124 results on '"Joseph J. Skitzki"'
Search Results
102. NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021.
- Author
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Swetter SM, Thompson JA, Albertini MR, Barker CA, Baumgartner J, Boland G, Chmielowski B, DiMaio D, Durham A, Fields RC, Fleming MD, Galan A, Gastman B, Grossmann K, Guild S, Holder A, Johnson D, Joseph RW, Karakousis G, Kendra K, Lange JR, Lanning R, Margolin K, Olszanski AJ, Ott PA, Ross MI, Salama AK, Sharma R, Skitzki J, Sosman J, Wuthrick E, McMillian NR, and Engh AM
- Subjects
- Brain Neoplasms secondary, Humans, Lymph Node Excision, Sentinel Lymph Node Biopsy, Melanoma diagnosis, Melanoma surgery, Melanoma therapy, Skin Neoplasms diagnosis, Skin Neoplasms surgery, Skin Neoplasms therapy
- Abstract
Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.
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- 2021
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103. Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.
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Gastman B, Agarwal PK, Berger A, Boland G, Broderick S, Butterfield LH, Byrd D, Fecci PE, Ferris RL, Fong Y, Goff SL, Grabowski MM, Ito F, Lim M, Lotze MT, Mahdi H, Malafa M, Morris CD, Murthy P, Neves RI, Odunsi A, Pai SI, Prabhakaran S, Rosenberg SA, Saoud R, Sethuraman J, Skitzki J, Slingluff CL, Sondak VK, Sunwoo JB, Turcotte S, Yeung CC, and Kaufman HL
- Subjects
- Clinical Trials as Topic, Humans, Immunotherapy methods, Medical Oncology standards, Tissue and Organ Procurement methods
- Abstract
Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy., Competing Interests: Competing interests: BG is a consultant for Quest Imaging and a speaker for Castle Biosciences. PKA has partner salary from Pfizer. GB has sponsored research agreements with Takeda Oncology, Olink Proteomics, and Palleon, honorarium from Novartis, and consulting for NW Biotherapeutics. SB is a consultant for BMS. LHB is a consultant for StemImmune/Calidi, NextCure, Replimmune, Western Oncolytics, Torque Therapeutics, Khloris, Pyxis, Cytomix, and Roche-Genentech. PEF is a consultant for Monteris Medical. RLF is a consultant for Aduro Biotech, Amgen, Astra-Zeneca/Medimmune, Bain Capital Life Sciences, BMS, EMD Serono, GSK, Iovance, Lilly, MacroGenics, Merck, Nanobiotx, Numab Therapeutics, Oncorus, Ono Pharmaceutcal Co., Pfizer, PPD, Regeneron, Tesaro, Torque Therapeutics, TTMS, and VentiRx Pharmaceuticals; has contracted research agreements with Astra-Zeneca/Medimmune, BMS, Merck, Tesaro, and TTMS, has partner consulting for Janssen, Lilly, Scibase, DermTech, BMS, and Pfizer, and has partner contracted research agreements with Regeneron, Janssen, BMS, Abbvie, BI, Castle Biosciences and Lilly.YF has relationships with Imagene, Merck, Eureka and Surgamo, and partner interest in Pfizer. MLim is a consultant for Tocagen, VBI and Strykes, and receives research funding from Arbor, BMS and Biohaven. MLotze receives salary from Nurix, Inc., royalty from Cellatrope, has IP rights in Intrexon, consults for Myst, Instill, Checkmate, Carisma and Surface Oncology, and has ownership interest in iRepertoire. HM has contracted research with Puma Biotechnology. RIN is a consultant for Novartis, Castle Biosciences, and Sanofi-Granzyme and has contracted research with Regeneron and Castle Biosciences. AO is a cofounder of Tactiva Therapeutics, Inc., and receives research support from AstraZeneca and Tesaro. SP is a consultant for Abbvie, Astra-Zeneca, Cue Biopharma, Fusion Biopharma, Merck, Newlink Genetics, Oncolys Biopharma, Oncosec, Replimmune and Sensei Bio, contracted research with Abbvie, Astra-Zeneca, Cue Biopharma, Sensei Bio and Tesaro, and investigator-initiated trials with ASTX Pharmaceuticals, Astra-Zeneca, Cue Biopharma, ImmuneDesign and Merck. SAR has patents held by the NCI and cooperative research agreements with Kite, Iovance and Ziopharm. CLS is a consultant for Celldex, CureVac and Castle Biosciences, and has institutional support from Celldex, Polynoma, GSK, Merck, 3M, Theraclion and Immatics. VKS is a consultant for Array, BMS, Merck, Novartis, Pfizer, Polynoma, Regeneron and Replimmune. JBS is on the advisory board of ABL Bio and is the scientific founder of Indapta Therapeutics. ST is a consultant for TVM Life Science, received honoraria from Astra-Zeneca, Celgene and Exactis Innovation, and has research grants from BMS and Iovance. CY is a consultant for Loxo, Merck and Adaptive Biotechnologies, has contracted research with Obi and Pfizer, and has ownership interest in Molpath Dx, LLC. HLK is an employee of Immuneering Coporation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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104. NCCN Guidelines Insights: Uveal Melanoma, Version 1.2019.
