bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter, randomized, phase II trial of anlotinib plus docetaxel versus docetaxel in EGFR-negative NSCLC patients after progression on first-line platinum-base chemotherapy: ALTER-L018.
Authors: Wu Lin , Wu Zhijun , Xiao Zemin , Ma Zhongsha , Weng Jie , Chen Yanhua , Cao Yongqing , Cao Peiguo , Xiao Maoliang , Zhang Hui , Duan Huaxin , Wang Qianzhi , Li Jia , Xu Yan , Pu Xingxiang , Li Kang 
Published: June 2021

e21186 Background: Docetaxel is one of the standard second-line treatments for advanced non-small cell lung cancer (NSCLC), but the effect is limited. The combination of docetaxel and antiangiogenic drug (ramucirumab/nintedanib) has demonstrated antitumor activity as second-line therapy in advanced NSCLC. Anlotinib, an oral multi-target angiogenesis TKI targeting the VEGFR, FGFR, PDGFR and c-Kit, can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial (ALTER0303). We conducted ALTER-L018 to evaluate improvement of the efficacy and safety of anlotinib plus docetaxel in EGFR-negative refractory advanced NSCLC. Methods: ALTER-L018 (NCT03624309) is an ongoing, open-label, multicenter, randomized, controlled comparative, phase II trial, which was performed at 10 sites in China. Eligible EGFR-negative NSCLC patients (pts), who has been assessed progression after first-line platinum-based chemotherapy (combined with or without Immune checkpoint inhibitors), were randomly assigned (in a 1:1 ratio) to group A (anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B (docetaxel: 75mg/m2 Q3W). The primary end point was PFS, and secondary end points included OS, ORR, DCR and safety. Results: Between Jan 14, 2019, and Feb 7, 2021, 73 patients (pts.) were enrolled and 8 pts. were excluded from the safety and efficacy analysis set (n = 65) due to inclusion violations. 65 pts characteristics (28 pts in group A / 37 pts in group B): median age: 55(40-71)/57(39-74); male: 82% / 78%; non-squamous NSCLC: 75% / 65%; Immunotherapy in the front line: 18% / 22%. Median PFS were 4.03 months (95%CI: 2.98-5.08) in group A and 1.7 months (95%CI: 0.45-2.95) in group B (HR 0.40; 95% CI :0.21-0.77; p = 0.004); In group A and B, ORR and DCR were 32.14% versus 8.11%(p = 0.042), 82.12% versus 54.05%(p = 0.29), respectively. The adverse events that possibly or definitely related to therapy occurred in 26 (93%) of pts. experienced total of 52 grade 1-2 adverse events in group A, and in 25 (68%) of pts. experienced total of 25 grade 1-2 adverse events in group B. The most common grade ≥3 TRAE were leukopenia (5, 18%), neutropenia (5, 18%) and thrombocytopenia (3, 11%) in group A, and leukopenia (3, 8%), neutropenia (2, 5%) and thrombocytopenia (1, 3%) in group B. Conclusions: This combination of anlotinib and docetaxel showed clinical benefit in EGFR-negative NSCLC patients in terms of PFS, ORR, and with manageable safety profile. It is a viable option for relapsed NSCLC, who has been assessed progression on first-line platinum-base chemotherapy combined with/without Immune checkpoint inhibitors, or who can’t tolerate Immunotherapy. Clinical trial information: NCT03624309.
PREX2 mutation serves as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma.
