Journal articles on the topic 'Melanoma Screening Trial (MST)'
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Elwood, J. M. "Screening for Melanoma and Options For-Its Evaluation." Journal of Medical Screening 1, no. 1 (January 1994): 22–38. http://dx.doi.org/10.1177/096914139400100107.
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A review of the published evidence presented here argues that screening for melanoma is recommended and practised at present, but with wide diversity of opinions about its value; there is evidence that screening has considerable potential for benefit, but the evidence of actual benefit is limited; and there are substantial costs and potential hazards from screening. On this basis the evaluation of screening procedures for melanoma is important, and options for this are discussed. The ideal study design to assess the efficacy of melanoma screening in reducing mortality is a large scale randomised trial. This may need a well coordinated proposal involving several centres in one or more countries, and the cost would be substantial. Without such a trial, however, it is most likely that increasing resources will be put into poorly designed screening programmes of unknown value. The simplest and strongest designs use individual randomisation, but group randomisation designs may have practical advantages, though they require a greater sample size. Designs based on general population screening, and on screening only high risk groups, are both considered. They answer different questions. In countries with high incidence the value of general population screening is probably the more critical. Not enough is known to specify the type and frequency of screening precisely; both screening by doctors and self screening require evaluation, and annual screening should probably be tested. The age range at risk will depend on the local incidence, but is likely to be quite wide — for example, 45–69, and both sexes need inclusion. Thus a suggested design for a moderate to high incidence area would be a trial, randomised by individual or group, assessing at least two annual rounds of both screening by doctor and self screening (ideally by a factorial design), for adults aged 45–69, with mortality over several years' follow up as the critical outcome. In an area with good data systems such a study could compare screening offered to some 260.000 subjects with 10 times that number of controls passively followed up, with 90% power to detect a one third reduction in mortality. A general assessment of costs over five years gave estimates of $8.3 million for the screening programme and $2.4 million for the evaluation. The much weaker designs, area based cohort studies using individual data or a simpler ecological comparison, and case-control studies, are also considered. If well designed with attention to their methodological limitations they may be valuable but are unlikely to be as definitive as a randomised trial.
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Djavid, Amir Reza, Connor Stonesifer, Benjamin T. Fullerton, Samuel W. Wang, Marlene A. Tartaro, Bradley D. Kwinta, Joseph M. Grimes, Larisa J. Geskin, and Yvonne M. Saenger. "Etiologies of Melanoma Development and Prevention Measures: A Review of the Current Evidence." Cancers 13, no. 19 (September 30, 2021): 4914. http://dx.doi.org/10.3390/cancers13194914.
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(1) Melanoma is the most aggressive dermatologic malignancy, with an estimated 106,110 new cases to be diagnosed in 2021. The annual incidence rates continue to climb, which underscores the critical importance of improving the methods to prevent this disease. The interventions to assist with melanoma prevention vary and typically include measures such as UV avoidance and the use of protective clothing, sunscreen, and other chemopreventive agents. However, the evidence is mixed surrounding the use of these and other interventions. This review discusses the heritable etiologies underlying melanoma development before delving into the data surrounding the preventive methods highlighted above. (2) A comprehensive literature review was performed to identify the clinical trials, observational studies, and meta-analyses pertinent to melanoma prevention and incidence. Online resources were queried to identify epidemiologic and clinical trial information. (3) Evidence exists to support population-wide screening programs, the proper use of sunscreen, and community-targeted measures in the prevention of melanoma. Clinical evidence for the majority of the proposed preventive chemotherapeutics is presently minimal but continues to evolve. (4) Further study of these chemotherapeutics, as well as improvement of techniques in artificial intelligence and imaging techniques for melanoma screening, is warranted for continued improvement of melanoma prevention.
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Primiero, Clare Amy, Aideen M. McInerney-Leo, Brigid Betz-Stablein, David C. Whiteman, Louisa Gordon, Liam Caffery, Joanne F. Aitken, et al. "Evaluation of the efficacy of 3D total-body photography with sequential digital dermoscopy in a high-risk melanoma cohort: protocol for a randomised controlled trial." BMJ Open 9, no. 11 (November 2019): e032969. http://dx.doi.org/10.1136/bmjopen-2019-032969.
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IntroductionMelanoma is Australia’s fourth most common cancer. Early detection is fundamental in maximising health outcomes and minimising treatment costs. To date, population-based screening programmes have not been justified in health economic studies. However, a skin surveillance approach targeting high-risk individuals could improve the cost-benefit ratio.Methods and analysisThis paper describes a 2-year longitudinal randomised controlled trial (RCT) to compare routine clinical care (control) with an intensive skin surveillance programme (intervention) consisting of novel three-dimensional (3D) total-body photography (TBP), sequential digital dermoscopy and melanoma-risk stratification, in a high-risk melanoma cohort. Primary outcomes will evaluate clinical, economic and consumer impact of the intervention. Clinical outcomes will evaluate differences in the rate of lesion excisions/biopsies per person, benign to malignant ratio for excisions and thickness of melanomas diagnosed. A health economic analysis using government data repositories will capture healthcare utilisation and costs relating to skin surveillance. Consumer questionnaires will examine intervention acceptability, the psychological impact, and attitudes towards melanoma risk and sun protective behaviour. Secondary outcomes include the development of a holistic risk algorithm incorporating clinical, phenotypic and genetic factors to facilitate the identification of those most likely to benefit from this surveillance approach. Furthermore, the feasibility of integrating the intervention with teledermatology to enhance specialist care in remote locations will be evaluated. This will be the first RCT to compare a targeted surveillance programme utilising new 3D TBP technology against current routine clinical care for individuals at high risk of melanoma.Ethics and disseminationThis study has received Human Research Ethics Committee (HREC) approval from both Metro South Health HREC (HREC/17/QPAH/816) and The University of Queensland HREC (2018000074).Trial registration numberANZCTR12618000267257; Pre-results.
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Matias, Mariana, Jacinta O. Pinho, Maria João Penetra, Gonçalo Campos, Catarina Pinto Reis, and Maria Manuela Gaspar. "The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval." Cells 10, no. 11 (November 9, 2021): 3088. http://dx.doi.org/10.3390/cells10113088.
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Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.
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Colman, Howard, Ken Boucher, Chris Stehn, David Kircher, and Sheri Holmen. "THER-07. DEVELOPMENT OF A NEW MOLECULAR PREDICTOR FOR RISK OF BRAIN METASTASES AND EFFICACY OF TARGETED THERAPY IN MELANOMA." Neuro-Oncology Advances 1, Supplement_1 (August 2019): i12. http://dx.doi.org/10.1093/noajnl/vdz014.050.
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Abstract Despite therapeutic advances in the treatment of melanoma, development of brain metastases (BM) continues to be a major manifestation of treatment failure. The ability to identify those patients who are at highest risk of developing brain metastases is limited with current methods. Development of sensitive and specific biomarkers to predict which stage II-III melanoma patients are at highest risk of BM would enable initiation of prospective clinical trials focused on both intensive surveillance and therapeutic prevention. To accomplish this goal, we embarked on an effort to optimize a combined molecular/clinical/pathologic predictor of BM risk. We firstanalyzed multiple gene expression datasets including TCGA (n = 437) and an independent series from Australia (n = 183) and identified a list of 60 consensus genes that is robustly predictive of development of melanoma BM (p < 0.05; FDR 5%). Next, we performed a similar analysis of association of miRNAs and melanoma BM risk which identified a set of miRNAs with significant predictive power. An optimized combined set of mRNA and miRNA markers was a better predictor of BM risk than either mRNA or miRNA list alone when applied to the TCGA data set. The combined predictor was most sensitive in separating patients with no metastases from those with either BM or systemic metastases. Current efforts are focused on optimizing miRNA and mRNA separation of patients specifically with BM from those with other mets, and with integrating the expression classifier with other clinical and pathologic predictive factors including: age, stage, thickness, location, histology, ulceration, gender. The sensitivity and specificity of the resulting clinical/molecular predictor will be validated in an independent retrospective cohort, and subsequently implemented in a prospective BM screening trial to determine real-world utility of this approach in preparation for prospective BM adjuvant/chemoprevention trials utilizing both immunotherapy and targeted therapy approaches.
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Sarasamma, Sreeja, Yu-Heng Lai, Sung-Tzu Liang, Kechun Liu, and Chung-Der Hsiao. "The Power of Fish Models to Elucidate Skin Cancer Pathogenesis and Impact the Discovery of New Therapeutic Opportunities." International Journal of Molecular Sciences 19, no. 12 (December 7, 2018): 3929. http://dx.doi.org/10.3390/ijms19123929.
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Animal models play important roles in investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic tools. Despite rapid progress in the understanding of disease mechanisms and technological advancement in drug discovery, negative trial outcomes are the most frequent incidences during a Phase III trial. Skin cancer is a potential life-threatening disease in humans and might be medically futile when tumors metastasize. This explains the low success rate of melanoma therapy amongst other malignancies. In the past decades, a number of skin cancer models in fish that showed a parallel development to the disease in humans have provided important insights into the fundamental biology of skin cancer and future treatment methods. With the diversity and breadth of advanced molecular genetic tools available in fish biology, fish skin cancer models will continue to be refined and expanded to keep pace with the rapid development of skin cancer research. This review begins with a brief introduction of molecular characteristics of skin cancers, followed by an overview of teleost models that have been used in the last decades in melanoma research. Next, we will detail the importance of the zebrafish (Danio rerio) animal model and other emerging fish models including platyfish (Xiphophorus sp.), and medaka (Oryzias latipes) in future cutaneous malignancy studies. The last part of this review provides the recent development and genome editing applications of skin cancer models in zebrafish and the progress in small molecule screening.
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Kok, Peey-Sei, Won-Hee Yoon, Sally Lord, Ian Marschner, Michael Friedlander, and Chee Khoon Lee. "Tumor Response End Points as Surrogates for Overall Survival in Immune Checkpoint Inhibitor Trials: A Systematic Review and Meta-Analysis." JCO Precision Oncology, no. 5 (July 2021): 1151–59. http://dx.doi.org/10.1200/po.21.00108.
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PURPOSE Many immune checkpoint inhibitors (ICIs) have been approved on the basis of tumor response end points in nonrandomized trials, including objective response rate (ORR) and duration and depth of response. We aimed to assess the validity of these end points as surrogate end points for overall survival (OS) in patients with advanced solid tumors treated with ICIs at trial and treatment arm levels. METHODS ICI trials in advanced solid cancers published between January 1, 2000, and March 31, 2020, were included. Correlations between ORR, durable response (DR) of ≥ 6 months, complete response (CR), and OS were assessed for treatment comparisons (trial-level) and for patients receiving ICI (arm-level), using weighted linear regression. RESULTS Sixty-three trials were eligible, including 58 randomized controlled trials and 20 nonrandomized controlled trials (78 ICI arms and 30,815 patients). The majority were phase III (63%), and OS was the most common primary end point (40%). In relative treatment comparisons, correlations between ORR risk ratio and OS hazard ratio (HR), 6-month DR ratio and OS HR, and CR ratio and OS HR were r = 0.58, r = 0.62, and r = 0.42, respectively. Exploratory studies in melanoma, non–small-cell lung cancer, and other tumors showed similar results, although 6-month DR ratio was strongly correlated with OS HR ( r = 0.89). Within ICI arms only, correlations between ORR and 12-month OS, 6-month DR and 12-month OS, and CR and 12-month OS were r = 0.76, r = 0.84, and r = 0.50, respectively, in all eligible trials. CONCLUSION Relative measures of tumor response (ORR, 6-month DR, and CR) are poor surrogate end points for OS in ICI studies. However, ORR and 6-month DR are prognostic of 12-month OS in ICI studies supporting their use for screening activity of novel agents in early-phase nonrandomized trials.