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Rao PK, Barker C, Coit DG, Joseph RW, Materin M, Rengan R, Sosman J, Thompson JA, Albertini MR, Boland G, Carson Iii WE, Contreras C, Daniels GA, DiMaio D, Durham A, Fields RC, Fleming MD, Galan A, Gastman B, Grossman K, Guild V, Johnson D, Karakousis G, Lange JR, Margolin K, Nath S, Olszanski AJ, Ott PA, Ross MI, Salama AK, Skitzki J, Swetter SM, Wuthrick E, McMillian NR, and Engh A
- Subjects
- Brachytherapy standards, Education, Medical, Continuing, Eye Enucleation standards, Humans, Medical Oncology education, Medical Oncology methods, Melanoma diagnosis, Melanoma pathology, Oncologists education, Tumor Burden, Uveal Neoplasms diagnosis, Uveal Neoplasms pathology, Medical Oncology standards, Melanoma therapy, Neoplasm Recurrence, Local prevention & control, Practice Guidelines as Topic, Uveal Neoplasms therapy
- Abstract
The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.
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- 2020
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105. Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.
- Author
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Coit DG, Thompson JA, Albertini MR, Barker C, Carson WE, Contreras C, Daniels GA, DiMaio D, Fields RC, Fleming MD, Freeman M, Galan A, Gastman B, Guild V, Johnson D, Joseph RW, Lange JR, Nath S, Olszanski AJ, Ott P, Gupta AP, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Wuthrick E, McMillian NR, and Engh AM
- Subjects
- Humans, Melanoma, Cutaneous Malignant, Medical Oncology standards, Melanoma diagnosis, Skin Neoplasms diagnosis
- Abstract
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.
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- 2019
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106. Intra-arterial Versus Intravenous Adoptive Cell Therapy in a Mouse Tumor Model.
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Visioni A, Kim M, Wilfong C, Blum A, Powers C, Fisher D, Gabriel E, and Skitzki J
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- Administration, Intravenous, Adoptive Transfer, Animals, Cell Movement, Disease Models, Animal, Femoral Artery surgery, Humans, Immunotherapy, Adoptive, Injections, Intra-Arterial, Melanoma immunology, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Neoplasms, Experimental, Tumor Burden, Tumor Microenvironment, Lymphocytes, Tumor-Infiltrating immunology, Melanoma therapy, T-Lymphocytes immunology
- Abstract
Adoptive cell transfer therapy for cancer has existed for decades and is experiencing a resurgence in popularity that has been facilitated by improved methods of production, techniques for genetic modification, and host preconditioning. The trafficking of adoptively transferred lymphocytes and infiltration into the tumor microenvironment is sine qua non for successful tumor eradication; however, the paradox of extremely poor trafficking of lymphocytes into the tumor microenvironment raises the issue of how best to deliver these cells to optimize entry into tumor tissue. We examined the route of administration as a potential modifier of both trafficking and antitumor efficacy. Femoral artery cannulation and tail vein injection for the intra-arterial (IA) and IV delivery, respectively, were utilized in the B16-OVA/OT-I mouse model system. Both IV and IA infusions showed decreased tumor growth and prolonged survival. However, although significantly increased T-cell tumor infiltration was observed in IA mice, tumor growth and survival were not improved as compared with IV mice. These studies suggest that IA administration produces increased early lymphocyte trafficking, but a discernable survival benefit was not seen in the murine model examined.
