Median age, histology, and smoking history were equivalent across each group. Improved OS was observed in our cohort for patients in which pre-treatment NLR < 4 (54.4m vs. 35.9m, p = 0.0069), LMR > 2 (54.4m vs. 32.3m, p = 0.0016), and PLR < 200 (54.4m vs. 27.5m, p = 0.0007), while PFS was unaffected when looking strictly at these cutoffs. We then observed that PFS could be better predicted after stratifying NLR, LMR, or PLR when taking into account whether ICI was administered as 1L or 2L. We also determined that changes in (Δ) NLR or LMR (but not PLR) by at least 20% between baseline and 4 weeks after initiation of ICI could predict duration of response to ICI. Conclusions: In conclusion, the NLR, LMR, and PLR are powerful surrogates for the tumor microenvironment and can predict responses to ICI in advanced NSCLC when used in the context of previous lines of therapy and subsequent pro-inflammatory changes. Our study shows that ICI used in the first-line setting results in more durable responses, and can overcome an unfavorable tumor microenvironment. In addition, we demonstrate that in NSCLC, durability of responses can be predicted by changes in these systemic inflammatory response markers early after the initiation of ICI.[Table: see text]
The efficacy and safety analysis of PD-1 inhibitor combined with interferon-α1b: A real-world study in Chinese metastatic melanoma patients.
Authors: Zhu Guannan , Shi Qiong , Li Chunying , Gao Tianwen 
Published: June 2021

e21507 Background: Clinical data on PD-1 inhibitor combined with interferon in metastatic melanoma treatment were still limited. The objective of this study was to assess the efficacy and safety of PD-1 inhibitor/interferon-α1b combination therapy for Chinese metastatic melanoma patients in the real world. Methods: We reviewed patients diagnosed as metastatic melanoma and had received PD-1 inhibitor (pembrolizumab, 2 mg/kg, every 3 weeks, intravenously or toripalimab 240mg every 2 weeks, intravenously) combined with interferon-α1b(10μg/kg, every other day, subcutaneously) in Xijing Hospital from Dec 2018 to Nov 2020. Efficacy and safety profiles were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 5.0, respectively. Results: In total 65 patients were reviewed in this study, including 13 cases with ECOG performance status ≥2. Acral and mucosal cases accounted for 47.7% and 23.1% respectively. In 27(41.5%) patients, the combination therapy was used as the first line treatment, whereas in the rest 38 patients as second or subsequent lines. The median follow-up period was 8 months (1.5-21 months). Median OS was 15 months (95CI%: 10.62-19.38 months). Median PFS was 6 months (95CI%: 2.54-9.46 months). 6-month and 1-year PFS rate were 48.1% and 35.3%. 6-month and 1-year OS rate were 80.9% and 59.8%. Objective response was seen in 18.46% cases, with 12.31% of patients exhibiting ongoing response. The best confirmed disease control rate was 73.85%. Multivariate analysis demonstrated that overall survival was significantly associated with ECOG performance status ≥2 (OR=3.32，95%CI=1.14-9.66 ), regardless of age(≥65), elevated LDH, PD-1 inhibitor type and the line of the combination therapy. Select treatment related AEs (TRAEs) of any grade were observed in 57(87.69%) patients. The leading 3 TRAEs were lymphopenia, fatigue and fever. Grade 3 to 4 TRAEs were recorded in 2 cases. Grade 4 hyponeutrophilia occurred in a patient with ECOG status 3 using interferon-α1b plus toripalimab and resulted in discontinuation of both PD-1 inhibitor and IFN-α1b. Grade 3 headache was reported by one patient using interferon-α1b plus pembrolizumab and was solved with celecoxib 200mg daily. No drug-related deaths were reported. Conclusions: PD-1 inhibitor combining interferon-α1b therapy shows promising efficacy and acceptable toxicity in this real-world cohort of Chinese metastatic melanoma patients.[Table: see text]
Is radiation necrosis in radiated melanoma brain metastasis increasing because immunotherapy is contributing to this or are patients just living longer?
Authors: Buchbinder Elizabeth Iannotti , Shi Diana D. , Pfaff Kathleen L. , Manos Michael P. , Ouyang Olivia , Liu David , Rodig Scott J. , Aizer Ayal 
Published: June 2021

