bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuous intravenous infusion Rh-endostatin in combination with dacarbazine and cisplatin as the first-line therapy for metastatic melanoma.
Authors: Cui Chuanliang , LIAN BIN , Wang Xuan , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , Yan Xieqiao , Tang Bixia , Zhou LI , Guo Jun 
Published: May 2019

e21007 Background: Immunotherapy and targeted therapy have dramatically improved the survival of advanced melanoma patients (pts), but they show relative lower efficacy in Asian pts especially in acral and mucosal subtypes. Rh-Endostatin (endostar) is a potent endogenous inhibitor of angiogenesis. Previous studies have indicated that endostar combined with dacarbazine (DTIC) was effective in the treatment of metastatic melanoma. To further improve the effectiveness, this study was designed to observe the efficacy and safety of continuous infusion (CIV) of endostar combined with DTIC and cisplatin as the first line therapy for advanced melanoma pts. Methods: Pts with treatment naive, ECOG 0/1, and unresectable stage IIIC or IV melanoma were enrolled. DTIC (250 mg/m2, intravenous infusion, day 1-5), cisplatin (75 mg/m2, intravenous infusion, separated in 3 days) and endostar (15 mg/m2, CIV, day 1-14) were administered in a 28-day cycle until disease progression or intolerable toxicity. The primary endpoint was progression free survival (PFS). Secondary endpoints included disease control rate (DCR) and safety. Results: From January 2016 to May 2018, 64 pts were enrolled and 50 pts were evaluable. 26 pts were female. The median age was 50 years (range 28-71 years) old. 10/64 (15.6%) were primary mucosal and 21/64 (32.8%) were primary acral, 40 pts were at stage IV and 32% pts got BRAF mutation. At the last follow up of Dec 2018, 5 pts achieved partial response and 27 pts got stable disease. The objective response rate was 10%. The DCR was 64%. The median PFS was 6.0 months (95% CI 1.7-10.3 months). The median overall survival was not reached. The most common adverse events were nausea (56.25%), vomiting (31.25%) and leucopenia (29.7%). Grade 3-4 toxicity was few, one got intermittent palpitation and one got atrial fibrillation, which caused drug discontinuation and recovered to normal. Conclusions: Continuous infusion of endostar plus DTIC and cisplatin improved median PFS as the first line therapy for advanced melanoma. This combination therapy was well tolerated and might be recommended as the first line therapy for advanced melanoma. Clinical trial information: NCT03095079.
Immune related adverse events (irAE) of mono-, combination, and sequential therapy regimens of ipilimumab (IPI), nivolumab (NIV), and pembrolizumab (PEM) for advanced melanoma.
Authors: Almutairi Abdulaali , McBride Ali , Sundararajan Srinath , Abraham Ivo 
Published: May 2019

e21011 Background: The immunotherapy agents IPI, NIV, and PEM have transformed the management of advanced melanoma but are associated with irAEs. We estimated the incidence of irAEs as observed in clinical trials of mono, combination , and sequential regimens of these agents in the advanced melanoma setting. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in USA, Europe, Australia, and Japan for phase 1-3 trials of IPI, NIV, and PEM in advanced melanoma. Random effect meta-analysis was utilized to estimate the incidence of irAEs (expressed as % with 95%CI) for all agents in mono-, combination, and sequential regimens. Results: 56 reports (32 published articles, 7 updates, 15 results published on clinicaltrials.gov and 2 regulatory documents) of 37 trials and relating unique and independent irAE data were included in the analysis. See Table. Conclusions: IPI mono had higher incidence rates of all grade and ≥ grade 3 hypophysitis and colitis but lower rates of all grade hypothyroidism, pneumonitis, and vitiligo than NIV or PEM mono. Combination and sequential regimens had higher irAE incidence rates compared to monotherapies except for grade ≥3 hypophysitis in PEM+IPI and NIV→IPI, and grade ≥3 vitiligo as well as all grade colitis and hypophysitis in IPI →NIV. Table. Incidence rates of select irAEs expressed as % with 95%CI (‡ all grade; * ≥ grade 3). [Table: see text]
Cyclooxygenase inhibitor use during checkpoint blockade immunotherapy and effect on time to progression for metastatic melanoma patients.
Authors: Wang Shang-Jui , Khullar Karishma , Yegya-Raman Nikhil , Kim Sinae , Silk Ann W. , Malhotra Jyoti , Gentile Michael A. , Mehnert Janice M. , Jabbour Salma K. 
Published: May 2019