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- 2018
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107. Malignant adnexal tumors of the skin: a single institution experience.
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Oyasiji T, Tan W, Kane J 3rd, Skitzki J, Francescutti V, Salerno K, and Khushalani NI
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- Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Recurrence, Local therapy, Neoplasms, Adnexal and Skin Appendage therapy, Prognosis, Retrospective Studies, Skin Neoplasms therapy, Survival Rate, Sweat Gland Neoplasms therapy, Young Adult, Eccrine Glands pathology, Neoplasm Recurrence, Local pathology, Neoplasms, Adnexal and Skin Appendage pathology, Skin Neoplasms pathology, Sweat Gland Neoplasms pathology
- Abstract
Background: Malignant adnexal tumors of the skin (MATS) are rare. We aimed to measure the survival of patients with MATS and identify predictors of improved survival., Methods: A retrospective review of MATS treated at our institution from 1990 to 2012., Results: There were 50 patients within the time period. Median age was 59.5 years (range 22-95); primary site was the head and neck (52%); most common histologic subtypes were skin appendage carcinoma (20%) and eccrine adenocarcinoma (20%); and the vast majority were T1 (44%). Most patients (98%) underwent surgical treatment. Chemotherapy and radiation were administered to 8 and 14% of patients, respectively. Recurrence rate was 12%. Median OS was 158 months (95% CI, 52-255). OS and recurrence-free survival at 5 years were 62.4 and 47.4% and at 10 years 56.7 and 41.5%, respectively. Five-year and 10-year disease-specific survival (DSS) was 62.9%. Age > 60 years was an unfavorable predictor of OS (HR 12.9, P < .0008) and recurrence-free survival (RFS) (HR 12.53, P < .0003). Nodal metastasis was a negative predictor of RFS (HR 2.37, P < 0.04) and DSS (HR 7.2, P < 0.03) while treatment with chemotherapy was predictive of poor DSS (HR 14.21, P < 0.03)., Conclusions: Younger patients had better OS and RFS. Absence of nodal metastasis translated to better RFS and DSS. Lymph node basin staging is worth considering in the workup and treatment.
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- 2018
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108. Conditional Survival-Based "Abbreviated" Routine Cancer Surveillance for Pathologic Stage IB Melanoma.
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Kukar M, Gabriel E, May R, Cho E, Lichtenthal M, Groman A, Skitzki J, Francescutti V, and Kane JM 3rd
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- Disease-Free Survival, Early Detection of Cancer methods, Extremities, Female, Head and Neck Neoplasms mortality, Head and Neck Neoplasms pathology, Humans, Lymphatic Metastasis, Male, Melanoma pathology, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Prognosis, Sentinel Lymph Node Biopsy, Skin Neoplasms pathology, Tertiary Care Centers, Thorax, Melanoma mortality, Neoplasm Recurrence, Local mortality, Skin Neoplasms mortality
- Abstract
A negative sentinel lymph node biopsy (SLNB) for stage IB (T1b/T2a N0) melanoma would predict an excellent long-term prognosis. Combined with the concept of conditional survival, an "abbreviated" cancer surveillance strategy was implemented to reduce the number of visits and total length of follow-up. Retrospective review of all pathologic stage IB melanoma patients (negative SLNB) at a single institution between 2006 and 2008 after implementation of an "abbreviated" cancer surveillance; clinic visits every six months for five years followed by one annual visit (total follow-up six years). Patient demographics, tumor characteristics, and information regarding recurrences were obtained. Recurrence-free, disease-specific, and overall survival were calculated. Eighty-seven patients underwent the "abbreviated" cancer surveillance. Median age was 55.4 years and 50.6 per cent were male. Median Breslow thickness was 1.1 mm (range 0.5-2.0 mm) and 1.1 per cent were ulcerated. Primary tumor site was 49 per cent extremities, 39 per cent trunk, and 12 per cent head/neck. Median follow-up was 68.6 months. Five-year recurrence-free, disease-specific, and overall survivals were 89, 95, and 88 per cent, respectively. During surveillance, 10 patients had concerning symptoms or physical findings prompting subsequent workup, all of which were negative for recurrence/metastases. There were only three true melanoma recurrences; all were distant metastases and presented symptomatically between scheduled follow-up visits. In light of the excellent prognosis for pathologic (SLNB negative) stage IB melanoma, an "abbreviated" cancer surveillance schedule based on conditional survival would reduce both direct and indirect costs in this cohort. The few recurrences were symptomatic and unlikely to have changed with more intensive surveillance.