e21518 Background: The use of immune checkpoint inhibitors, particularly combination ipilimumab and nivolumab, has drastically changed the management of patients with melanoma brain metastasis. Select patients also benefit from brain-directed stereotactic radiation. Radiation necrosis is a risk associated with stereotactic radiation that oncologists have been observing more frequently in the era of immunotherapy. Methods: Patients were identified who had a history of metastatic melanoma treated with stereotactic brain radiation who subsequently developed radiation necrosis. Brain tissue from those patients with a subsequent resection of their radiation necrosis was obtained and examined for immune infiltrate and other factors. The tissue obtained was evaluated by blinded pathologists who graded % viable tissue, % necrosis, % tumor and % fibrosis. In addition, they graded inflammation on a scale of 1-3. Results: Seven patients were identified who had surgery for radiation necrosis following radiation to melanoma brain metastasis. Tissue was available for five patients. Two patients had received no prior immunotherapy, one patient had received ipilimumab and two patients received combination ipilimumab and nivolumab. The samples obtained consisted of almost entirely viable brain tissue or necrosis. There was minimal inflammation seen in all patients’ samples including those who had not received immunotherapy and those who had. Conclusions: Radiation necrosis in patients on immunotherapy who receive brain-directed stereotactic radiation is a rising problem. On pathologic evaluation increased immune infiltrate is not observed in patients on immunotherapy with radiation necrosis compared to those who never received immunotherapy. This suggests that the increased rates of radiation necrosis may be more likely associated with longer survival as opposed to a direct causative effect from the immunotherapy although with our limited sample size this will need further exploration.[Table: see text]
Robust prediction of response to immunotherapy in a mixed cohort of previously treated and immunotherapy-naive melanoma patients.
Authors: Abbott Charles , McDaniel Lee , Pyke Rachel , Levy Eric , Navarro Fabio , Zhang Simo V. , Wang Jing , McClory Rena , Snyder Michael , Jang Sekwon , Boyle Sean Michael , Chen Richard 
Published: June 2021

e21548 Background: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers. Methods: Pre-treatment samples from 51 unresectable, stage III/IV melanoma patients who underwent anti-PD-1 therapy were characterized to assess factors influencing response. RECIST criteria were used to evaluate tumor response to therapy, with a median follow-up of 24 months. For each patient, a single paired FFPE tumor and normal blood sample was collected and profiled using Personalis’ ImmunoID NeXT Platform; an augmented exome/transcriptome platform and analysis pipeline which produces comprehensive tumor mutation information, gene expression profiling, neoantigen characterization, HLA typing and LOH, TCR repertoire profiling, and tumor microenvironment profiling. These data were then integrated to form a composite neoantigen presentation score (NEOPS) for each patient. Results: We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. Neoantigen burden score (NBS) was derived from SHERPA, our exome and transcriptome integrative neoantigen prediction model. We found that NBS more significantly stratified responders and non-responders (P = 0.016) than TMB alone (P = 0.049). A broader score, NEOPS, incorporated DASH, to capture HLA allele-specific loss of heterozygosity and additional antigen presenting machinery resistance mechanisms. NEOPS consequently demonstrated a stronger association with response (p = 0.002). We used area under the curve (AUC) to benchmark NEOPS performance against established mutational and transcriptomic predictive models, demonstrating the model was more predictive of response in both the treatment naive setting, as well as in a mixed cohort of treatment-naive and experienced patients. These findings were confirmed in an independent cohort of patients (n = 110), suggesting that NEOPS is a robust, novel biomarker of ICB response in melanoma. Conclusions: Given the complex nature of resistance to immunotherapy, as well as potential toxicities associated with treatment, there is a need for biomarkers that can more accurately predict response. Here we demonstrate that NEOPS can significantly improve stratification of patient response. We also demonstrate that data intensive biomarkers like NEOPS can be clinically practical, with comprehensive tumor profiling in our clinical cohort achieved using very limited tumor tissue.
Multiple primary melanoma in association with other personal and family history of cancers.
Authors: Yang Xi , Karapetyan Lilit , Bo Na , Wang Hong , Sander Cindy , Kirkwood John M. 
Published: June 2021