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Brastianos, Priscilla Kaliopi, Erin Twohy, Carey K. Anders, A. John Iafrate, Peter A. Kaufman, Justine Vanessa Cohen, Rebecca Suk Heist, et al. "Alliance A071701: Genomically guided treatment trial in brain metastases." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS2573. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps2573.
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TPS2573 Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .
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Shah, Payal D., Alexander Chan Chi Huang, Xiaowei Xu, Paul J. Zhang, Robert Orlowski, Tina Matlawski, Joanne Shea, et al. "Phase I trial of autologous cMET-directed CAR-t cells administered intravenously in patients with melanoma & breast carcinoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 10035. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.10035.
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10035 Background: Advanced relapsed/refractory melanoma and metastatic triple-negative breast cancer are lethal diseases for which effective therapies are limited. We conducted a pilot phase I clinical trial (NCT03060356) to establish the safety and feasibility of intravenous autologous chimeric antigen receptor (CAR) T cell immunotherapy targeting cMET, a cell-surface antigen that is highly expressed in these cancers. Methods: Subjects had metastatic or unresectable melanoma (Mel) or triple-negative breast cancer (BC) with ≥30% expression of cMET on archival tissue or screening biopsy. Eligible subjects had measurable disease and progression on at least 1 prior therapy. Patients (pts) received up to 6 doses (1x108 total T-cells per dose) of RNA electroporated anti-cMET CAR T cells over a 2-week period without antecedent lymphodepleting chemotherapy. Subjects underwent pre- and post-infusion biopsies. The primary objective was to determine feasibility and safety of treatment. Results: 77 subjects (39 mel, 38 BC) were prescreened for tumor cMET expression and 37 (17 mel, 20 BC) met the eligibility threshold. Seven pts (4 BC, 3 Mel) received cMET-directed CAR T infusions on study. Mean age was 50 years (35-64); median (M) ECOG 0 (0-1); M prior lines of chemotherapy/immunotherapy were 4/0 for BC pts and 1/3 for Mel pts. 6 of 7 pts received all planned CAR T cell infusions, and 1 received 5 infusions. 5 pts experienced grade (G) 1 or G 2 toxicity that was possibly or definitely related to study. Toxicities occurring in ≥1 pt included: anemia (n = 3), fatigue (n = 2), and malaise (n = 2). No G ≥3 toxicities or cytokine release syndrome were observed. No pts discontinued therapy due to toxicity. Best response was stable disease in 4 pts (2 BC, 2 Mel) and PD in 3 pts (2 BC, 1 Mel). Messenger RNA signals corresponding to CAR T cells were detected by RT-PCR in the peripheral blood of all pts during the infusion period and in 2 pts after the infusion period. 6 pts underwent baseline biopsy and 4 pts underwent post-infusion biopsy. Immunohistochemical stains of CD3, CD4, CD8, CD163, L26, PD1, PDL1, Foxp3, Ki67, Granzyme B and Phospho-S6 were performed on pre- and post-treatment tissue biopsies and are being evaluated. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells was safe and feasible. Future directions include examination of this target using a lentiviral construct in combination with lymphodepleting chemotherapy. Clinical trial information: NCT03060356.
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Simonelli, Matteo, Emiliano Calvo, Diwakar Davar, Jason Melear, Donald Richards, Matthew Dallos, Martin Gutierrez, et al. "Abstract CT119: A randomized, double-blind phase 2 evaluation of the anti-IL-8 monoclonal antibody BMS-986253 + nivolumab + ipilimumab vs nivolumab + ipilimumab in patients with advanced melanoma that progressed on/after anti-PD-(L)1 therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT119. http://dx.doi.org/10.1158/1538-7445.am2022-ct119.
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Abstract Purpose: This phase 1/2 trial evaluates the novel immunotherapy BMS-986253 in combination with immune checkpoint inhibitors (NCT03400332). Interleukin-8 (IL-8) is an immunosuppressive chemokine often elevated in the serum of patients with cancer. High serum IL-8 concentration is associated with poor prognoses and resistance to immunotherapies, including anti-programmed death-1 (PD-1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents (Schalper et al. Nat Med 2020;26:688). The addition of anti-IL-8 therapy to anti-PD-1 nivolumab (NIVO) and anti-CTLA-4 ipilimumab (IPI) may sensitize patients with high serum IL-8 levels to immune checkpoint inhibition. BMS-986253, a fully human IgG1 anti-IL-8 monoclonal antibody, in combination with NIVO ± IPI is under investigation in a phase 1/2 trial of patients with advanced solid tumors. Initial results from part 1 indicate BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities (Davar et al. J Immunother Cancer 2020;8. Abstract 394). Preliminary antitumor activity was observed, including partial responses in 5 of 28 patients with melanoma that had progressed on or after prior anti-PD-(L)1 therapy, a population with high unmet medical need. Part 2 is a randomized, double-blind phase 2 study comparing the efficacy of BMS-986253 in combination with NIVO + IPI vs NIVO + IPI in patients with advanced melanoma that progressed on or after prior anti-PD-(L)1 therapy. Trial Design: Patients eligible for part 2 have histologically confirmed, unresectable, stage III/IV melanoma, have progressed on or after anti-PD-(L)1 treatment, had an anti-PD-(L)1 agent as their most recent therapy, and have not received anti-CTLA-4 treatment. PD-L1 and BRAFV600 mutation status (wild-type and BRAF mutations permitted) must be documented, and serum IL-8 levels will be measured at screening. Patients will be randomized 1:1 to receive BMS-986253 + NIVO + IPI or placebo + NIVO + IPI and stratified by serum IL-8 level, BRAF V600E status, and lactate dehydrogenase level. The dose and frequency of BMS-986253, NIVO, and IPI will be determined by part 1 data. Treatment with BMS-986253 or placebo and NIVO will continue ≤ 3 years or until disease progression or intolerance. The primary objective is to compare progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1 between treatment arms in patients with baseline serum IL-8 levels > 10 pg/mL. Secondary objectives include PFS by BICR in all randomized patients, overall response rates by BICR per RECIST v1.1, overall survival, safety, pharmacokinetic profile, immunogenicity of BMS-986253, and associations of baseline factors with response. Recruitment will continue until ≈170 patients are enrolled. Citation Format: Matteo Simonelli, Emiliano Calvo, Diwakar Davar, Jason Melear, Donald Richards, Matthew Dallos, Martin Gutierrez, Victor Moreno, Thomas Marron, Sylvie Rottey, Angela Orcurto, Susana Barriga, Jessy Fan, Elizabeth Gibson, Santanu Dutta, Vivek Arora, Ignacio Melero. A randomized, double-blind phase 2 evaluation of the anti-IL-8 monoclonal antibody BMS-986253 + nivolumab + ipilimumab vs nivolumab + ipilimumab in patients with advanced melanoma that progressed on/after anti-PD-(L)1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT119.
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Samlowski, Wolfram E., James Moon, Merle Witter, Michael B. Atkins, John M. Kirkwood, Megan Othus, Antoni Ribas, Vernon K. Sondak, and Lawrence E. Flaherty. "CNS metastases as a site of progression on SWOG intergroup study S0008: A phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 (BCT) versus high-dose interferon (HDI) in patients with high-risk melanoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8527. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8527.
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8527 Background: Central nervous system (CNS) metastases (mets) are common in stage IV melanoma patients (pts). However, the incidence of CNS mets in pts with high-risk regional melanoma (HRM; stages IIIA-N2a thru IIIC N3) is not well described. A recent large prospective S0008 trial provided an opportunity to evaluate the contribution of CNS mets to treatment failure and survival. Methods: All pts had HRM treated with wide excision and full regional lymphadenectomy. Pts were then randomized to receive treatment with either BCT or HDI. All eligible pts were included in the analysis. Relapse/progression in the CNS (PCNS) was retrospectively identified only if clearly documented in case report forms. The cumulative incidence of PCNS in the presence of the competing hazard of death was estimated and potential risk factors were explored using the methods of Fine and Gray. Survival from PCNS was measured from date of PCNS to date of death. Results: 402 patients were evaluated (BCT: 200, HDI: 202), with median follow (if alive) of 6 years. The site of progression was identified in 162 (78 %) of 208 pts relapsing on study. Clearly documented PCNS occurred in 53/402 pts (13%). PCNS as a component of initial relapse/progression occurred in 34 patients (8%) and an additional 19 patients (5%) had delayed PCNS following initial systemic relapse. Most PCNS (85%) occurred within 3 years of initial surgery. Differences between arms were not significant (22 on BCT, and 31 on HDI)(p=0.21). Lymph node macromets demonstrated a strong correlation with development of PCNS (p=0.01). Neither primary tumor ulceration nor head and neck primary site were significant risk factors. Survival from diagnosis of brain mets was short (median 6 mo BCS, 5 mo HDI, p=0.93). Conclusions: Although the S0008 trial was not specifically designed to evaluate PCNS, a retrospective analysis identified a high CNS failure rate (at least 13%) in HRM pts, including 8% as the initial site of relapse. Further studies are needed to evaluate if screening for CNS mets in high-risk pts is useful and whether early treatment improves survival.
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Iglesias, Jose Luis, Radha Prathikanti, Bo Ma, Paulette Mattson, Deb Kedrowski, Jamie Lowe, Nandita Bose, et al. "A multicenter, open-label, phase II study of PGG beta-glucan and pembrolizumab in patients (pts) with advanced melanoma (MEL) following progression on treatment with checkpoint inhibitors (CPI) or triple negative breast cancer (TNBC) failing front-line chemotherapy for metastatic disease." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS3105. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps3105.
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TPS3105 Background: Imprime PGG (Imprime) is a Pathogen- Associated Molecular Pattern that enhances innate immune cell killing, counteracts immune suppression and triggers activation and maturation of antigen presenting cells. Imprime’s ability to trigger a coordinated innate and adaptive immune response is critical for enhancing the efficacy of CPIs in several pre-clinical tumor models. We are now exploring the combination of PGG beta-glucan and Pembrolizumab, a humanized mAb against programmed death receptor-1 (PD-1) in the clinic. In previous trials, Pembro yielded a 33% ORR and 23 mo mOS in 655 pts with advanced MEL and an 18.5% ORR and 11.2 mo mOS in 27 evaluable pts with metastatic/recurrent TNBC (Ribas et al., 2016; Nanda et al., 2016). Pre-treatment levels of anti-beta glucan antibodies (ABA) are correlated with pt response to Imprime. Methods: This Phase 2 study is enrolling ABA positive pts with advanced MEL following progression on treatment with a CPI or metastatic TNBC failing front-line chemotherapy. The study is a Simon optimal 2-stage design with sample size of 12 pts of each tumor type in Stage 1. If response and AE criteria (≤ 4 [or ≤ 33%] pts with grade 3/4 in Cycle 1) for each tumor type are met, an additional 17 pts with MEL and 30 pts with TNBC will be enrolled in Stage 2. Primary endpoints of the study are ORR (based on RECIST 1.1) and safety. Secondary endpoints include TTR, CRR, DoR, PFS, and OS. PK data will be profiled. Exploratory endpoints include ORR and PFS based on irRECIST, analysis of an ABA biomarker, immune cell activation markers, and changes in the tumor immune microenvironment. Screening and enrollment are underway in the US. Biothera Pharmaceuticals, Inc. is sponsoring the trial (ClinicalTrials.gov NCT02981303) under a collaborative agreement with Merck. Clinical trial information: NCT02981303.