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- 2017
109. Water lavage as an adjunct to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).
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Gabriel E, Singla S, Kim M, Fisher D, Powers C, Visioni A, Attwood K, and Skitzki J
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- Combined Modality Therapy, Female, Humans, Male, Middle Aged, Retrospective Studies, Therapeutic Irrigation methods, Water, Chemotherapy, Cancer, Regional Perfusion, Cytoreduction Surgical Procedures, Hyperthermia, Induced, Peritoneal Neoplasms drug therapy, Peritoneal Neoplasms surgery
- Abstract
Background: Water lavage (WL) during gastrointestinal cancer surgery has osmotically mediated lytic effects on tumor cells. We investigated the safety and efficacy of WL with CRS-HIPEC., Methods: This is a retrospective review, 1/2003-7/2014, of a single institution experience with CRS-HIPEC comparing patients who had WL (WL+) to those who did not (WL-)., Results: Of 157 CRS-HIPECs, 16 (10.2%) were WL+. WL+ had more PCI scores >20 compared to WL- (56.3% vs 19.4%, respectively, p = 0.003); however, the completeness of cytoreduction (CC) was similar. There were no differences in hospital length of stay or post-operative complications. The average POD 1 sodium (Na) level was statistically lower in the WL+ group (133.6 ± 2.5 vs 135.5 ± 3.2 mEq/L, p = 0.023); however, the average Na at discharge for each group was 140 mEq/L. There were no differences in 3-year OS (3WL+:0.63 vs WL-:0.68, p = 0.97) or RFS (WL+:0.32 vs WL-:0.39, p = 0.47). A subset analysis for patients with PCI >20 showed no difference between groups., Conclusions: WL offers a low cost, safe and theoretically efficacious method of tumor cell lysis for peritoneal malignancy., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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110. New Does Not Always Mean Better: Isolated Limb Perfusion Still Has a Role in the Management of In-Transit Melanoma Metastases.
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Puzanov I and Skitzki J
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- Chemotherapy, Cancer, Regional Perfusion, Humans, Hyperthermia, Induced, Melanoma, Skin Neoplasms