e21029 Background: In tumors, cyclooxygenase (COX) activity leads to biosynthesis of prostaglandin E2 which can inhibit T-cell and dendritic cell function, thereby allowing immune evasion. Preclinical models have shown therapeutic synergy between COX inhibitors (COXi) and anti-PD-1 inhibition (PD-1i) immunotherapy (IT). We hypothesized that patients (pts) treated with checkpoint blockade IT and concurrent COXi would have improved responses compared to those treated with IT and no COXi. Methods: We retrospectively analyzed 65 metastatic melanoma pts who received IT (PD-1i/PD-L1i/CTLA4i) between 5/2011-11/2017 on their 1st course of IT. Of these pts, 38.5% (N = 25) took concurrent COXi (aspirin, NSAIDs, or selective COX-2i) and 61.5% (N = 40) did not. We compared differences in baseline characteristics and time to progression (TTP) between IT-treated melanoma pts who did or did not receive COXi, using the Kaplan-Meier method and Cox regression. TTP was defined as time from IT start to progression of disease (POD) as determined by the treating physician based on CT or PET/CT scans, or last known alive. Results: Mean age was 66 yrs; male: 64.6%; BRAF mutant: 29.2%, ECOG 0/1/2: 60%/35.4%/4.6%; steroid use: 47.7% during IT; and prior non-checkpoint blockade IT: 13.8%. IT was stopped due to POD in 53.8% of pts, IT toxicity 6.2%, completed therapy 24.6%, and treatment holiday 15.4%. There were no significant differences in baseline characteristics between pts who did or did not receive COXi during IT, except for mean age (70 (COXi) versus 63 yrs (no COXi), p = 0.019). Pts that received COXi had longer TTP (median 245 days) vs without COXi (median 85 days, p = 0.0002). On multivariate analysis, COXi was associated with longer TTP (HR 0.34, p = 0.0004) after accounting for age, gender, steroid use, and ECOG PS ≥1. Immune-related toxicity was not significantly different with or without COXi (p = 0.73). Conclusions: Our findings suggest that in metastatic melanoma pts treated with IT, concurrent COXi use may result in a longer TTP, without increasing toxicity. These findings warrant further study to continue to augment outcomes for pts.
Specificity of markers CD44 and S100 for skin melanoma and nevi tissues.
Authors: Goroshinskaya Irina A. , Kit Oleg I. , Frantsiyants Elena M. , Bandovkina Valeria A. , Pozdnyakova Viktoria V. , Shikhlyarova Alla I. , Akhmedova Amira A. , Khokhlova Olga V. , Neskubina Irina V. , Cheryarina Natalia D. 
Published: May 2019

e21036 Background: The high metastatic potential of melanoma and the need for long-term patient monitoring causes the search for tumor markers of this malignant neoplasm. Our aim was a comparative analysis of levels of tumor-specific proteins CD44 and S100 and protein composition in melanocytic lesions of the skin. Methods: We studied 86 samples of cutaneous melanoma and nevus tissues, their perifocal tissues and resection line tissues obtained during tumor excision from 23 patients with cutaneous melanoma pT1-4N0-1M0 and 14 patients with nevi. Intact skin samples obtained from non-cancer patients during reconstructive plastic surgery were used as the comparison group. All patients gave their written informed consent. Levels of CD44 (BenderMedSystems, USA) and S100 (Fujirebio, Sweden) were determined by ELISA in 10% homogenates of all tissues; total protein levels were determined by standard spectrometry and fractional composition of proteins were studied by turbidimetric method. Statistical processing of results was performed using the Statistika 6.0 program with Student’s t-test for two independent groups. Results: Melanoma was characterized by a sharp increase in S100B levels, 28 and 7 times exceeding the levels in intact tissues and nevi. The level of CD44 in melanoma tissue was increased only by 2 times, in nevus tissue - by 48%. The ratio of albumin and gamma globulins in the tissue of melanoma and nevi was 79% and 29% lower than in healthy skin. A more than twofold increase in the gamma globulin fraction in the melanoma tumor tissue against a decrease in albumin and the absence of changes in other globulins, as well as a moderate but statistically significant increase in the gamma globulin fraction in nevi tissue, indicates that S100B and CD44 proteins belong to the gamma globulin fraction. Conclusions: A highly specific increase of S100 levels and a less specific increase of CD44 levels in supernatant liquid of melanoma tissue homogenates, together with the predominance of the gamma globulin fraction, allow considering such factors as a prognostically unfavorable sign of tumor progression, which can be important when choosing a personalized treatment strategy.
Response to PD-1 inhibition in early- and late-relapsing cutaneous melanoma.
Authors: Fitzgerald Kelly , Daud Adil 
Published: May 2019