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Lam, Megan, Justin Di Lu, Levi Elhadad, Cathryn Sibbald, and Raed Alhusayen. "Common Dermatologic Disorders in Down Syndrome: Systematic Review." JMIR Dermatology 5, no. 1 (February 8, 2022): e33391. http://dx.doi.org/10.2196/33391.
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Background Down syndrome (DS) has been associated with cardiovascular, gastrointestinal, and immune-related abnormalities. Several dermatologic conditions, including hidradenitis suppurativa, have also been found to be associated with DS. Objective The objective of this study was to characterize the prevalence, presentation, and unique features of dermatologic disorders associated with DS. Methods Electronic searches of EMBASE (via Ovid), MEDLINE (via Ovid), and Web of Science databases were conducted on December 14, 2020. Observational studies including case reports of patients with DS presenting with concomitant primary dermatologic disorder were included. Results This systematic review captured 40 observational studies and 99 case reports, including 10 observational studies that examined the prevalence of common skin disorders in patients with DS. The most common dermatologic conditions reported includes atopic dermatitis (8 studies, n=180; 19.7% mean prevalence), hidradenitis suppurativa (15, n=478; 3.2%), ichthyosis (4, n=16; 4.7%), lichen nitidus (6, n=6; 1.1%), psoriasis (21, n=65; 4.8%), alopecia areata (27, n=253; 7.4%), vitiligo (8, n=40; 4.4%), onychomycosis (3, n=198; 24.7%), calcinosis cutis (14, n=15), connective tissue nevi (6, n=6), dermatofibroma (3, n=3), melanoma (3, n=3), syringomas (14, n=182; 21.2%), and elastosis perforans serpiginosa (19, n=24; 0.5%). Conclusions Our results indicate an increased prevalence of common cutaneous disorders in patients with DS, particularly infectious, inflammatory, autoimmune, and connective tissue conditions. Current guidelines for the screening, general management, and use of systemic immunomodulatory agents in this patient population are lacking. Patients with DS would benefit from screening for dermatologic disorders not otherwise regularly performed for earlier diagnosis and treatment. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42021226295; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=226295
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Hamid, Omid, Ding Wang, Tae Min Kim, Sang-We Kim, Nehal J. Lakhani, Melissa Lynne Johnson, Roman Groisberg, et al. "Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9515. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9515.
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9515 Background: Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021). Methods: Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1. Results: 48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade ≥3 serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing. Conclusions: The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.
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Shen, Yu, and Marvin Zelen. "Screening Sensitivity and Sojourn Time From Breast Cancer Early Detection Clinical Trials: Mammograms and Physical Examinations." Journal of Clinical Oncology 19, no. 15 (August 1, 2001): 3490–99. http://dx.doi.org/10.1200/jco.2001.19.15.3490.
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PURPOSE: To estimate sensitivities of breast cancer screening modalities and preclinical duration of the disease from eight breast cancer screening clinical trials. PATIENTS AND METHODS: Screening programs invariably lead to diagnosis of disease before signs or symptoms are present. Two key quantities of screening programs are the sensitivity of the disease detection modality and the mean sojourn time (MST). The observed screening histories in a periodically screened cohort make it possible to estimate these quantities of interest. We applied recently developed statistical methods to data from eight randomized breast cancer screening trials to estimate the sensitivities of early detection modalities and MST. Moreover, when a screening trial involved two screening modalities, our methods enabled the estimation of the individual sensitivity of each screening modality. RESULTS: We analyzed breast cancer data from several screening trials and have relatively complete data from the Health Insurance Plan (HIP), Edinburgh, and two Canadian studies. The screening sensitivity for mammography, physical examination, and MST were, respectively, HIP: 0.39, 0.47, and 2.5 years; Edinburgh: 0.63, 0.40, and 4.3 years; Canadian (age 40 to 49 at entry): 0.61, 0.59, and 1.9 years; Canadian (age 50 to 59 at entry): 0.66, 0.39, and 3.1 years. CONCLUSION: The public debate on early breast cancer detection is mainly centered on mammograms. However, the current study indicates that a physical examination is of comparable importance. Cautious interpretation of trial differences is required as a result of various experimental designs and the age dependency of screening sensitivity and MST.
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Sharma, Sombeer, Aakash Deep, and Arun K. Sharma. "Current Treatment for Cervical Cancer: An Update." Anti-Cancer Agents in Medicinal Chemistry 20, no. 15 (October 27, 2020): 1768–79. http://dx.doi.org/10.2174/1871520620666200224093301.
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Cervical cancer is the leading gynecologic health problem which is considered as the 4th most widespread tumour in women. The prevalence of this fatal ailment is emerging gradually across the globe as about 18.1 million new cancer cases have been reported in 2018. The predominance of cervical cancer has been significantly found in low and middle-income countries as cervical cancer ranks fourth for both incidence and mortality, conversely, there are no effective screening systems available. This mortal state is certainly influenced by exposure of human papillomavirus, dysregulation of caspase enzyme, elevated expression of Inhibitor Apoptotic Protein (IAP), overexpression of Vascular Endothelial Growth Factors (VEGF), active/passive smoking, and dysfunction of the immune system. Generally, the clinical trial on pipeline drugs leads to the development of some promising new therapies that are more effective than standard approaches and often unavailable outside of the clinical setting. Indeed, several biological interventions that can modulate the pathological cascade of cervical cancer are still under investigation. Thus, there is a need to further summarise the promising therapies for cervical cancer as we have accomplished in HER2-positive breast cancer by targeting HER2 therapies and immune checkpoint inhibitors in melanoma. The present report revealed the pharmacokinetic/ pharmacodynamics aspects of various pipeline drugs that are promising for the treatment of cervical cancer. Moreover, the study revealed the possible mechanism, adverse drug reaction, combined therapy and pleiotropic action of these under investigational drugs, which can further improve the therapeutic efficacy and restrict the imaginable harmful effects.
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Wang, Tianjiao, Jean-Marc Navenot, Stavros Rafail, Mark Carroll, Ruoxi Wang, Cheryl McAlpine, Swethajit Biswas, et al. "Abstract LB001: Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB001. http://dx.doi.org/10.1158/1538-7445.am2022-lb001.
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Abstract Autologous T-cells engineered with T-cell receptors (TCRs) targeting tumor antigens are promising therapies for metastatic solid cancers.1 Specific peptide enhanced affinity receptor (SPEAR) T-cell therapies are T-cells with engineered HLA-restricted TCRs that precisely target tumor cells with specific antigens, such as MAGE-A4 (a cancer testis antigen), presented on the surface by HLA molecules. In SPEAR T-cell clinical trials targeting MAGE-A4, a 2-step prescreen is done before enrolment. 1) Patients undergo HLA typing via a high-resolution (allelic, 4-digit) sequence-based assay, and those who are positive for the inclusion alleles (HLA-A*02:01P, 02:02P, 02:03P, 02:06P) and not positive for the exclusion allele A*02:05P are eligible. 2) Tumor MAGE-A4 testing is done via an immunohistochemical clinical trial assay (MAGE-A4+ cutoff: ≥30% tumor cell staining at ≥2+ intensity) in HLA-eligible patients. A screening protocol (NCT02636855) has been used in Phase 1 trials of first- and next-generation SPEAR T-cells targeting MAGE-A4 (NCT03132922, NCT04044859) with responses in multiple MAGE-A4+ tumors. As of November 19, 2021, 6,168 patients with 9 solid tumor types were screened at 32 sites across North America and Europe in this screening protocol; among which, 2,744 were HLA-eligible (eligibility rate: 45%, range per tumor type: 42%-55%). HLA-A*02:01 was the most frequent HLA-A*02 allele. Of these HLA-eligible patients, 1,549 had tumor tissues evaluable for MAGE-A4 expression; among which, 313 were MAGE-A4+ (MAGE-A4+ rate: 20%, range: 8%-54%) (Table). MAGE-A4 showed highest prevalence in synovial sarcoma and myxoid/round cell liposarcoma but was seen across all tumor types investigated. Our results will be discussed in the context of tumor histopathology, disease status, and demography. HLA and MAGE-A4 biomarker data will inform the therapeutic opportunities for SPEAR T-cells targeting MAGE-A4 in metastatic solid cancers. 1. D’Angelo et al. Cancer Discov. 2018;8:944. HLA eligibility and MAGE-A4 prevalence in a screening protocol (NCT02636855) Indication Esophageal cancer Esophagogastric junction cancer Gastric cancer Head and neck squamous cell carcinoma Non-small cell lung cancer Melanoma Ovarian cancer Urothelial cancer Synovial sarcoma and myxoid/round cell liposarcoma HLA screened (N) 284 228 271 601 3189 668 539 270 118 HLA eligible (%) 46 45 43 42 43 50 49 43 55 MAGE-A4 evaluable (N) 104 91 73 200 457 245 225 93 61 MAGE-A4 positive (%) 22 25 8 22 14 16 24 32 54 Citation Format: Tianjiao Wang, Jean-Marc Navenot, Stavros Rafail, Mark Carroll, Ruoxi Wang, Cheryl McAlpine, Swethajit Biswas, Francine Brophy, Erica Elefant, Paige Bayer, Sandra McGuigan, Dennis Williams, George Blumenschein, Marcus Butler, Jeffrey M. Clarke, Justin F. Gainor, Ramaswamy Govindan, Victor Moreno, Janet Tu, David S. Hong. Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB001.
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Davar, Diwakar, Matteo Simonelli, Martin Gutierrez, Emiliano Calvo, Jason Melear, Sarina Piha-Paul, Donald Richards, et al. "394 Interleukin-8–neutralizing monoclonal antibody BMS-986253 plus nivolumab (NIVO) in biomarker-enriched, primarily anti–PD-(L)1–experienced patients with advanced cancer: initial phase 1 results." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A419. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0394.