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- 2016
111. Key gaps in pathologic reporting for appendiceal mucinous neoplasms: time for universal synoptic reporting?
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Al-Sukhni E, LeVea C, Skitzki J, Kane J 3rd, and Francescutti V
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- Humans, Pathology, Clinical trends, Prognosis, Research Design trends, Retrospective Studies, Statistics as Topic, Appendiceal Neoplasms pathology, Pathology, Clinical statistics & numerical data, Research Design statistics & numerical data
- Abstract
Introduction: The prognosis of appendiceal mucinous neoplasms (AMN) is directly related to their histopathology. Existing classification schemes encompass tumors with widely divergent clinical behaviors within a single diagnosis, making it difficult for clinicians to interpret pathology reports to counsel patients on optimal management. We sought to examine pathology reports generated for AMN for inclusion of essential histologic features., Methods: Pathology reports of appendectomy specimens with a diagnosis of AMN (2002-2015) at our center ("internal") and from referring institutions ("external") were retrospectively reviewed for inclusion of the following 5 essential items: layer of invasion, mucin dissection (low grade neoplasms only), perforation, margins, and serosal implants., Results: Sixty-nine patients were included, 54 with external reports available. Benign/low grade tumors comprised 29.0% and 27.8% of internal and external reports, respectively. Thirty-seven internal reports (53.6%) were signed out by specialist gastrointestinal pathologists. External reports were 66.7% complete for layer of invasion, 26.7% for mucin dissection, 64.8% for perforation, 68.5% for margins, 53.7% for serosal implants, and 18.5% for all items. Internal reports were 75.4% complete for layer of invasion, 40.0% for mucin dissection, 40.6% for perforation, 82.6% for margins, 69.6% for serosal implants, and 17.4% for all items. Eight external (14.8%) and 24 internal (34.8%) reports were synoptic. Synoptic reports were more likely to be complete for all key items both external and internal., Conclusion: Most pathology reports are incomplete for essential features needed for management and discussion of AMN with patients. Synoptic reports improve completeness of reporting for these tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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112. Technical Considerations for the Generation of Adoptively Transferred T Cells in Cancer Immunotherapy.
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Visioni A and Skitzki J
- Abstract
A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits. Preclinical investigations and human trials have utilized natural killer (NK) cells, dendritic cells (DC), macrophages, T-cells or B-cells for ACT with the most intense research focused on T-cell ACT. T-cells are exquisitely specific to the target of its T-cell receptor (TCR), thus potentially reducing the amount of collateral damage and off-target effects from treatment. T-cells also possess a memory subset that may reduce the risk of recurrence of a cancer after the successful treatment of the primary disease. There are several options for the source of T-cells used in the generation of cells for ACT. Perhaps the most widely known source is T-cells generated from tumor-infiltrating lymphocytes (TILs). However, studies have also employed peripheral blood mononuclear cells (PBMCs), lymph nodes, and even induced pluripotent stem cells (IPSCs) as a source of T-cells. Several important technical considerations exist regarding benefits and limitations of each source of T-cells. Unique aspects of T-cells factor into their ability to be efficacious in ACT including the total number of cells available for ACT, the anti-tumor efficacy on a per cell basis, the repertoire of TCRs specific to tumor cells, and their ability to traffic to various organs that harbor tumor. Current research is attempting to unlock the full potential of these cells to effectively and safely treat cancer., Competing Interests: The authors have no conflict of interests to report regarding this manuscript.
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- 2016
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113. NCCN Guidelines Insights: Melanoma, Version 3.2016.
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Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE 3rd, Daniels GA, DiMaio D, Fields RC, Fleming MD, Gastman B, Gonzalez R, Guild V, Johnson D, Joseph RW, Lange JR, Martini MC, Materin MA, Olszanski AJ, Ott P, Gupta AP, Ross MI, Salama AK, Skitzki J, Swetter SM, Tanabe KK, Torres-Roca JF, Trisal V, Urist MM, McMillian N, and Engh A
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- Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Humans, Immunotherapy, Melanoma etiology, Molecular Targeted Therapy, Neoplasm Staging, Retreatment, Treatment Outcome, Melanoma diagnosis, Melanoma therapy
- Abstract
The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma., (Copyright © 2016 by the National Comprehensive Cancer Network.)
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- 2016
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114. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.
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Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE 3rd, Daniels GA, DiMaio D, Ernstoff M, Fields RC, Fleming MD, Gonzalez R, Guild V, Halpern AC, Hodi FS Jr, Joseph RW, Lange JR, Martini MC, Materin MA, Olszanski AJ, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Torres-Roca JF, Trisal V, Urist MM, McMillian N, and Engh A
- Subjects
- Humans, Melanoma diagnosis, Melanoma therapy
- Abstract
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections., (Copyright © 2016 by the National Comprehensive Cancer Network.)
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- 2016
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115. Current Immunotherapies for Sarcoma: Clinical Trials and Rationale.