e21559 Background: Patients (PTs) with cutaneous melanoma are at increased risk of developing second primary melanoma and non-melanoma skin cancers. The primary aim of this study was to define the association between MPM and personal history of non-melanoma skin cancers and other non-skin cancers. The secondary aim was to evaluate the association between MPM and the presence of other cancers among first-degree relatives (FDRs). Methods: We performed a retrospective case-control study including cases with MPM and controls with single primary melanoma (SPM) from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The proportions and percentages of non-melanoma skin cancer, other non-skin cancer, 1st degree family history of melanoma, and 1st degree family history of other non-melanoma cancers were calculated separately for MPM and SPM groups. Fisher’s exact tests were performed to test whether MPM was associated with these variables. For each significant variable, a multivariable logistic regression model was used to test its association with MPM after adjusting for age, gender, melanoma staging, and smoking status. Results: In total, 311 PTs (39.2% men; median age at initial diagnosis 51years) were enrolled, including 194 with SPM (38.6%; 51) and 117 with MPM (39.8%; 48). 28 (9%) of PTs had squamous cell carcinoma (SCC), and 63 (20%) had basal cell carcinoma (BCC). The most common non-skin cancers in the whole cohort were prostate (4.8%), breast (3.8%), hematological (1.9%), colorectal (1.3%), and cervical cancers (1.3%). FDR history of melanoma, non-melanoma skin cancer, and other cancers were positive in 15.4%, 7.1% and 46.3% PTs, respectively. The most common non-skin cancers in FDRs were breast, prostate, lung, colorectal and hematological malignancies. In comparison to PTs with SPM, PTs with MPM were more likely to have SCC (14.5% vs 5.7%, p=0.013) but not BCC and other non-skin cancers. FDRs of PTs with MPM had higher prevalence of melanoma (23.1% vs 10.8%, p=0.005), prostate cancer (31.9% vs 5.3%, p=0.0002) but not other non-melanoma skin and non-skin cancers. In multivariate analysis the association remained significant between MPM and SCC (OR 2.7, 95% CI 1.1-6.6, p=0.032), FDR history of melanoma (OR 2.0, 95% CI 1.03-4.1, p=0.042), and FDR history of prostate cancer (OR 5.6, 95% CI 1.6-20.3, p=0.008). Conclusions: MPM is associated with higher prevalence of SCC and FDR history of melanoma and prostate cancer, but not BCC and other non-melanoma cancers in comparison to SPM.
Short-course neoadjuvant intratumoral immunotherapy establishes immunologic memory in murine melanoma.
Authors: Aiken Taylor J. , Komjathy David , Rodriguez Mat , Feils Arika , Gillies Stephen D. , Erbe Amy K. , Rakhmilevich Alexander L. , Sondel Paul M. 
Published: June 2021

e21561 Background: GD2 is disialoganglioside preferentially expressed in neuroblastoma and melanoma and anti-GD2 directed therapies are used clinically in neuroblastoma, with ongoing clinical trials in melanoma. We are currently developing an in situ vaccination approach using intratumoral (IT) delivery of an immunocytokine (IC) consisting of IL-2 linked to an anti-GD2 monoclonal antibody. While IT-IC monotherapy does not cure mice bearing established B78 melanoma tumors, it is effective when combined with local radiation therapy (RT). Here, we tested whether short course IT-IC monotherapy prior to surgical resection could result in a robust adaptive immune response preventing tumor recurrence following rechallenge after surgery. Methods: Mice bearing 50-100mm3 GD2-expressing melanoma (B78) tumors were treated with a 5-day course of 50μg IT-IC and complete surgical resection was performed 3 days following the final treatment. The immune infiltrate of resected tumors was assessed by flow cytometry. Rechallenge experiments consisted of either 2x106 B78 cells injected into the contralateral flank or 2x105 B16-GD2 cells injected via tail vein for pulmonary metastasis rechallenge. Results: IT-IC treated tumors had fewer viable tumor cells, increased CD8 T-cells, and an improved CD8:Treg ratio. Rejection of B78 contralateral flank rechallenge (implanted 40 days following surgical resection of the primary tumor) was observed in 78% (7/9) of mice treated with IT-IC compared to 50% (5/10) that received surgery alone and 0% (0/5) of naïve mice. Immunologic memory was potent in neoadjuvant-treated mice early after surgery, with all mice (5/5) rejecting contralateral B78 rechallenge that occurred on the day of surgery compared to 0% (0/5) in both surgery-alone and naïve mice. Neoadjuvant IT-IC also prevented the development of B16-GD2 lung metastasis compared to naïve mice or the surgery-alone group (when the IV injected experimental metastases were given 80 days following surgery). Conclusions: While ineffective in curing large B78 melanoma flank tumors as monotherapy, mice receiving neoadjuvant IT-IC developed robust immunologic memory preventing recurrence following surgery. The memory response was present as early as the day of surgery and was sufficient to prevent pulmonary metastasis. IT-IC should be further investigated as a neoadjuvant therapy for preventing recurrence in high-risk settings.
Artificial intelligence (AI) comparison of social media-based patient-reported outcomes of PD-1, BRAF, and CTLA-4 inhibitors for melanoma treatment.
Authors: Su Ashley , Jueng Jeremy , Dupuis Léonie , Brooks Ian , Sinha Ritika , Maner Brittany , Dellavalle Robert , Burton Vernon , Solomon James A. 
Published: June 2021