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BackgroundInterleukin 8 (IL-8) is a C-X-C chemokine that exerts protumorigenic effects in the tumor microenvironment, including recruiting immunosuppressive PMN-MDSCs and promoting angiogenesis.1–3 Elevated serum IL-8 (sIL-8) is a negative prognostic indicator in patients with solid tumors and may have predictive value in patients treated with immunotherapies.2 4 5 BMS-986253, a fully human-sequence IgG1κ anti–IL-8 monoclonal antibody, binds IL-8 and prevents signaling through CXCR1/CXCR2 and has been shown to be safe in patients with advanced cancers.3 We present initial results of BMS-986253 + NIVO from a phase 1/2a trial in patients with advanced cancers who had detectable sIL-8 levels, the majority of whom had progressed on/after prior anti–PD-(L)1 (NCT03400332).MethodsDuring safety evaluation/dose exploration, patients with advanced metastatic solid tumors (melanoma, NSCLC, SCCHN, RCC, or UCC) and detectable sIL-8 (>10 pg/mL at screening) received BMS-986253 600 (n=16), 1200 (n=15), or 2400 mg (n=18) Q4W, or 1200 (n=12) or 2400 mg (n=59) Q2W, + NIVO 480 mg intravenously Q4W. Safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity were evaluated (investigator-assessed, RECIST v1.1).ResultsAs of March 20, 2020, 120 patients (median age, 63 years [range, 35–87 years]) received BMS-986253 + NIVO; 97% of patients received prior anti–PD-(L)1 therapy, and 25% received prior anti–CTLA-4 therapy. BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities observed. Most TRAEs were grade 1–2. The most common (≥5% of patients) TRAEs (any grade; grade 3–4) were fatigue (9%; 1%), nausea (7%; 0%), rash/rash maculopapular (6%; 0%), pruritus (5%; 0%), and decreased appetite (5%; 0%). Grade 3–4 serious TRAEs were reported in 2 patients (infusion-related reaction, BMS-986253 2400 mg Q2W + NIVO; AST/ALT increased, BMS-986253 1200 mg Q4W + NIVO). BMS-986253 exposure increased dose proportionally and was not altered with NIVO. BMS-986253 resulted in dose-dependent reductions in free sIL-8 levels, with tumor IL-8 suppression detected in most patients evaluated; additional pharmacodynamic endpoints will be presented. Partial responses were observed in multiple tumor types, including 5 of 28 patients with melanoma who had progressed on/after prior anti–PD-(L)1; 4 of the 5 patients were also previously treated with anti–CTLA-4.ConclusionsBMS-986253 + NIVO demonstrated a tolerable safety profile with dose-proportional pharmacokinetics and robust sIL-8 suppression. Preliminary antitumor activity was observed across a range of doses/regimens in this biomarker-enriched, anti–PD-(L)1–experienced, heterogeneous patient population with advanced cancers. These findings support further evaluation of BMS-986253 in select advanced tumors.AcknowledgementsThe authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study.Trial RegistrationNCT03400332Ethics ApprovalThis study was approved by the WCG Independent Review Board, approval number 20172711.ReferencesDavid JM, Dominguez C, Hamilton DH, et al. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel) 2016;4:22.Schalper KA, Carleton M, Zhou M, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat Med. 2020;26:688–692.Bilusic M, Heery CR, Collin JM, et al. Phase I trial of HuMax-IL-8 (BMS-986253), an anti–IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer 2019;7:240.Yuen KC, Liu L-F, Gupta V, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat Med 2020;26:683–698.Sanmamed MF, Perez-Gracia JL, Schalper KA, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti–PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol 2017;28:1988–1995.
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Hellinen, Laura, Sina Bahrpeyma, Anna-Kaisa Rimpelä, Marja Hagström, Mika Reinisalo, and Arto Urtti. "Microscale Thermophoresis as a Screening Tool to Predict Melanin Binding of Drugs." Pharmaceutics 12, no. 6 (June 16, 2020): 554. http://dx.doi.org/10.3390/pharmaceutics12060554.
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Interactions between drugs and melanin pigment may have major impacts on pharmacokinetics. Therefore, melanin binding can modify the efficacy and toxicity of medications in ophthalmic and other disease of pigmented tissues, such as melanoma. As melanin is present in many pigmented tissues in the human body, investigation of pigment binding is relevant in drug discovery and development. Conventionally, melanin binding assays have been performed using an equilibrium binding study followed by chemical analytics, such as LC/MS. This approach is laborious, relatively slow, and limited to facilities with high performance quantitation instrumentation. We present here a screening of melanin binding with label-free microscale thermophoresis (MST) that utilizes the natural autofluorescence of melanin. We determined equilibrium dissociation constants (Kd) of 11 model compounds with melanin nanoparticles. MST categorized the compounds into extreme (chloroquine, penicillin G), high (papaverine, levofloxacin, terazosin), intermediate (timolol, nadolol, quinidine, propranolol), and low melanin binders (atropine, methotrexate, diclofenac) and displayed good correlation with binding parameter values obtained with the conventional binding study and LC/MS analytics. Further, correlation was seen between predicted melanin binding in human retinal pigment epithelium and choroid (RPE-choroid) and Kd values obtained with MST. This method represents a useful and fast approach for classification of compounds regarding melanin binding. Thus, the method can be utilized in various fields, including drug discovery, pharmacokinetics, and toxicology.
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Aitken, J. F., J. M. Elwood, J. B. Lowe, D. W. Firman, K. P. Balanda, and I. T. Ring. "A randomised trial of population screening for melanoma." Journal of Medical Screening 9, no. 1 (March 2002): 33–37. http://dx.doi.org/10.1136/jms.9.1.33.
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Tarhini, Ahmad A., Paul Lorigan, and Sancy Leachman. "Operable Melanoma: Screening, Prognostication, and Adjuvant and Neoadjuvant Therapy." American Society of Clinical Oncology Educational Book, no. 37 (May 2017): 651–60. http://dx.doi.org/10.1200/edbk_174930.
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The importance of reducing the numbers of patients with late-stage melanoma, identifying which patients are most likely to progress, and treating these patients at the earliest possible stage cannot be overemphasized. Improved screening of patients prior to diagnosis has the advantage of identifying early-stage disease that is for the most part treatable by surgical methods. The process of melanoma screening is rapidly evolving through population-based programs, mobile health technologies, and advanced imaging tools. For patients with newly diagnosed melanoma, accurately estimating disease prognosis has important implications for management and follow-up. Prognostic factors are individual host- or tumor-related factors or molecules that correlate with genetic predisposition and clinical course. These include clinical covariates and host and tumor proteomic/genomic markers that allow the prognostic subclassification of patients. Adjuvant therapy for high-risk surgically resected melanoma targets residual micrometastatic disease with the goal of reducing the risk of relapse and mortality. In the United States, three regimens have achieved regulatory approval for adjuvant therapy, including high-dose interferon alpha, pegylated interferon alpha, and ipilimumab at 10 mg/kg. Phase III trials have reported benefits in relapse-free survival (all regimens) and overall survival (high-dose interferon alpha and ipilimumab). The management of locally/regionally advanced melanoma may benefit from neoadjuvant therapy, which is the subject of several ongoing studies. Recent studies have shown promising clinical activity and yielded important biomarker findings and mechanistic insights.
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Mehta, M. P., A. Dagnault, P. Chabot, J. Suh, E. Chang, M. Fortin, R. Timmerman, J. Grecula, L. Eubank, and M. F. Renschler. "Identification of occult brain metastases amenable to stereotactic radiosurgery by motexafin gadolinium (MGd) based treatment planning MRI: Results of a phase II trial of MGd and whole brain radiotherapy (WBRT) with stereotactic radiosurgery (SRS)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2037. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2037.
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2037 Background: Motexafin gadolinium (MGd) is a novel anti-cancer agent that selectively localizes in tumors and is detectable by MRI. Previous studies of patients (pts) with brain metastases (BM) demonstrated the detection of occult lesions after MGd administration not visible with gadolinium MRI contrast. The purpose of this study was to evaluate if MRI scanning after MGd improves SRS treatment-planning and treatment outcome by identifying and better defining lesions that can be treated with the SRS boost. Methods: Pts with 1–4 BM (< 4 cm diameter, or, if multiple, < 3cm) received WBRT (37.5 Gy) and MGd, 5 mg/kg/day during weeks 2–3 of WBRT, plus MGd, 5 mg/kg prior to treatment planning MRI and prior to SRS (21 Gy for lesions = 2 cm, 18 Gy for lesions 2.1–3.0 cm, and 15 Gy for lesions 3.1–4.0 cm). MRI was obtained within 4 weeks prior to enrollment with standard contrast, and after WBRT for SRS treatment planning with MGd and standard contrast. Patients were followed for neurologic progression and survival. Results: 45 patients with either lung cancer (76%), breast cancer (11%), melanoma (7%), or other cancers (7%), a median age of 58 years (range 42–74), and a median of 2 BM (range 1–4) were evaluable. In 9 of 42 patients (21%) with MRI data available, the MGd-based treatment planning MRI demonstrated at least one occult lesion not visualized on the screening MRI. The MGd-based treatment planning MRI detected 1 occult lesion in 6 pts, 2 occult lesions in 1 patient, and 3 occult lesions in 2 patients. Median survival for evaluable pts is 10 months; median time to neurologic progression or radiologic progresssion is not reached at 15 months. Grade 3+ neurotoxicity was limited to 1 pt with tumor necrosis and 1 pt with motor weakness. Most common Grade 3+ adverse events were pneumonia (9%) and DVT (9%). Conclusions: MGd-based treatment planning MRI for SRS identified occult BM that are amenable to SRS and are undetected with standard gadolinium contrast agents in 21% of the pts enrolled in this phase II trial. Treatment with MGd, WBRT and SRS to all lesions visualized resulted in improved survival and local control compared with historical results. [Table: see text]
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Shi, Yuankai, Suxia Luo, Huan Zhou, Shengyu Zhou, Shan An, Zishu Wang, Sheng Yang, Ning Li, Xiaoli Li, and Xinyi Yang. "Phase I study of LBL-007, a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody in patients with advanced solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2523. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2523.
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2523 Background: LAG-3 is an immune checkpoint receptor expressed on activated T cells to negatively regulate these cells, resulted in tumor immune escape. LBL-007, a novel anti-LAG-3 antibody, was developed by screening of a human antibody phage display library and demonstrated specific binding to human LAG-3, stimulation of IL-2 release and blockage of LAG-3 binding to its ligands including MHC II. It has shown that LBL-007 significantly inhibited tumor growth in a mouse MC38 tumor model in hLAG-3 knock-in mice with more pronounced tumor inhibition when combined with an anti-PD-1 antibody. Methods: A phase I, multicenter, open-label and first-in-human study was conducted to evaluate the safety, tolerability, and PK in patients with advanced solid tumors. The dose escalation phase was designed with 6 dose cohorts of LBL-007 at 0.05, 0.25, 1, 3, 6 and 10 mg/kg (iv every 2 weeks), using a modified 3+3 design. Key inclusion criteria included: age≥18 years, histologically/cytologically confirmed advanced solid tumors, failed ≥2 lines of prior standard therapies, ECOG of 0-1, and adequate hematologic, renal, hepatic, and cardiac function. Patients who received anticancer or immunotherapy 4 weeks from first dose of LBL-007 were excluded. The primary endpoints were tolerability and safety. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Any potential efficacy was assessed by objective response rate (ORR) evaluated by CT/MRI per RECIST 1.1. Results: From March 12th, 2020 to Feb 9th, 2021, 17 patients were evaluated in this study. There were no dose limiting toxicities (DLTs) at any dose cohorts, and patients were tolerated very well. Overall, there were 129 adverse events (AEs), and 8 events were serious adverse event (SAE), of which 5 were defined as suspected unexpected serious adverse reaction (SUSAR), but most unlikely treatment related AEs (TRAEs). All AEs regardless of attribution included anemia, hypocalcemia, and flu related respiratory infection, etc. The most common AEs were anemia (14, 10.9%), hypocalcemia (6, 4.7%) and thrombocytopenia (4, 3.1%). Totally, there were 8 patients without disease progression, defined as SD at the first evaluation and sustained for 3.5-9 months. The target lesions in 2 of these 8 patients were reduced by 18.9% and 23.2% (both in esophagus cancer). The progression-free survival of these 2 patients was 4.4 and 9.0 months, respectively. Patients are also being enrolled into the indication exploratory phase (3 and 6 mg/kg), testing the combination therapy with an anti-PD-1 antibody in patients with melanoma and other solid tumors. Conclusions: The dose escalation part of the study revealed tolerability of LBL-007 with an impressive safety profile, and potentially some encouraging signs of anti-tumor activities. Clinical trial: Chinaclinicaltrials.org.cn (1900025904). Clinical trial information: CTR20210196.