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Mitsis D, Francescutti V, and Skitzki J
- Abstract
Sarcoma tumors are rare and heterogeneous, yet they possess many characteristics that may facilitate immunotherapeutic responses. Both active strategies including vaccines and passive strategies involving cellular adoptive immunotherapy have been applied clinically. Results of these clinical trials indicate a distinct benefit for select patients. The recent breakthrough of immunologic checkpoint inhibition is being rapidly introduced to a variety of tumor types including sarcoma. It is anticipated that these emerging immunotherapies will exhibit clinical efficacy for a variety of sarcomas. The increasing ability to tailor immunologic therapies to sarcoma patients will undoubtedly generate further enthusiasm and clinical research for this treatment modality.
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- 2016
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116. Incidence of Venous Thromboembolic Events in Mandated Risk Assessment versus Optional DVT Prophylaxis Era at a Large Tertiary Cancer Center.
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Kukar M, Asaro J, Aquino A, Groman A, Skitzki J, and Kane JM
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- Anticoagulants administration & dosage, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Incidence, Injections, Subcutaneous, Inpatients, Male, Neoplasms epidemiology, New York epidemiology, Outpatients, Prevalence, Retrospective Studies, Risk Factors, Venous Thromboembolism etiology, Heparin, Low-Molecular-Weight administration & dosage, Mandatory Programs, Neoplasms complications, Risk Assessment methods, Venous Thromboembolism epidemiology, Venous Thromboembolism prevention & control
- Abstract
Cancer patients are thought to be at high risk for venous thromboembolic events (DVT/PE). Beginning in October 2007, our tertiary cancer center instituted "mandated risk assessment" computerized DVT prophylaxis order entry, for all hospital admissions with an option for active opt out by the physician with a stated reason. Retrospective review of all DVT/PE events within 30 days of a hospital admission [any inpatient admission (IA) and outpatient surgery (OPS)] in comparable "optional (O)" (January 2005-September 2007) vs "mandated risk assessment (M)" (October 2007-May 2010) DVT prophylaxis order eras. Patient demographics, admission details, type of prophylaxis, treatment, and outcome were also analyzed. There were 16,363 for the O (11,944 IA/4,419 OPS) and 17,757 for the M (12,957 IA/4,800 OPS) DVT prophylaxis order eras. The number of DVT/PE events in the O era was 67 (prevalence 0.41%) versus 102 for the M era (prevalence 0.57%), P = 0.037. In the DVT/PE patients, DVT prophylaxis had been ordered during the index admission in 66 per cent for O versus 83 per cent for M (P = 0.008). Low-molecular-weight heparin was increasingly used in M era (33% vs 16%, P = 0.009). There was also no difference between O vs M era for status at DVT/PE diagnosis (outpatient 36% vs 24%) or associated symptoms. There were no deaths attributable to DVT/PE in the O era versus 3 deaths in the M era. Although DVT prophylaxis use improved with "mandated risk assessment" ordering, the DVT/PE incidence did not decrease. It may be difficult to overcome the surprisingly low baseline prevalence and multiple risk factors in this population.
- Published
- 2015
117. The Role of Regional Therapies for in-Transit Melanoma in the Era of Improved Systemic Options.
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Gabriel E and Skitzki J
- Abstract
The incidence of melanoma has been increasing at a rapid rate, with 4%-11% of all melanoma recurrences presenting as in-transit disease. Treatments for in-transit melanoma of the extremity are varied and include surgical excision, lesional injection, regional techniques and systemic therapies. Excision to clear margins is preferred; however, in cases of widespread disease, this may not be practical. Historically, intralesional therapies were generally not curative and were often used for palliation or as adjuncts to other therapies, but recent advances in oncolytic viruses may change this paradigm. Radiation as a regional therapy can be quite locally toxic and is typically relegated to disease control and symptom relief in patients with limited treatment options. Regional therapies such as isolated limb perfusion and isolated limb infusion are older therapies, but offer the ability to treat bulky disease for curative intent with a high response rate. These techniques have their associated toxicities and can be technically challenging. Historically, systemic therapy with chemotherapies and biochemotherapies were relatively ineffective and highly toxic. With the advent of novel immunotherapeutic and targeted small molecule agents for the treatment of metastatic melanoma, the armamentarium against in-transit disease has expanded. Given the multitude of options, many different combinations and sequences of therapies can be offered to patients with in-transit extremity melanoma in the contemporary era. Reported response and survival rates of the varied treatments may offer valuable information regarding treatment decisions for patients with in-transit melanoma and provide rationale for these decisions.