Authors: Cai Lifang , Chen Dongsheng , Zhang Qin , Duan Qianqian , Liu Yaqin , Li Si , Xiao Mingzhe 
Published: June 2021

e21504 Background: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes. Previous work suggested that PREX2 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of function in melanoma is needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples (including 122 melanoma) from different patients, and the public database of TACG was also compared. Data from Snyder-64 study (n = 64, anti- CTLA-4 therapy) was retrieved and analysed. 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. Results: In clinical cohort, the frequency of PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 5.94 % (211 in 3547). Meanwhile, the frequency of PREX2 mutation in TCGA cohort was 5.06 % (555 in 10953). In melanoma datebase, the frequency of PREX2 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 6.55 % (78 in 122). Meanwhile, the frequency of PREX2 mutation in melanoma in TCGA cohort was 25.56 % (113 in 422). We further analyzed Kaplan-Meier curves from Snyder-64 study (n = 64, anti- CTLA-4 therapy). In Snyder-64 study melanoma cohort, mutation of PREX2 was associated with higher neoantigen load (P = 0.02) and higher mutation count (P = 0.0027) in melanoma. PREX2 mutation was associated with prolonged overall survival (OS) trend compared with PREX2 wt in melanoma cohort (P = 0.09). Conclusions: In our study, the frequency of PREX2 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. PREX2 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating neoantigen load and mutation count.
Analysis of demographics and outcomes of surgical resection in the CNS of patients with melanoma.
Authors: Guddati Achuta Kumar , Komiya Takefumi , Hector Picon , Krutchik Allan N. , Kumar Gagan 
Published: June 2021

e21534 Background: Patients with melanoma frequently develop central nervous system metastases. Oligometastatic disease is often treated either by surgical resection or by stereotactic radiotherapy. This study investigates the trends and clinical outcomes of patients with melanoma who have undergone surgical procedures on the central nervous system during their hospitalization. Methods: A retrospective cohort study was performed based on admissions of adult patients who underwent craniectomy/surgical resection for metastatic melanoma from 2002 -2014 using the Nationwide Inpatient Sample database. The primary outcome measure was all-cause in-hospital mortality. Secondary outcomes included length of hospital stay(LOS) and discharge disposition (home/home with health care and skilled nursing facilities/long term acute care (SNF/LTAC)). Factors associated with in-hospital mortality were examined by multivariable logistic regression. We adjusted for patient and hospital characteristics, payer, and comorbid conditions. We also examined trends of mortality for the study years. P was kept at 0.05. Results: There were an estimated 5972 discharges of patients with melanoma undergoing craniectomy/surgical resection during the study period. Patients undergoing surgical interventions were typically males (69%) and whites (79%). 98% of procedures were performed at teaching hospitals. Unadjusted all-cause in-hospital mortality was 3.1%. There was no significant difference in mortality over 13 years. Age, gender, and race were not associated with increased in-hospital mortality. Median LOS was 5 days (IQR 3-9 days). LOS was longer in elderly and those with higher Charlson co-morbid index. Of the survivors, 76% were discharged to home or with home healthcare while 24% were discharged to SNF/LTAC. Patients with age > 65 (OR 2.9; 95%CI 2.2-3.9, p < 0.001) and those with higher Charlson co-morbid index (OR 1.2; 95%CI 1.1-1.3) had higher odds for being discharged to SNF/LTAC. Conclusions: Patients who undergo craniectomy/surgical resection for melanoma have a low in-hospital mortality rate. One quarter of patients are discharged to SNF/LTAC.
Proteomics meets transcriptomics: Identification of tumor tissue signatures specific to anti-PD1 treatment in late-stage melanoma patients.