e21038 Background: Up to 45% of stage I-II melanomas will relapse within 5 years, and some relapses occur more than 10 years after surgical resection. Little is known about the differences in tumor characteristics, including immunogenicity, of early- vs. late-relapsing melanoma, or the implication of these differences in response to PD-1 inhibition. Methods: A retrospective cohort study was conducted to compare time from definitive treatment of localized melanoma to relapse with response to pembrolizumab. Patients with prior stage I-II melanoma who relapsed, and then treated with pembrolizumab, were included in the study. Time to relapse was compared with overall response rate. Results: Among the study population, 66 patients initially presented with early stage disease that relapsed within the study period. The median time to relapse was 5 years (range 0.5-33 years, interquartile range 7.25, Q1 = 2, Q2 = 9.25). 9 patients (14%) relapsed within 2 years of surgery; these patients had a higher overall response rate to pembrolizumab than late-relapsing patients with marginal significance (88% vs 50%, p = 0.056). The difference became less significant when patients who relapsed before or after 5 years (70% vs 47%, respectively, p = 0.20), and before or after 10 years (64% vs 45%, p = .31). Conclusions: Patients with early-relapsing melanoma had higher ORR to pembrolizumab than patients with late-relapsing disease, with early relapse defined as earlier than 2 years from definitive surgical intervention. Late relapsing tumors may harbor mechanisms of resistance to immune checkpoint inhibition.
Does the initial biopsy type affect clinically important outcomes in malignant melanoma? A meta-analysis.
Authors: Fayyaz Fatima , Shellenberger Richard A 
Published: May 2019

e21041 Background: Malignant melanoma continues to have an increasing incidence worldwide without a decline in mortality, despite advances in treatment and early detection which have led to improved mortality outcomes for most malignancies. Early detection is particularly favorable for melanoma localized to the site of disease, which confers a five year survival rate of 98.4 %. Guidelines from the American Academy of Dermatology (AAD) give three acceptable options for the initial management of pigmented lesions suspicious for melanoma: elliptical excision, wide punch excision and a deep shave or saucerization. Methods: We performed a systematic review and meta-analysis to better define the evidence for differences between punch incisional and excisional biopsy with regard to clinically important outcomes in the evaluation of skin lesions suspicious for melanoma. These were melanoma specific mortality, all-cause mortality, Breslow tumor thickness, and melanoma recurrence. The comparison groups were punch incisional and excisional biopsy; there was insufficient data to include shave biopsies. Results: The result of pooling the studies that track melanoma specific mortality finds that there is a higher, but non-significant rate of death among those in the punch incisional group. The pooled risk ratio is 1.21, p = 0.153. The results of pooling the all-cause mortality studies also finds a higher, but non-significant, rate of death among the punch incisional group, RR = 1.03, p = 0.390. Pooling the two studies that examine Breslow thickness found that values in the punch incisional group are significantly lower, with a standardized mean difference of -0.17, p = 0.006. Finally, the pooled risk ratio for recurrence was not significant, RR = 1.161, p = 0.198. Conclusions: Until further data is available, there is no evidence to suggest a preferred diagnostic procedure in the initial evaluation of pigmented lesions suspected of cutaneous melanoma related to clinically important outcomes. To our knowledge, this is the first meta-analysis done on this important question regarding melanoma epidemiology and public health.
Melanoma nodal management in Ontario following ASCO/SSO guidelines.
Authors: Latosinsky Steven , Shariff Salimah , Allen Britney 
Published: May 2019