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Sharman, Jeff Porter, Jerome H. Goldschmidt, John M. Burke, Beth A. Hellerstedt, Kristi McIntyre, Christopher A. Yasenchak, Thomas E. Boyd, et al. "CD30 expression in nonlymphomatous malignancies." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3069. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3069.
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3069 Background: CD30 is commonly expressed in Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma. Expression of CD30 in other solid tumors and non-lymphomatous malignancies has been reported but not investigated systematically. CD30 is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate (ADC) that is approved for the treatment of patients with relapsed HL and systemic ALCL after failure of other therapies. A study was initiated to determine the incidence of CD30 expression in non-lymphomatous malignancies and to identify patients who may be candidates for treatment with brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies were eligible for screening if they were relapsed or refractory to previous therapy or had no effective treatment options available. Archived tissue from solid tumors was tested for CD30 expression by immunohistochemistry (IHC); fresh bone marrow or blood samples from multiple myeloma or leukemia patients were tested by flow cytometry. Patients were considered CD30 positive and eligible for a companion treatment protocol with brentuximab vedotin if ≥10% of malignant cells stained positive by IHC or ≥20% by flow cytometry. Results: At this interim analysis, a total of 875 patients have been tested for CD30 expression: 95% had solid tumors, 3% had leukemia, and 2% had multiple myeloma. Twenty-two patients (2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer (7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of 4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid carcinoma (33%). One patient was identified with CD30-positive mast cell leukemia. In positive patients, the percent of CD30-positive malignant cells varied between 10 and 80%. Conclusions: CD30 expression was observed in multiple types of non-lymphomatous malignancies, thereby identifying additional populations who may be candidates for treatment with a CD30-targeted ADC, such as brentuximab vedotin. A companion clinical trial with brentuximab vedotin is currently ongoing.
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Corcoran, Ryan Bruce, Gerald Steven Falchook, Jeffrey R. Infante, Omid Hamid, Wells A. Messersmith, Adil Daud, Eunice Lee Kwak, et al. "Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3507. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3507.
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3507 Background: TheBRAF V600 mutation occurs in 5-10% of metastatic CRC, predicts poor prognosis, and may predict lack of response to standard therapy. The combination of inhibitors of BRAF (dabrafenib; D) and MEK (trametinib; T) has shown significant efficacy in BRAF-mutant melanoma. The safety, efficacy, and pharmacodynamic effects of this combination were studied in BRAF-mutant CRC patients (pts). Methods: BRAF mutant CRC pts were enrolled to an initial efficacy cohort of 26 pts and a subsequent pharmacodynamic (PD) expansion cohort that included biopsies of 15 pts at screening and at steady state. So far, 36 pts have enrolled, including 10 in the PD cohort. Eligible pts had previously-treated BRAFV600E mutant stage IV CRC. Pts were treated with D (150mg BID) and T (2mg QD). Additional analyses were performed on available archival tissues. Results: Data are available for 36 pts: ECOG performance status 0 (58%) or 1 (42%), 81% had received ≥ 2 prior chemotherapy regimens, 36% had received prior EGFR inhibitor treatment, and 83% had ≥ 1 biologic therapy. Among 34 pts with >1 restaging assessment as of November 2012, 1 (3%) achieved a complete response (confirmed, on study >12m), 3 (9%) achieved a partial response (1 confirmed to date), and 18 (53%) had stable disease (SD). Minor responses were seen in 7/18 pts (39%) with SD. Median PFS was 3.5 mo (95% CI: 1.8-4.9); overall duration on study range: 0.03–15.2 mo 7 pts (24%) remained on study for ≥6 cycles with 9 pts still on study. The most frequent AEs, any grade, included pyrexia (67%), nausea (56%), fatigue (53%), chills (47%), vomiting (39%), headache (31%), peripheral edema (31%), anemia (28%), and decreased appetite (28%). 2 pts (6%) discontinued due to AEs. Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ±29%) and relative (69% ±28%, normalized to total ERK) reduction in pERK. Conclusions: Further investigation is needed, as this combination is tolerable at full monotherapy doses of each drug, with manageable toxicities, and has activity in a subset of BRAF mutant pts. Updated safety, efficacy, and correlative data will be presented. Clinical trial information: NCT01072175.
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Cust, A. E., J. F. Aitken, P. D. Baade, D. C. Whiteman, H. P. Soyer, and M. Janda. "Why a randomized melanoma screening trial may be a good idea." British Journal of Dermatology 179, no. 5 (September 20, 2018): 1227–28. http://dx.doi.org/10.1111/bjd.17089.
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Hyde, Mark A., Douglas Grossman, Yelena P. Wu, Saundra Buys, Lisa H. Gren, and Mia Hashibe. "Vitamin D, melanoma risk, and tumor thickness in PLCO cancer screening trial patients." Journal of the American Academy of Physician Assistants 33, no. 6 (June 2020): 35–41. http://dx.doi.org/10.1097/01.jaa.0000662388.18867.42.
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Maeda, Tetsuo, Ukihide Tateishi, Shigenobu Suzuki, Yasuaki Arai, E. Edmund Kim, and Kazuro Sugimura. "Magnetic Resonance Screening Trial for Hepatic Metastasis in Patients with Locally Controlled Choroidal Melanoma." Japanese Journal of Clinical Oncology 37, no. 4 (April 1, 2007): 282–86. http://dx.doi.org/10.1093/jjco/hym018.
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Clouthier, Derek L., Cindy Yang, Scott Lien, Diana Gray, Ilaria Colombo, Stephanie Lheureux, Jeremy Howard Lewin, et al. "A technical feasibility report on correlative studies from the investigator-initiated phase II study of pembrolizumab (Pembro) immunological response evaluation (INSPIRE)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11607. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11607.
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11607 Background: Validated biomarkers of response to immune checkpoint inhibitors are needed. Methods: INSPIRE (NCT02644369) is a biomarker-driven study to comprehensively evaluate changes in genomic and immune landscapes in tumors and blood of patients (pts) treated with pembro at 200 mg IV Q3W. It consists of 5 histological cohorts of 20 evaluable pts each: head and neck squamous cell cancer (SCCHN), triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC), melanoma (MM) and mixed solid tumors (MST). All pts undergo pre- and on-treatment (week 6-9) fresh tumor biopsies (bx), and at progression for responders. The first core bx is for immunohistochemistry and subsequent cores are pooled to create single cell suspension for 5 prioritized biomarker assay groups: (1) whole exome/RNA-/TCR-sequencing; (2) T/B/NK, APCs, and/or Treg phenotyping; (3) patient-derived xenografts; (4) RNA-seq on viably sorted immune populations; (5) TIL expansion and characterization. Serial blood samples for immunophenotyping, chemokines/cytokines and ctDNA are collected. Results: 53 pts were enrolled from March 21, 2016-January 16, 2017 (5 SCCHN, 8 TNBC, 17 HGSOC, 7 MM, 16 MST). 84 tumor bx (53 pre-, 30 on-treatment, 1 progression) and 244 blood-based biomarker samples have been collected. The most common sites of tumor bx were: lymph nodes (27%), liver (22%) and skin (14%) (see table). For the 5 cohorts, the % of tumor bx with sufficient cellularity for biomarker assay groups 1 and 2 are: SCCHN (33%), TNBC (9%), HGSOC (52%), MM (55%), MST (55%). Conclusions: This report provides robust technical feasibility data to plan immune and molecular characterization of tumor and blood-based biomarkers in pts receiving ICI. Clinical trial information: NCT02644369. [Table: see text]
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Zhang, Hongjun, Xiangnan Liu, Yong’an Chen, Rui Xu, and Shengli He. "KDOAM-25 Overcomes Resistance to MEK Inhibitors by Targeting KDM5B in Uveal Melanoma." BioMed Research International 2022 (September 28, 2022): 1–9. http://dx.doi.org/10.1155/2022/1556485.
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Background. Uveal Melanoma (UM) is a potentially lethal cancer, and epigenetics may participate in the regulation of MEK resistance. This study is aimed at targeting the epigenetic kinase to overcome the resistance to MEK inhibitor. Method. We developed the 92.1 and OMM1 MEK-inhibitor resistant cell lines by culturing them in the trametinib (Tra) mixed medium. We utilized CCK8 analysis for detecting the viability of the cell. Western blot was used to determine the ERK1/2 and Akt phosphorylation. Small compound library screening assays were carried out by CCK8 analysis. To test the apoptosis, we employed flow cytometric analysis with Annexin-V/PI. Western blot and CCK8 were used to explore the epigenetic regulation of KDM5B in MEK-resistance cell lines. To knock out the expression level of KDM5B, we used the CRISPR/Cas9 by lentivirus delivering well-validated shRNAs in pLKO.1 vector. The directly binding affinity of KDOAM-25 to KDM5B was determined by drug affinity responsive target stability (DARTS) and microscale thermophoresis (MST). Results. The phosphorylation of ERK1/2 and Akt (T308) was inhibited in OMM1 cell lines. However, inhibition of Tra was abolished in OMM1-R cell lines. From a compound screening assay, we identified that KDOAM-25 robustly inhibited the viability and colony formation of MEK-resistance cell lines. Furthermore, KDOAM-25 significantly promoted cell death in OMM1-R cells. H3K4me3 (tri-methylation of lysine 4 on histone H3) and H3K27ac (acetyl of lysine 27 on histone H3) were both upregulated in OMM1-R cells. Tra significantly inhibited the expression of KDM5B in OMM1-P cells. However, the effect on KDM5B was abolished in OMM1-R cells. Knockdown of KDM5B robustly suppressed the cell viability in OMM1-R cells. KDOAM-25 directly interacted with KDM5B. Conclusion. KDOAM-25 inhibited the viability and colony formation and promoted cell death of MEK-resistance cell lines through H3K4me3 and H3K27ac, indicating that KDOAM-25 may be a potential therapeutic agent for MEK resistance in UM patients.
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Urosevic, V., Ph Chollet, A. Adenis, J. Chauvergne, P. Fargeot, H. Roche, P. Kerbrat, M. A. Lentz, P. Fumoleau, and B. Chevallier. "Results of a phase II trial with cystemustine in advanced malignant melanoma. A trial of the EORTC Clinical Screening Group." European Journal of Cancer 32, no. 1 (January 1996): 181–82. http://dx.doi.org/10.1016/0959-8049(95)00473-4.