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- 2015
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118. Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents.
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Frys S, Simons Z, Hu Q, Barth MJ, Gu JJ, Mavis C, Skitzki J, Song L, Czuczman MS, and Hernandez-Ilizaliturri FJ
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- Animals, Apoptosis drug effects, Boronic Acids pharmacology, Bortezomib, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cytarabine pharmacology, Drug Resistance, Neoplasm drug effects, Female, G1 Phase Cell Cycle Checkpoints drug effects, Humans, Lymphoma, B-Cell metabolism, Lymphoma, B-Cell pathology, Male, Mice, Mice, SCID, Pyrazines pharmacology, Rituximab, Xenograft Model Antitumor Assays, bcl-X Protein metabolism, Antibodies, Monoclonal, Murine-Derived pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzamides pharmacology, Histone Deacetylase Inhibitors pharmacology, Lymphoma, B-Cell drug therapy, Pyridines pharmacology
- Abstract
Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2015
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119. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist.
- Author
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Burdelya LG, Brackett CM, Kojouharov B, Gitlin II, Leonova KI, Gleiberman AS, Aygun-Sunar S, Veith J, Johnson C, Haderski GJ, Stanhope-Baker P, Allamaneni S, Skitzki J, Zeng M, Martsen E, Medvedev A, Scheblyakov D, Artemicheva NM, Logunov DY, Gintsburg AL, Naroditsky BS, Makarov SS, and Gudkov AV
- Subjects
- Animals, Anticarcinogenic Agents pharmacology, Breast Neoplasms metabolism, Cell Line, Tumor, Colonic Neoplasms metabolism, Female, Flow Cytometry, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Killer Cells, Natural metabolism, Liver drug effects, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, NF-kappa B metabolism, Neoplasm Transplantation, Neutrophils metabolism, Radiation-Protective Agents pharmacology, Signal Transduction, fas Receptor metabolism, Liver metabolism, Peptides pharmacology, STAT3 Transcription Factor metabolism, Toll-Like Receptor 5 agonists
- Abstract
Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.
- Published
- 2013
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120. Primary signet-ring cell carcinoma of the axilla.
- Author
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Droubi D, Zeitouni NC, Skitzki J, and Bogner PN
- Subjects
- Humans, Lymphoma, Non-Hodgkin complications, Male, Middle Aged, Axilla pathology, Carcinoma, Signet Ring Cell pathology, Neoplasms, Second Primary pathology, Skin Neoplasms pathology
- Abstract
Primary cutaneous histiocytoid or signet-ring cell carcinoma represents an extremely rare adnexal neoplasm that most frequently presents on the eyelid but more rarely may present in the axilla. As this tumor can resemble metastatic carcinoma with signet-ring cells, especially lobular carcinoma of the breast, it can often present a diagnostic challenge. We present a case of cutaneous signet-ring cell carcinoma presenting in the axilla and outline the challenges of diagnosing this rare malignancy., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)
- Published
- 2013
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121. Academic university practice: program selection and the interview process.
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Skitzki J, Reynolds HL, and Delaney CP
- Abstract
The decision to go into academic surgery, rather than private practice, is often multifactorial and includes the opportunity to participate in research, education, and patient care. The current job market for academic colon and rectal surgeons can be described as favorable and growing as there is a push for major academic institutions to obtain fellowship-trained colorectal surgeons. In selecting a job, one should be familiar with the department characteristics. This requires obtaining the answers to multiple questions and negotiation of institutional commitment.