e21054 Background:Methods:Results: Conclusions:The American Society of Clinical Oncology and Society of Surgical Oncology (ASCO/SSO) published a joint guideline in 2012 regarding indications for sentinel lymph node biopsy (SLNB) in cutaneous melanoma. The guideline supported completion lymph node dissection (CLND) for all patients with a positive SLNB. We examined the rates and predictors of SLNB and CLND for melanoma patients in Ontario (population 13.6 million) following guideline publication. Methods: We used the Ontario Cancer Registry (OCR) to identify cutaneous melanoma patients diagnosed in 2013. Patient records were linked to prospectively maintained health administrative databases to obtain details for each patient including surgical procedures. Results: We identified 3298 melanoma patients from Ontario in 2013 of which 1,973 (59.8%) could be analyzed. The majority, 1,227 (62.2%) had a local excision alone, while 746 (37.8%) had a SLNB. SLNB was performed on T1, T2, T3 and T4 primary melanomas in 13.9%, 67.8%, 62.6% and 47.2% of cases respectively. Receipt of a SLNB was positively associated with a younger age (< 80), higher T stage, and non-head and neck primary in multivariate analysis. Of the patients who received a SLNB 136 (18.2%) were found to be node positive. A CLND was performed in 82 (60.3%) of these patients. Conclusions: In Ontario only two-thirds of intermediate thickness melanomas (T2, T3) received a SLNB as recommended by the ASCO/SSO guidelines. Utilization was lower for head and neck patients and higher for younger (< 80 years) patients. Use of CLND for positive SLNB was also low relative to the guidelines.
Preliminary safety results of a phase II study investigating pembrolizumab in combination with postoperative intensity modulated radiotherapy (IMRT) in resected high risk cutaneous squamous cell cancer of the head and neck.
Authors: Koyfman Shlomo A. , Gastman Brian , Vidimos Allison T. , Joshi Nikhil Purushottam , Lucas Jennifer , Poblete-Lopez Christine , Vij Alok , Meine Jon , Burkey Brian B. , Ku Jamie , Lamarre Eric , Prendes Brandon , Scharpf Joseph , Billings Steven D , Samsa Julia , Robinson Shelley Beth , Adelstein David J. , Geiger Jessica Lyn 
Published: May 2019

e21056 Background: High risk cutaneous squamous cell cancer of the head and neck (cSCC-HN) have suboptimal outcomes with surgery and postoperative radiation. We report preliminary safety outcomes of a phase II study (NCT03057613) exploring the safety and efficacy of the addition of Pembrolizumab to postoperative IMRT. Methods: Patients with cSCC-HN were eligible for this IRB approved study if they had resection of all gross disease and demonstrated (a) invasion of the skeleton or skull base; (b) node positive disease; (c) or a tumor > 2cm with ≥1 of the following risk factors: recurrent disease, perineural invasion, lymphovascular space invasion, poorly differentiated, positive margins, satellitosis or in-transit metastases. Immune competent pts and those with CLL were eligible. This study aimed to accrue 34 evaluable patients to assess a primary safety endpoint of dose limiting toxicity (DLT) defined as any grade ≥3 toxicity at least possibly related to the immunotherapy. Assuming toxicity of < 20% is acceptable and > 40% is unacceptable, if ≥11 of 34 (32%) patients experienced a DLT, the regimen would be considered unsafe. Results: Of 15 pts already enrolled on this study, 11 have completed the protocol treatment. There were no DLTs observed to date. Grade 2 immune related toxicity was seen in two patients, one with bullous pemphigoid and another with lymphopenia and peripheral neuropathy and weakness in his hands in the setting of a prior cervical spine injury. Both responded to steroids and recovered completely. Based on this initial cohort, the 95% confidence intervals (CI) on DLTs for the entire cohort is 0-28%. Using the most conservative CI of 28%, the likelihood of 11 of the remaining 23 patients experiencing a DLT is 3.4%. Assuming a CI of 20%, the risk is 0.3%. None of the 11 pts who have completed protocol therapy have experienced a recurrence. Conclusions: The addition of Pembrolizumab to postoperative IMRT in high risk cSCC-HN is safe and will be studied in a randomized phase III adjuvant study (Keynote 630). This phase II study will continue to enroll CLL patients to assess safety and efficacy signals in this unique higher risk population. Clinical trial information: NCT03057613.
Cancer Immune Control Dynamics (CICD): A clinical data driven model of systemic immunity.
Authors: Markovic Svetomir , Sprau Allan , McElroy Virginia , Nevala Wendy Kay , Leontovich Alexey , Frisch Harold 
Published: May 2019