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Markham, Merry Jennifer, Kerri Wachter, Neeraj Agarwal, Monica M. Bertagnolli, Susan Marina Chang, William Dale, Catherine S. M. Diefenbach, et al. "Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology." Journal of Clinical Oncology 38, no. 10 (April 1, 2020): 1081. http://dx.doi.org/10.1200/jco.19.03141.
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Each year Clinical Cancer Advances: ASCO’s Annual Report on Progress Against Cancer highlights the most important clinical research advances of the past year, including the Advance of the Year, and identifies priority areas where ASCO believes research efforts should be focused moving forward. In 2020, ASCO names the Refinement of Surgical Treatment of Cancer as the Advance of the Year. Years of progress in developing new systemic cancer therapies has not only improved patient survival and quality of life but is now transforming surgical approaches to cancer treatment. The emergence of novel systemic therapies combined in new and better ways is significantly changing the role of cancer surgery. ASCO’s selection of Refinement of Surgical Treatment of Cancer as the 2020 Advance of the Year recognizes recent strides seen in the effectiveness of these treatments in reducing the amount of surgery, and even the need for it, while increasing the number of patients who can undergo surgery when needed. Other advances highlighted in the report include progress in cancer prevention, molecular diagnostics, and cancer treatment—surgery, radiotherapy, combination therapy, immunotherapy, and other types of therapies. The report also features ASCO's 2020 list of Research Priorities to Accelerate Progress Against Cancer. These priorities represent promising areas of research that have the potential to significantly improve the knowledge base for clinical decision-making and address vital unmet needs in cancer care. A MESSAGE FROM ASCO’S PRESIDENT Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn’t been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies. Clinical research is about saving and improving the lives of individuals with cancer. It’s a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO’s Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology. ASCO’s 2020 Advance of the Year—Refinement of Surgical Treatment of Cancer—highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery. Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer. While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can’t rest on our laurels. With ASCO’s Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we’ve identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress. Of course, the effectiveness or number of new treatments is meaningless if patients don’t have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge. Sincerely, Howard A. “Skip” Burris III, MD, FACP, FASCO ASCO President, 2019-2020
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Hanrahan, P. F., C. A. D’Este, S. W. Menzies, T. Plummer, and P. Hersey. "A randomised trial of skin photography as an aid to screening skin lesions in older males." Journal of Medical Screening 9, no. 3 (September 1, 2002): 128–32. http://dx.doi.org/10.1136/jms.9.3.128.
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OBJECTIVES: We have previously shown that photographs assist in detection of change in skin lesions and designed the present randomised population based trial to assess the feasibility of photographs as an aid to management of skin cancers in older men. SETTING: 1899 men over fifty, identified from the electoral roll in two regions in New South Wales (NSW), Australia, were invited by mail to participate. METHODS: A total of 973 of 1037 respondents were photographed and randomised into intervention (participants given their photographs) or control groups (photographs withheld by investigators). At one and two years from the time of photography, all participants were advised to see their primary care practitioner for a skin examination. Those in the intervention group were examined with their photographs and those in the control group without their photographs. RESULTS: The results indicated that the practitioners were more likely to leave suspicious lesions in place for follow up observation (37% v 29%) (p=0.006) and less likely to excise benign non pigmented lesions (20 v 32%). There was little difference in excision rates for benign pigmented lesions (21% v 23%). Lesions excised were more likely to be non-melanoma skin cancer (58% v 42%) from patients who had photographs compared to those without photographs (p=0.005). The use of skin photography resulted in a substantial savings due to the reduced excision of benign lesions. CONCLUSIONS: These results suggest that it would be feasible to conduct a large scale randomised trial to evaluate the value of photography in early detection of melanoma and that such a trial could be cost effective due to the reduced excision of benign skin lesions.
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Thompson, John F., Mario Santinami, Thomas Jouary, Eugeny Levchenko, Bernard Mark Smithers, Laurent Mortier, Jean Jacques Grob, et al. "MAGE-A3 expression in patients screened for the DERMA trial: A phase III trial testing MAGE-A3 immunotherapeutic in the adjuvant setting for stage IIIB-C-Tx melanoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8559. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8559.
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8559 Background: Administration of MAGE-A3 immunotherapeutic involves the active immunization of patients (pts) with tumors expressing the MAGE-A3 protein. This new investigational approach has been previously assessed in two phase II trials, one in pts with metastatic melanoma (NCT00086866) and another in pts with completely resected non-small cell lung cancer (NCT00290355). Based on the positive responses observed in both studies, a randomized phase III placebo controlled trial assessing MAGE-A3 immunotherapeutic as adjuvant treatment in pts with resected, regionally advanced melanoma (stage IIIB-C-Tx AJCC/UICC 2010) is currently ongoing (DERMA Phase III trial, NCT00796445). Methods: Formalin-fixed, paraffin-embedded tumor tissues were prepared from surgically removed metastatic lymph nodes and tested for MAGE-A3 expression by qRT-PCR. Other baseline patient and tumor characteristics were collected during screening to further investigate factors that could potentially influence MAGE-A3 expression. Results: Between Dec 1, 2008 and Oct 25, 2011, 3917 pts were screened. Of the 3,183 valid samples (excluding the 513 inconclusive tests [66% for poor quality, 27% out-of range, 7% miscellaneous]) and the 221 missing samples, 2,092 (65.7%) were positive for MAGE-A3 expression. In these stage III melanoma pts, no difference in MAGE-A3 expression levels were identified with regard to (1) disease stage - IIIB (62.6%), IIIC (66.5%) and IIITx (66.2%); (2) gender - male (64.2%), female (68.1%); (3) age group - 18 to 39 years (63.2%), 40 to 49 years (65.3%), 50 to 59 years (66.8%), 60 to 69 years (68.1%) and 70 years and over (63.4%) and (4) region: Europe (66.1%), North America (63.0%) and rest of the world including Argentina, Brazil, Australia, Mexico, Taiwan, Japan, Korea (67.9%). Conclusions: Expression of the MAGE-A3 gene in the DERMA trial population (stage IIIB-IIIC-IIITx) was 66%. It was not correlated with age, gender, disease stage or geographic region. This expression frequency is consistent with published data in metastatic melanoma (Van den Eynde, 1997; Vourc’h-Jourdain et al, 2009) and has potentially important clinical implications.
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Lyle, Megan, and Georgina V. Long. "Diagnosis and Treatment ofKIT-Mutant Metastatic Melanoma." Journal of Clinical Oncology 31, no. 26 (September 10, 2013): 3176–81. http://dx.doi.org/10.1200/jco.2013.50.4662.
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A 52-year-old man has unresectable locally recurrent melanoma of the left foot ( Fig 1 ) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm2. Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High-resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation.
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Marshall, Ernest, Chris Romaniuk, Paula Ghaneh, Helen Wong, Marie McKay, Mona Chopra, Sarah Coupland, and Bertil Damato. "High-risk uveal melanoma: A prospective study evaluating the role of magnetic resonance imaging of the liver." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8564. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8564.
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8564 Background: Almost 50% of uveal melanomas are fatal. Metastatic death occurs almost exclusively with tumours showing chromosome 3 loss and 8q gain. Metastases, which almost always involve the liver, are resectable in some patients. They are rarely detectable when the patient presents with the primary ocular tumour. Screening is therefore necessary, but there is no consensus as to who should be screened, how often, and for how long. Methods: Uveal melanoma patients with ECOG performance status 0-2 were eligible if their risk of metastatic death at 5 years exceeded 50%. Survival probability was estimated by multivariate analysis of tumour stage, histological grade and genetic tumour type. Patients underwent screening 6monthly, clinical examination, non-contrast liver MRI and liver function tests for at least five years. Results: Between Jan 2000 and November 2010, 279 high-risk patients were referred for screening. Of these, 188 (84 male, 104 female) accepted screening and underwent as least 1 MRI. The median age was 63 years (IQR 16.5). Median basal tumour diameter was 16.5mm (IQR 5.25). Chromosome 3 loss was detected in 175 tumours. Median follow up time was 28.8 months (IQR 29.1). Median relapse-free survival was 33 months (95% CI 28-38) with a 35% relapse-free survival at 5 years. After a median of 18 months (IQR 20), screening detected metastases in 90/188 (48%), 83 of whom were asymptomatic. 12 patients underwent R0 liver resection, which increased the median survival from 10 (95% CI 8.1 - 11.9) to 24 (95% CI 20.2- 27.8) months. The screening programme stimulated a UK NCRI portfolio of clinical trials in which 23 of these patients were subsequently treated. Conclusions: Six-monthly liver MRI detects metastases from uveal melanoma at an early stage, thereby enhancing opportunities for surgical metastatectomy, clinical trial participation and prolonging life.
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Robinson, June K., Namita Jain, Ashfaq A. Marghoob, William McGaghie, Michael MacLean, Pedram Gerami, Brittney Hultgren, Rob Turrisi, Kimberly Mallett, and Gary J. Martin. "A Randomized Trial on the Efficacy of Mastery Learning for Primary Care Provider Melanoma Opportunistic Screening Skills and Practice." Journal of General Internal Medicine 33, no. 6 (February 5, 2018): 855–62. http://dx.doi.org/10.1007/s11606-018-4311-3.
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Zhu, Lucía, Natalia Yebra, Diana Retana, Carmen Blanco-Aparicio, Sonia Martínez, Riccardo Soffietti, Luca Bertero, et al. "42. IDENTIFICATION OF BRAIN METASTASIS VULNERABILITIES USING METPLATFORM." Neuro-Oncology Advances 2, Supplement_2 (August 2020): ii8. http://dx.doi.org/10.1093/noajnl/vdaa073.030.
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Abstract The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. In this study, we report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures). We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. Debio-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, we have also used METPlatform to perform unbiased proteomics of brain metastases in situ. By applying this analysis to brain metastases treated with the chaperone inhibitor, we uncovered non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.
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Lupo-Stanghellini, Maria Teresa, Giacomo Oliveira, Raffaella Greco, Luca Vago, Attilio Bondanza, Fabio Ciceri, Claudio Bordignon, and Chiara Bonini. "TK-Cells Safety and Efficacy in Allogeneic Hematopoietic Stem Cell Transplantation: Long-Term Clinical and Molecular Assessment in 128 Treated Patients." Blood 120, no. 21 (November 16, 2012): 3061. http://dx.doi.org/10.1182/blood.v120.21.3061.3061.