Authors: Sklodowski Kamil , Mallardo Domenico , Vowinckel Jakob , Capone Mariaelena , Soste Martin , Madonna Gabriele , Vanella Vito , Warren Sarah , Ascierto Paolo Antonio 
Published: June 2021

e21543 Background: Despite advances of anti-PD1 treatment in melanoma, still large subset of patients does not respond or relapses due to primary or acquired resistance. One potential way to overcome the mechanisms of resistance is to identify molecular signatures associated with response to treatment. Here, we are presenting the results of an integrated deep transcriptomic and proteomic analysis of melanoma tissue samples coming from patients prior the treatment with anti-PD1. The combination of targeted transcriptomic approach with unbiased proteomic approach allowed for identification of a molecular response signature specific to anti-PD1 therapy. Methods: Unbiased quantification of proteins in tumor tissues was done using data-independent acquisition (DIA) LC-MS technology. Proteins from tissue samples were denatured, digested, and analyzed on a mass spectrometer. A deep spectral library was generated, and proteins were quantified using Spectronaut software (Biognosys). From the same tumor tissue RNA was extracted and subjected to transcriptomic analysis with NanoString nCounter using the PanCancer IO 360 panel. Integration analysis using latent components, a generalized PLS and sparse sGCCA method implemented in R mixOmics package was used for signature discovery. Results: Studied cohort was balanced for gender, BRAF mutations and stage. Treatment included Nivolumab or Pembrolizumab. Only among responding subjects, low grade (≤ 2) skin toxicity was identified at a significant level (p-value < 0.05). In total, 22 samples were measured (nine non-responders and 13 responders). Overall, the analysis of proteome across all samples resulted in 8548 proteins being identified and quantified. The IO 360 panel contained 770 targets. In combined analysis, 10 mRNA targets together with 64 protein targets were highly associated with response to treatment. Two top candidates identified for mRNA and proteins were SIGLEC5 and ACP6 respectively. The panel of 74 features was sufficient to separate all subjects using unsupervised hierarchical clustering into to two main clusters enriched for responders and non-responders (p-value < 0.05). String-DB analysis revealed numerous interactions and associations within identified panel. Functional analysis using GO enrichment showed major involvement of the selected mRNA and proteins in T-cell regulation as well as in neutrophil degranulation and antigen receptor mediated signaling. Conclusions: Combination of both omics assays provides a very comprehensive image of tumor tissue responses to anti-PD1 treatment in late-stage melanoma patients. Identified candidates show striking changes in responder and non-responder groups and should undergo further validation for use in precision medicine.
Impact of immunotherapy on survival differences in patients with melanoma and chronic lymphocytic leukemia.
Authors: Tripathi Raghav , Bordeaux Jeremy S. , Rothermel Luke , Mangla Ankit 
Published: June 2021

e21550 Background: Chronic lymphocytic leukemia (CLL) is well known to be associated with secondary malignancies like melanoma. Patients with melanoma and CLL are known to have poorer prognosis compared to patients without CLL. Checkpoint inhibitors (CPI) started gaining traction in 2011 after ipilimumab approval and are widely used in treatment of advanced melanoma. The objective of this study is to determine the survival of patients with melanoma and CLL in the era of CPI (2011 onwards) compared to previous years. Methods: We identified patients with melanoma and CLL reported to the Surveillance, Epidemiology, and End Results (SEER-18) program. We created cohorts of patients with melanoma and CLL vs. melanoma without CLL and split the cohorts into patients diagnosed from 2000-2010 and 2011-2017 to evaluate the impact of immunotherapy on overall all-cause survival. Kaplain-Meier survival curves were created for each of the four cohorts using the Ederer/direct-adjusted survival method. Standard Cox regression models adjusted for age and sex used to compare survival between subgroups. Two-sided p-values < 0.05 were considered significant. Results: From 2000-2017, 536,264 patients with melanoma were included in this study. 2,945 [0.55%] patients had coexisting CLL. Most patients were male (303,477 [56.6%]), age 60-79 (235,833 [44.0%]), non-Hispanic white (499,151 [93.08%]), and diagnosed from 2000-2010 (285,292 [53.2%]) with melanoma of the trunk (156,722 [29.2%]). From 2000-2010, patients with melanoma had an average survival of 91.4 months (95% CI 88.7-94.1) and those with coexisting CLL had an average survival of 59.3 months (95% CI 58.1-60.6). From 2011-2017, patients with melanoma had an average survival of 129.1 months (95% CI 127.7-130.5) and those with coexisting CLL had an average survival of 116.0 months (95% CI 113.5-118.5). The difference in survival in patients with melanoma vs. melanoma and CLL in 2000-2010 (32.1 months) is significantly greater than that of patients from 2011-2017 (13.1 months, p < 0.05). Conclusions: Although CLL continues to confer a survival disadvantage in patients with melanoma, the survival of patients with CLL and melanoma is better in the CPI-era. We also demonstrate that in the CPI era the gap between the survival of patients with melanoma and CLL and melanoma alone is also reducing significantly.