e21058 Background: Recent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This will lead to improvements in the efficacy of existing immune therapies (patient selection; drug combinations) and insight into new therapeutic targets that may significantly reduce the time to new therapeutics discoveries capable of meaningful clinical impacts. Methods: A systems analysis approach (Cancer Immune Control Dynamics, CICD) attempts to identify the differences between systemic immune homeostasis of healthy volunteers versus patients with metastatic malignant melanoma based on serial measurements of a set of conventional peripheral blood biomarkers of immune function (15 cell subsets and 35 cytokines) assessed daily over 7-10 days. The modeling strategy takes aerospace engineering control theory and system identification algorithms to analyze the state of an individual’s immune system based on the biomarkers’ dynamic non-linear oscillatory behaviors. The analysis framework builds on the classical predator-prey equations commonly used to model biological system dynamics. Tens of thousands of biologically possible biomarker interactions are modeled by a set of matrix equations that creates a system interaction model. CICD quantifies the system equations with biomarker values and solves it to measure the interactions. Results: Quantification of thousands of unique biomarker relationships per participant enables classification based on their immune profile rather than their clinical diagnosis and a basis for a visualization of a person’s immunity state. Conclusions: Results provide initial evidence that a model-based analysis of serially collected biomarker data can lead to biological insights into human immunity, of potential benefit in clinical decisions. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.
Nation-wide trends in mortality of patients with ocular and orbit melanoma: 2000 to 2014.
Authors: Forehand William , Gopishetty Swathi , Shahbandi Ashkan , Guddati Achuta Kumar 
Published: May 2019

e21061 Background: Ocular and orbit melanoma is a rare subtype of melanoma for which outcomes have not been adequately reported. In this study we he have analyzed the incidence-based mortality trends of ocular and orbit melanoma over a 15 year period. Most ocular melanomas originate from the uvea and to a lesser extent from the conjunctiva. Primary orbital melanoma is exceedingly rare. The incidence of ocular melanoma has been stable for the past few decades but incidence-based mortality has not been studied over the past 15 years. Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was utilized to query the incidence-based mortality for all patients diagnosed with ocular and orbit melanoma for the years 2000 to 2014. The results were grouped by gender and race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander). Paired T-test was used to determine statistically significance difference between various subgroups (p < 0.05). Results: Incidence-based mortality has been the highest in Caucasian/White patients from 2000 to 2014 followed by African American/Black and Asian/Pacific Islander patients. American Indian/Alaskan native patients appear to have the least mortality. There was a statistically significant difference (p < 0.05) in mortality between Caucasian/White patients from 2000 to 2014 followed by African American/Black and Asian/Pacific Islander patients. The sample size for African American/Black and American Indian/Alaskan native patients was too low for discerning a meaningful trend in mortality. Overall it appears that Caucasian males and females have a far higher and worsening incidence-based mortality compared to other races. Conclusions: Ocular melanoma and orbit melanoma are rare entities which are predominantly seen in Caucasian/White patients. This study shows that the incidence-based-mortality has been worsening for these patients in the past two decades. These entities have poor prognosis and have not been studied extensively in immunotherapy trials. This study highlights the need for new clinical trials to help improve the mortality rates.