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Abstract Abstract 3061 Background and methods. Suicide gene therapy (SGT) applied to allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been one of the first clinical applications of gene therapy. In allo-HSCT the antileukemic potential mediated by alloreactive lymphocytes towards patient-specific antigens, such as minor and major histocompatibility antigens, is counterbalanced by the Graft-versus-Host-Disease (GvHD). The risk of GvHD increases with the level of HLA disparity between host and donor, and leads to impaired quality of life and reduced survival, particularly in patients (pts) transplanted from HLA-mismatched donors. In this contest SGT has been applied to modulate alloreactivity, by inserting the HSV-tk gene in donor lymphocytes. This suicide gene/prodrug system requires cell cycle for optimal killing. In the context of allo-HSCT, this characteristic ensures a further level of specificity in GvHD control, by allowing to selectively kill highly proliferating alloreactive cells during GvHD, while sparing resting T cells. We assessed long-term safety in TK cells treated pts. Results. Overall 128 pts have been treated worldwide in 10 phase I-II clinical trials with donor lymphocytes expressing the HSV-tk suicide gene, with the purpose of enforcing the graft-versus-tumor (GvT) effect and/or promoting a functional post-transplant immune reconstitution (IR) while allowing control of GvHD. This approach proved highly feasible, safe and effective in promoting a dynamic and patient-specific modulation of alloreactivity. TK cells engrafted in the majority of pts and a clinical benefit, measured as improvement of hematopoietic chimerism, malignant regression and/or IR, was reported for 65 pts (51%). GvHD grade II-IV was observed in 28 pts (22%) and was always rapidly and completely controlled by the activation of suicide machinery. A selected population of 57 pts, treated at San Raffaele Institution, was studied in more detail for long-term analysis: 23 pts received cells to treat relapse occurring after an HLA-identical allo-HSCT (Ciceri F et al, Blood. 2007: 109; 4698–470) and 34 pts to improve IR after haploidentical HSCT (Bonini C et al, Blood. 2002; 100: 115a; Ciceri F, Bonini C et al, Lancet Oncology. 2009; 10: 489–500). No adverse event correlated to the gene transfer procedure was ever reported. Genetically modified cells engrafted in 90% of treated pts and could be detected in vivo, at low frequencies for up to 14 years (y). In the HLA-identical setting 11 pts obtained clinical response of the malignant disease and 3/11 are alive with a median follow-up of 15y. Two pts are in complete remission (CR), while one pt affected by chronic myelomonocytic leukemia relapsed 15y post transplant. This pt was subsequently treated with a second transplant from an unrelated match donor and is now in CR 1 year after transplant. In the haploidentical setting, 25 pts/34 reached the target of IR and 9 are alive and in CR with a median follow-up of 7y. Four out of 9 experienced GVHD in the early phase post IR, none presented signs, symptoms, complications related to GvHD and none needed pharmacological treatment in long-term. According to international guideline for long-term follow-up (Majhail NS et al, BBMT. 2012; 18: 348–371) all pts underwent regular screening and clinical evaluation. No major infections occurred in the late phase, no ocular, oral, respiratory, hepatic, renal, genitourinary, muscle-skeletal or neurological distress. Noteworthy 3 pts developed second cancer (2 skin cancer non-melanoma, 1 endometrial cancer), 2 pt hypothyroidism, 1 pt coronary artery disease and 3 pts metabolic syndrome. No evidence of psychosocial symptoms was reported. Immunity against the transgene was reported in pts who received TK cells late after an HLA-identical allo-SCT. The quality of IR at the time of TK cells administration was the most predictive variable. On the contrary, no immunity against HSV-tk was ever detected in pts who received TK cells after transplantation of haploidentical CD34-selected cells, indicating that the infusion of TK cells to highly immunosuppressed pts is not limited by the development of transgene-specific immune responses. Conclusions. Long-term assessment confirmed the overall high benefit/risk ratio of the TK-cell approach in allo-HSCT. A phase III multicentric, randomized clinical trial sponsored by MolMed, is currently undergoing in the context of haploidentical HSCT. Disclosures: Bordignon: MolMed SpA: Employment. Bonini:MolMed S.p.A.: Consultancy.
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Ohmoto, Akihiro, Shinichi Yachida, and Chigusa Morizane. "Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer." International Journal of Molecular Sciences 20, no. 3 (January 29, 2019): 561. http://dx.doi.org/10.3390/ijms20030561.
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Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.
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Primiero, Clare A., Anna Finnane, Tatiane Yanes, Betsy Peach, H. Peter Soyer, and Aideen M. McInerney-Leo. "Protocol to evaluate a pilot program to upskill clinicians in providing genetic testing for familial melanoma." PLOS ONE 17, no. 12 (December 7, 2022): e0275926. http://dx.doi.org/10.1371/journal.pone.0275926.
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Introduction Genetic testing for hereditary cancers can improve long-term health outcomes through identifying high-risk individuals and facilitating targeted prevention and screening/surveillance. The rising demand for genetic testing exceeds the clinical genetic workforce capacity. Therefore, non-genetic specialists need to be empowered to offer genetic testing. However, it is unknown whether patient outcomes differ depending on whether genetic testing is offered by a genetics specialist or a trained non-genetics clinician. This paper describes a protocol for upskilling non-genetics clinicians to provide genetic testing, randomise high-risk individuals to receive testing from a trained clinician or a genetic counsellor, and then determine whether patient outcomes differed depending on provider-type. Methods An experiential training program to upskill dermatologically-trained clinicians to offer genetic testing for familial melanoma is being piloted on 10–15 clinicians, prior to wider implementation. Training involves a workshop, comprised of a didactic learning presentation, case studies, simulated sessions, and provision of supporting documentation. Clinicians later observe a genetic counsellor led consultation before being observed leading a consultation. Both sessions are followed by debriefing with a genetic counsellor. Thereafter, clinicians independently offer genetic testing in the clinical trial. Individuals with a strong personal and/or family history of melanoma are recruited to a parallel-group trial and allocated to receive pre- and post- genetic testing consultation from a genetic counsellor, or a dermatologically-trained clinician. A mixed method approach measures psychosocial and behavioural outcomes. Longitudinal online surveys are administered at five timepoints from baseline to one year post-test disclosure. Semi-structured interviews with both patients and clinicians are qualitatively analysed. Significance This is the first program to upskill dermatologically-trained clinicians to provide genetic testing for familial melanoma. This protocol describes the first clinical trial to compare patient-reported outcomes of genetic testing based on provider type (genetic counsellors vs trained non-genetic clinicians).
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Anderson, Steven, Kenneth J. Bloom, Dino U. Vallera, Josef Rueschoff, Cliff Meldrum, Robert Schilling, Barbara Kovach, et al. "Multisite Analytic Performance Studies of a Real-Time Polymerase Chain Reaction Assay for the Detection of BRAF V600E Mutations in Formalin-Fixed, Paraffin-Embedded Tissue Specimens of Malignant Melanoma." Archives of Pathology & Laboratory Medicine 136, no. 11 (November 1, 2012): 1385–91. http://dx.doi.org/10.5858/arpa.2011-0505-oa.
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Context.—A polymerase chain reaction–based companion diagnostic (cobas 4800 BRAF V600 Mutation Test) was recently approved by the US Food and Drug Administration to select patients with BRAF-mutant metastatic melanoma for treatment with the BRAF inhibitor vemurafenib. Objectives.—(1) To compare the analytic performance of the cobas test to Sanger sequencing by using screening specimens from phase II and phase III trials of vemurafenib, and (2) to assess the reproducibility of the cobas test at different testing sites. Design.—Specimens from 477 patients were used to determine positive and negative percent agreements between the cobas test and Sanger sequencing for detecting V600E (1799T>A) mutations. Specimens were evaluated with a massively parallel pyrosequencing method (454) to resolve discordances between polymerase chain reaction and Sanger results. Reproducibility of the cobas test was assessed at 3 sites by using 3 reagent lots and an 8-member panel of melanoma samples. Results.—A valid cobas result was obtained for all eligible patients. Sanger sequencing had a failure rate of 9.2% (44 of 477). For the remaining 433 specimens, positive percent agreement was 96.4% (215 of 223) and negative percent agreement, 80% (168 of 210). Among 42 cobas mutation-positive/Sanger V600E-negative specimens, 17 were V600E positive and 24 were V600K positive by 454. The cobas test detected 70% of V600K mutations. In the reproducibility study, a correct interpretation was made for 100% of wild-type specimens and specimens with greater than 5% mutant alleles; V600E mutations were detected in 90% of specimens with less than 5% mutant alleles. Conclusions.—The cobas test (1) had a lower assay failure rate than that of Sanger, (2) was more sensitive in detecting V600E mutations, (3) detected most V600K mutations, and (4) was highly reproducible.
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Locke, Darren, Steven Bernstein, Frank Lynch, Koushan Siami-Namini, Jackie M. Walling, Thomas Yonker, and Geoffrey Yarranton. "An IHC Screen For EphA3 Positive FFPE Tumors." Blood 122, no. 21 (November 15, 2013): 4965. http://dx.doi.org/10.1182/blood.v122.21.4965.4965.
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Abstract Eph receptors are the largest subgroup of the receptor tyrosine kinases (RTK). Unlike other RTK, these function principally during development. Quiescent in postembryonic tissues, Eph expression by adult tissues is abnormal and implicated in tumor initiation, invasion and metastasis. Aberrant EphA3 expression is seen in solid and hematologic tumors, particularly advanced stage lymphoproliferative and myeloproliferative diseases. In this regard, targeting EphA3 may constitute a novel treatment for hematological malignancy. With clinical utility in mind, i.e., patient selection for anti-EphA3 therapy, a panel of commercial and proprietary (KaloBios) antibodies was screened by Western Blot for reactivity to recombinant Eph receptors (EphA3, EphA4, EphA5, EphA7, EphB2, EphB3). Those with EphA3 binding selectivity were further screened (QualTek) by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) normal and diseased human bone marrow (NLBM, AML) as well the LK63 pre-B-ALL cell line from which EphA3 was originally isolated. Different tissue pretreatments were used for antigen/epitope retrieval of EphA3, including steam-heating in citrate-based or Tris & chelator-based buffers, subsequent/or protease digestion, or neither. Following each antigen/epitope retrieval procedure, antibody reactivity for EphA3 was assessed by light microscopy using enzymatic biotin, tyramide and polymer-based detection techniques. In each instance, the location of the EphA3/antibody complex was visualized with 3,3-diaminobenzidine that precipitates a discrete insoluble reaction product in presence of enzyme (HRP). Nuclei were counterstained with hematoxylin to assess cell/tissue morphology. From this screen, one antibody (with an epitope in the cytoplasmic CT-domain of EphA3) was chosen for further assay optimization based on its selective reactivity towards LK63 and AML and low selective reactivity towards NLBM. Assay optimization included, amongst other aspects, evaluation of EphA3 expression in a panel of NLBM and hematopoietic tumors (200+ specimens inclusive of acute & chronic leukemia, peripheral T-cell & B-cell neoplasm, Hodgkin & non-Hodgkin lymphoma, multiple myeloma, myelodysplasic syndrome, myeloproliferative neoplasm) by a board-certified hematopathologist. In NLBM, the frequency of EphA3+ immature-blast cells (CD34+ or CD117+) was insignificant. Less than 10% CD34+/CD117+ cells were EphA3+. Elevated EphA3 expression (percentage EphA3+ nucleated cells) was observed in most hematopoietic tumors. For example, in multiple myeloma, tumor cells were typically EphA3+/CD138+ plasma cells. For AML, leukemic CD34+ or CD117+ blasts/initiating cells were typically EphA3+. Some CD138- plasma cells or leukemic CD34-/CD117- cells were also EphA3+. Correlation was made between EphA3 expression and specific tumor maturation stages, differentiation status and/or tumor aggressiveness. Tumors in blast crisis presented elevated EphA3 expression, e.g., CML in accelerated or blastic crisis but not chronic phase. Elevated EphA3 expression was noted in pre-B-ALL & pro-B-ALL (early pre-B-ALL) rather than mature B-cell ALL. EphA3 expression for some peripheral B-cell neoplasms correlated well with tumor grade: high grade, poorly differentiated (typically aggressive) B-cell lymphomas or follicular lymphomas were EphA3+. A similar relationship was noted for non-Hodgkin lymphoma (Hodgkin lymphoma was EphA3-). Preclinical screening also provided evidence for EphA3 expression by stroma/fibroblast (mostly lymphoma) and vasculature/endothelium, further rationale for development of reliable tools for profiling EphA3 in hematologic tumors and other malignancies. Using well-characterized normal and diseased FFPE bone marrow biopsies, this IHC assay for EphA3 has subsequently been validated (QualTek) to provide data that is not directly available from routine histopathology review and that supports use of the assay for profiling EphA3 in specific hematologic tumors and for patient selection in early Phase clinical trial/s of an anti-EphA3 monoclonal antibody (KB004, KaloBios). Beyond this, EphA3 targeted therapy with KB004 is anticipated for treatment of solid tumors. Recent genome-wide surveys identify EphA3 amongst the most frequently overexpressed genes in pancreatic, colon and lung carcinoma, melanoma and glioblastoma. Disclosures: Locke: QualTek Molecular Labs: Employment. Bernstein:QualTek Molecular Laboratories: Employment, Equity Ownership. Lynch:QualTek Molecular Laboratories: Employment, Equity Ownership. Siami-Namini:QualTek Molecular Laboratories: Consultancy. Walling:KaloBios: Consultancy; Corcept Therapeutics: Consultancy; Prothena: Consultancy; New Gen Therapeutics: Consultancy; Valent Technologies: Consultancy; LBC Pharmaceuticals: Consultancy; Amgen: Equity Ownership; BioMarin: Equity Ownership; Crown BioScience: Membership on an entity’s Board of Directors or advisory committees. Yonker:KaloBios: Employment, Equity Ownership. Yarranton:KaloBios: Employment, Equity Ownership; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; StemLine Therapeutics: Equity Ownership.