Modified operations to permit safe and timely delivery of essential surgical care for high-risk skin cancer during a pandemic.
Authors: Jackson Cullison Stephanie Renae , Celen Arda , Doudican Nicole Adell , Stevenson Mary , Carucci John A. 
Published: June 2021

e21565 Background: Many surgical practices closed at the onset of the COVID-19 pandemic raising concerns that delayed cancer care might impact patient outcomes. We implemented operational changes to safely remain open and treat tumors with potential to threaten life or function. We studied the impact of these changes on safety, access, and treatment. Methods: A single-center retrospective study was conducted in an academic office-based dermatologic surgery practice. All patients consented to research. “Pre-pandemic” (Nov. 2019 – March 21, 2020) consultations served as controls. Consultations during the “pause” (March 22 - June 8, 2020) and “reopening” (June 9 – Sept. 30, 2020) were evaluated for time to treatment, tumor area, and upstaging. One-way ANOVA or Fisher Exact analyses were performed with P < 0.05 significant. Operational changes included (1) modified scheduling, staffing, and rooming; (2) COVID-19 symptom screening; (3) N95 masks and shields for patient contact; (4) triage by tumor acuity; (5) same day or video consultation; and (6) increased utilization of same day biopsy and surgery for suspicious lesions. Results: Data from 698 patients (23-103 yrs of age, avg 71 yrs) yielded 876 tumors treated by Mohs surgery (n = 776), standard excision (n = 73), staged excision (n = 14) or electrodessication and curettage (n = 13). The average time from biopsy or consultation to treatment was faster during the pause and reopening relative to pre-pandemic (Table). More frozen section diagnostic biopsies were performed in the pause (n = 6) and reopening (n = 4) compared to pre-pandemic (n = 0). Post-operative defects were similar to pre-pandemic sizes (3.2 cm2) during the pause (3.9 cm2) and reopening (3.2 cm2) (p = 0.72). A reduction in treatment of basal cell carcinoma (BCC, Χ2= 0.04) and shift toward treatment of higher risk tumors such as cutaneous squamous cell carcinoma (SCC, 49% of tumors during pause vs 37% pre-pandemic) and melanoma (11% pause vs 4.7% pre-pandemic) was noted. The percentage of SCC upstaged after treatment increased during the pause (42%, Χ2= 0.02) vs pre-pandemic (18.5%) or reopening (17.4%). Conclusions: Time to treatment, tumor size, and SCC upstaging pre-pandemic and during the reopening fail to identify any significant access interruptions. This likely reflects practice modifications of increased same day surgery, frozen section diagnostic biopsy, and tumor triage. Lack of COVID-19 transmission attributable to maintained operations suggests that essential surgical care can be delivered safely to patients with high-risk skin cancers during a pandemic.[Table: see text]
Aminergic status in the brain of urokinase gene-deficient mice with malignant tumors growing in presence of chronic neurogenic pain.
Authors: Pogorelova Yulia A. , Kaplieva Irina V. , Frantsiyants Elena M. , Surikova Ekaterina I. , Bandovkina Valeria A. , Neskubina Irina V. , Cheryarina Natalia D. , Shalashnaya Elena V. , Kachesova Polina S. , Nemashkalova Ludmila A. , Kit Oleg I. , Pozdnyakova Viktoria V. 