e21572 Background: Due to side effects and adverse psychosocial factors, there can often be a disconnect between clinical impression and the patient perspective of treatment. Melanoma patients frequently use social media to discuss their disease sentiments and outcomes, providing a window into patient insight, otherwise not readily attainable. We analyzed publicly available full text posts on multiple social media platforms concerning melanoma treatments PD-1 inhibitors (pembrolizumab/Keytruda, nivolumab), BRAF inhibitors (dabrafenib, vemurafenib), and CTLA-4 inhibitor (ipilimumab/Yervoy) associated with Patient Global Impression of Change (PGIC) terms to compare and identify patient burden. Methods: Millions (12,599,313) of publicly available online social media text data were extracted and run through Brandwatch Artificial Intelligence-powered database and machine learning algorithm to categorize treatment-specific posts with PGIC terms associated with sentiment. Results: Out of 52,962 posts related to a select list of melanoma treatments, we identified Keytruda (6,080), nivolumab (1,614), dabrafenib (529), vemurafenib (329), and ipilimumab (1715) posts. The top ten types of posts by volume for each treatment were predominantly positive for PGIC terms (improving, well, progress) while being associated with negative emotions (fear and sadness). Patient-perceived better treatments were associated with decrease fear. PD-1 inhibitor Keytruda displayed markedly less fear (56.9%) with a very high positive PGIC (92.3%) in comparison with PD-1 inhibitor nivolumab with decreased positive PGIC (78.0%) and increased fear (81.6%). Likewise, this patten was discovered for the BRAF inhibitors and CTLA-4 inhibitor, albeit less distinct: dabrafenib (positive PGIC 86.4%, fear 71.9%), vemurafenib (positive PGIC 78.0%, 81.6%), ipilimumab (positive PGIC 75.0%, fear 79.3%). Conclusions: Our initial results indicate that despite patients reporting good outcomes from melanoma treatment, they remain fearful. Nonetheless, a trend is identified between patient-perceived better treatment and decreased patient fear. This analysis can help bridge the gap of understanding patient perspective and provides an indication for translation into more effective clinical and pharmaceutical response.
Shave biopsy of pediatric melanocytic tumors compromises staging and therapy planning.
Authors: Daley Jessica , Kirkwood John M. , Seynnaeve Brittani 
Published: June 2021

e21576 Background: Melanoma is the dominant skin cancer of pediatric patients, and accounts for 1-3% of pediatric malignancies. The prognosis for both adults and children with melanoma correlates with stage at diagnosis, and initial Breslow depth is a critical determinant. Kaplan-Meier melanoma-specific survival curves show survival rates ranging from 98% (T1a) to 75% (T4b) at 10 years for adult patients with stage I and II disease at diagnosis. Pediatric patients are known to present with thicker primary melanomas as compared to their adult counterparts. The preferred biopsy method of the American Academy is Dermatology for melanoma is excisional, however partial shave biopsy is most frequently performed in children, given its simplicity, efficiency, and often low clinical suspicion for cutaneous malignancy. Despite the ease of this biopsy technique, shave biopsy has a high rate of base transection, reducing accuracy of microstaging, which is crucial for therapy planning. Methods: Retrospective chart review evaluation of the potential effects of biopsy method on staging, surgical recommendations, and treatment approach for pediatric patients with melanocytic tumors. Results: Data was available for 91 pediatric patients with a spectrum of melanocytic tumors ranging from atypical with unknown malignant potential, to melanoma. Patient characteristics including gender, age at biopsy, biopsy method, status of biopsy margins, recommendations for re-excision, sentinel lymph node biopsy, and treatment plan were collected and analyzed. There were 48 females and 43 males with age range 1—22 years (mean 10 years). Sixty-eight of 91 (75%) tumors had a positive margin (deep, peripheral, or both) on diagnostic biopsy, 52/68 (76.5%) were obtained using shave method. Evaluating the deep margin specifically, 50/91 (55%) tumors had a positive deep margin, 46/50 (92%) of which were obtained using shave method. No tumor evaluated by punch had a positive deep margin (0/18). Of all shave biopsies, 77% had positive deep margin as opposed to only 13% using alternative biopsy methods. In 10/91 (11%) patients, surgical recommendations were changed based on inaccurate microstaging and positive deep biopsy margins, 9/10 (90%) of these patients had undergone shave biopsy. Most (8/10) patients had melanoma, the remaining 2/10 had highly atypical spitzoid tumors in which melanoma could not be ruled out. Conclusions: Pediatric patients with melanocytic tumors most commonly underwent shave biopsy as the initial diagnostic biopsy method. This method of biopsy was associated with higher incidence of positive margins at diagnosis and more aggressive definitive surgical management. These findings suggest that more routine use of excisional biopsy in pediatric patients with lesions being evaluated for malignancy could decrease the incidence of inaccurate microstaging and reduce the need for more aggressive definitive surgical management.