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Maller, Bradley, Vani Nath Simmons, Margaret M. Byrne, and Tawee Tanvetyanon. "Outcomes of lung cancer screening among cancer survivors: An NCCN institution experience." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1595. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1595.
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1595 Background: In 2013, the USPTF recommended low-dose CT (LDCT) screening for individuals at high risk of lung cancer based on data from the National Lung Screening Trial. However, the trial excluded participants with cancer diagnosis < 5 years except for non-melanoma skin cancer, making it unclear whether the data will be generalizable to cancer survivors. This population, while at increased risk of secondary lung cancer, may be prone to false positive results due to anatomic defects or recurrent cancers. Our NCCN institution serves a large number of cancer survivors. We evaluated the outcomes of LDCT screening and the adherence to annual screening among cancer survivors, compared with individuals without cancer history (IWC). Methods: Prospectively maintained database of LDCT screening participants was analyzed. Eligibility was per NCCN criteria and cancer survivors needing regular chest CT were not offered LDCT. Participants were asked to complete a self-administered questionnaire on risk factors. Positive result was defined as Lung-RADS ≥3, corresponding to nodule ≥6 mm. Adherence to LDCT screening was defined as having T1 screening, excluding those < 18 months from T0 at time of analysis. Predicted risk of lung cancer was calculated per PLCOm2012 model. Results: To date, 454 subjects have undergone LDCT screening. Positive results occurred in 60 subjects (13.2%) at T0; lung cancer was diagnosed in 10 subjects (2.2%); and other cancers were diagnosed in 5 subjects (1.1%). There were 152 cancer survivors, including survivors of breast (52), prostate (26), bladder or kidney (19), lung (14), and head and neck cancer (13). The median time from cancer treatment to LDCT screening was 6 years (range 0-55). Cancer survivors were older than IWC: median age 67.4 vs. 63.5 years ( p< 0.001) and more likely to be active smokers: 37.5% vs. 29.5%, ( p= 0.09). The median predicted risk of lung cancer at 6 year was 5.5% vs. 3.2%, ( p= 0.15). No significant difference in the screening outcomes was found between groups. Among cancer survivors (N = 152), positive screening occurred in 15 (9.9%); lung cancer was diagnosed in 1 (0.7%); and other cancers were diagnosed in 3 subjects (1.9%). Non-adherence to LDCT screening occurred in 31 out of 152 cancer survivors (20.4%), compared with 81 out of 262 (30.9%) IWC, ( p= 0.02). Conclusions: About one-third of LDCT screenings at this NCCN institution occurred among cancer survivors. We found no evidence of increased false positive results. However, a higher rate of adherence to annual screening was observed among cancer survivors than IWC.
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Snoswell, Centaine L., Jennifer A. Whitty, Liam J. Caffery, Lois J. Loescher, Nicole Gillespie, and Monika Janda. "Direct-to-consumer mobile teledermoscopy for skin cancer screening: Preliminary results demonstrating willingness-to-pay in Australia." Journal of Telemedicine and Telecare 24, no. 10 (October 22, 2018): 683–89. http://dx.doi.org/10.1177/1357633x18799582.
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Introduction Internationally, teledermoscopy has been found to have clinical and economic efficacy. This study aims to identify the attributes of a mobile teledermoscopy service that consumers prefer. This preliminary study was set within a broader randomised control trial (RCT) investigating the effectiveness of direct to consumer mobile teledermoscopy. Methods We undertook a discrete choice experiment (DCE). The DCE comprised 24 choice sets, divided into in two blocks of 12. For each choice set, respondents were asked to make discrete choices between two opt-out choices and two skin cancer screening service options described by seven attributes. A mixed logit model was used to estimate preferences for skin cancer screening services. Consumer preferences weights were used to calculate marginal willingness-to-pay (WTP) for skin cancer screening services. Results The DCE was completed by 113 consumer respondents. Consumers’ preference for dermatologist involvement in their diagnosis, increased accuracy, and reduced excisions were all statistically significant in driving choice between service models. Consumers preferred having a professional involved in their skin cancer screening, rather than performing a self-examination. Consumers were only WTP $1.18 to change from a GP visit to mobile teledermoscopy (diagnosis using a phone camera). However, they were WTP $43 to have their results reviewed by a dermatologist rather than a GP, and $117 to increase the chance of detecting a melanoma if it was present from 65-75% to 95%. Conclusion Skin cancer screening services which are delivered by health professionals, rather than skin self-examination, are preferred by consumers. Consumers were willing to pay for their preferred skin cancer screening method, especially if a dermatologist was involved.
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Hay, Jennifer L., Kimberly A. Kaphingst, David Buller, Elizabeth Schofield, Kirsten Meyer White, Andrew Sussman, Dolores Guest, et al. "Behavioral and Psychological Outcomes Associated with Skin Cancer Genetic Testing in Albuquerque Primary Care." Cancers 13, no. 16 (August 12, 2021): 4053. http://dx.doi.org/10.3390/cancers13164053.
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Public availability of genetic information is increasing; thus, efforts to improve diversity in basic and translational research in genomics is a top priority. Given the increasing U.S. incidence and mortality of melanoma, and the prevalence of common melanocortin-1 receptor (MC1R) gene melanoma risk variants in the general population, we examined genomic testing of MC1R for skin cancer risk in a randomized controlled trial in Albuquerque, New Mexico primary care. Participants were 48% Hispanic and were randomized 5:1 to a MC1R test invitation or usual care. We assessed 3 month sun protection, skin cancer screening, and skin cancer worry outcomes associated with testing, and key effect moderators (e.g., cancer risk perceptions, and skin cancer risk factors). Our findings indicate that the primary outcomes were unchanged by the MC1R test offer, test acceptance, and level of risk feedback. Moderator analyses showed that those with lower risk perception, and those with skin that readily tans, significantly increased their sun protection in response to higher than average risk feedback. Risk feedback did not prompt cancer worry, and average risk feedback did not erode existing sun protection. This study paves the way for the development of tailored strategies to address low skin cancer risk awareness in this understudied context of public health genomics.
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Johnson, Laura A., Richard A. Morgan, Mark E. Dudley, Lydie Cassard, James C. Yang, Marybeth S. Hughes, Udai S. Kammula, et al. "Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen." Blood 114, no. 3 (July 16, 2009): 535–46. http://dx.doi.org/10.1182/blood-2009-03-211714.
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Abstract Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA− and CD45RO+ after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA+ and CD45RO− phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate–antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.
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Butow, Phyllis N., Jane Turner, Jemma Gilchrist, Louise Sharpe, Allan Ben Smith, Joanna E. Fardell, Stephanie Tesson, et al. "Randomized Trial of ConquerFear: A Novel, Theoretically Based Psychosocial Intervention for Fear of Cancer Recurrence." Journal of Clinical Oncology 35, no. 36 (December 20, 2017): 4066–77. http://dx.doi.org/10.1200/jco.2017.73.1257.
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Purpose Fear of cancer recurrence (FCR) is prevalent, distressing, and long lasting. This study evaluated the impact of a theoretically/empirically based intervention (ConquerFear) on FCR. Methods Eligible survivors had curable breast or colorectal cancer or melanoma, had completed treatment (not including endocrine therapy) 2 months to 5 years previously, were age > 18 years, and had scores above the clinical cutoff on the FCR Inventory (FCRI) severity subscale at screening. Participants were randomly assigned at a one-to-one ratio to either five face-to-face sessions of ConquerFear (attention training, metacognitions, acceptance/mindfulness, screening behavior, and values-based goal setting) or an attention control (Taking-it-Easy relaxation therapy). Participants completed questionnaires at baseline (T0), immediately post-therapy (T1), and 3 (T2) and 6 months (T3) later. The primary outcome was FCRI total score. Results Of 704 potentially eligible survivors from 17 sites and two online databases, 533 were contactable, of whom 222 (42%) consented; 121 were randomly assigned to intervention and 101 to control. Study arms were equivalent at baseline on all measured characteristics. ConquerFear participants had clinically and statistically greater improvements than control participants from T0 to T1 on FCRI total ( P < .001) and severity subscale scores ( P = .001), which were maintained at T2 ( P = .017 and P = .023, respectively) and, for FCRI total only, at T3 ( P = .018), and from T0 to T1 on three FCRI subscales (coping, psychological distress, and triggers) as well as in general anxiety, cancer-specific distress (total), and mental quality of life and metacognitions (total). Differences in FCRI psychological distress and cancer-specific distress (total) remained significantly different at T3. Conclusion This randomized trial demonstrated efficacy of ConquerFear compared with attention control (Taking-it-Easy) in reduction of FCRI total scores immediately post-therapy and 3 and 6 months later and in many secondary outcomes immediately post-therapy. Cancer-specific distress (total) remained more improved at 3- and 6-month follow-up.
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Athavale, Ambarish M. "Capsule Commentary on Robinson et al.: A Randomized Trial on the Efficacy of Mastery Learning on Primary Care Providers’ Melanoma Opportunistic Screening Skills and Practice." Journal of General Internal Medicine 33, no. 6 (February 15, 2018): 946. http://dx.doi.org/10.1007/s11606-018-4360-7.
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Amin, Asim, Mohammed M. Milhem, Georgina V. Long, Christopher J. Hoimes, Theresa Michelle Medina, Robert Martin Conry, Christopher D. Lao, et al. "Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced/metastatic melanoma resistant to anti-PD-1/PD-L1 therapy." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9555. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9555.
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9555 Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH > ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; > 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.