Published: June 2021

e21582 Background: The fibrinolytic system of the brain is important for its normal functioning and participation in processes that are significant in various stressful influences, including tumor growth and chronic neurogenic pain (CNP). These pathological conditions change the activity of the brain neurotransmitter system. On the other hand, urokinase deficiency is associated with significant inhibition of tumor growth, while CNP – with its stimulation. The purpose of the study was to analyze the effect of CNP on the levels of biogenic amines in the brain of mice with urokinase deficiency (uPA-/-) with transplanted B16/F10 melanoma. Methods: The study included male and female mice: С57ВL/6 (uPA+/+, n = 48) and C57BL/6-Plautm1.1Bug-ThisPlauGFDhu/GFDhu (urokinase gene-knockout - uPA-/-, n = 48). Mouse strains were divided into subgroups (each n = 6): intact; with CNP (bilateral sciatic nerve ligation); 21 days after subcutaneous transplantation of B16/F10 melanoma; 21 days of B16/F10 melanoma growth in presence of CNP (B16/F10+CNP), with tumor transplantation 2 weeks after the sciatic nerve ligation. Levels of adrenaline (A), noradrenaline (NA), dopamine (DA), histamine, serotonin (5HT), and 5-hydroxyindoleacetic acid (5OHIA) were determined in the brain by ELISA (Cusabio, China). Statistical processing - Statistica 10.0. Results: Levels of NA, DA and 5HT in the brain of intact uPA-/- mice were 3.5, 2.1 and 1.9 times higher (p < 0.05), respectively, than in intact uPA+/+ animals, while histamine and 5OHIA were on average 2.0 times lower. The dynamics of cerebral levels of biogenic amines in uPA-/- mice with pathological factors, alone or combined, had practically no gender specificity, with rare exceptions. So, 5HT levels increased up to 4.5 times in uPA-/- mice of both sexes in response to CNP or B16/F10 growth. Melanoma growth in presence of CNP, on the contrary, decreased 5HT by 3-10 times and DA by 1.6 times (p < 0.05) both in males and females, and decreased NA by 1.6 times (p < 0.05) in females. Conclusions: CNP together with melanoma inhibits the initial activation of the HA-, DA- and 5HT-ergic systems in the brain of uPA-/- mice, which may be an important pathogenetic mechanism of the cancellation of genetically determined inhibition of subcutaneous B16/F10 melanoma growth in urokinase deficiency.
Suppression of tumor development by another tumor in primary immunodeficiency in experiment.
Authors: Surikova Ekaterina I. , Frantsiyants Elena M. , Kaplieva Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Neskubina Irina V. , Kotieva Inga Movlievna , Shumarin Konstantin A. , Zhukova Galina V. 
Published: June 2021

e21583 Background: Multiple primary malignant tumors (MPMTs) are characterized by the presence of several primary neoplasms in one patient. The purpose of the study was to create an experimental model of MPMTs with one dominating tumor. Methods: The study included 21 female BALB/c Nude mice. The main group included mice with simultaneous subcutaneous inoculation of tumors: Guerin's carcinoma (0.5 million tumor cells in 0.5 ml of saline solution) under the right scapula and B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline solution) under the left scapula. Control groups included females with melanoma or carcinoma inoculated at the same dosage and volume as in the main group. Results: In a MPMT model, tumors appeared 3 times faster than in controls and demonstrated larger volumes: melanoma – by 7.5 times, carcinoma – by 2.2 times; the survival of mice with MPMTs decreased. Carcinoma in a MPMT model metastasized to melanoma and almost completely suppressed its growth. Melanoma was represented by a small “island” of tumor tissue 3-4 mm in diameter and was located just under the skin at the site of injection of melanoma cells. The light part of the same loose pasty consistency as the dark part, with a diameter of 6-7 mm, was located around the dark “center” of melanoma. The rest part of the tumor located under the left scapula looked like an elongated grayish-pink node of a dense elastic consistency - just like the tumor located under the right scapula, which was much larger in volume. The right and left tumors did not merge with each other; there was a small distance of about 2-3 mm between them. A small lesion of caseous necrosis, 6–7 mm in diameter, was recorded in the center of the right tumor node of Guerin's carcinoma; there was no necrosis in the left tumor. Smaller size, the absence of necrosis and visually more “young” carcinoma tissue on the left indicated its later appearance than that on the right, which, in combination with the remnants of melanoma fused to the left tumor and the absence of “contact” between the left tumor and the right one, indicated the metastatic nature of Guerin’s carcinoma on the left. B16/F10 melanoma did not metastasize. Conclusions: In simultaneous subcutaneous inoculation of murine B16/F10 melanoma and rat Guerin’s carcinoma to female BALB/c Nude mice, carcinoma cells metastasized to melanoma and suppressed its growth.