- Published
- 2006
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122. Hurdles to lymphocyte trafficking in the tumor microenvironment: implications for effective immunotherapy.
- Author
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Fisher DT, Chen Q, Appenheimer MM, Skitzki J, Wang WC, Odunsi K, and Evans SS
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- Animals, Blood Vessels metabolism, Cell Adhesion Molecules metabolism, Humans, Inflammation immunology, Neoplasms blood supply, Chemotaxis, Leukocyte physiology, Immunotherapy methods, Immunotherapy trends, Models, Immunological, Neoplasms immunology, Neoplasms therapy, T-Lymphocytes physiology
- Abstract
An important consideration in the development of T cell-based cancer immunotherapy is that effector T cells must efficiently traffic to the tumor microenvironment in order to control malignant progression. T cell trafficking to target tissues is orchestrated by dynamic interactions between circulating lymphocytes and endothelial cells lining blood vessels. It is informative, in this regard, to compare and contrast the molecular mechanisms governing lymphocyte extravasation at distinct vascular sites: (1) high endothelial venules (HEV) of secondary lymphoid organs, which are portals for efficient trafficking of naive and central memory T lymphocytes; (2) non-activated endothelium of normal tissues that mediate relatively low basal levels of trafficking but are rapidly transformed into HEV-like vessels in response to local inflammatory stimuli; and (3) vessels within the intratumoral region and the surrounding peritumoral areas. These vessels can be distinguished by differential expression of hallmark trafficking molecules that function as molecular beacons directing lymphocyte migration across vascular barriers. This article reviews evidence that recruitment of effector T cells to the intratumoral microenvironment is impeded by sub-threshold expression of trafficking molecules on tumor microvessels. Emerging data support the thesis that when considered from the perspective of extravasation, vessels embedded within the intratumoral microenvironment of established tumors do not exhibit stereotypical characteristics of a chronic inflammatory state. A major challenge will be to develop therapeutic approaches to improve trafficking of effector T lymphocytes to tumor sites without skewing the balance in favor of a chronic inflammatory milieu that facilitates tumor maintenance and progression.
- Published
- 2006
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123. Donor cell cycling, trafficking, and accumulation during adoptive immunotherapy for murine lung metastases.
- Author
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Skitzki J, Craig RA, Okuyama R, Knibbs RN, McDonagh K, Chang AE, and Stoolman LM
- Subjects
- Animals, Cell Cycle, Cell Division, Cell Movement, Cells, Cultured, Female, Fibrosarcoma metabolism, Fibrosarcoma secondary, Flow Cytometry, Interleukin-2 metabolism, Lung Neoplasms metabolism, Lung Neoplasms secondary, Lymph Nodes pathology, Mice, Mice, Inbred C57BL, Pertussis Toxin, Spleen pathology, Tumor Cells, Cultured, Fibrosarcoma therapy, Immunotherapy, Adoptive, Lung Neoplasms therapy, Lymphocytes, Tumor-Infiltrating pathology, T-Lymphocytes pathology
- Abstract
Adoptive cellular immunotherapy treats metastatic cancer by infusing cultured T cells derived from resected tumors or primed lymph nodes. The infused cells must accumulate in metastatic lesions to suppress growth; however, this process and the resulting clinical response are dynamic and evolve during the days and weeks following cell infusion. This study used novel experimental techniques to determine the fate of infused, cultured tumor-draining lymph node (TDLN) cells during the treatment of murine pulmonary micrometastases. After infusion, the cultured TDLN cells accumulated in the pulmonary vasculature, systemic lymph nodes, and spleen. Donor cells were initially confined to alveolar capillaries with no movement into metastases. Within 4 h, TDLN cells began migrating across pulmonary postcapillary venules and first appeared within metastases. After 24 h, most donor cells in the lung were associated with tumor nodules. Donor cell proliferation within the lung and lymphoid organs was detected within 24 h of infusion and continued throughout the 5-day period of observation. Furthermore, those proliferating in lymphoid organs trafficked back to the tumor-bearing lungs, accounting for approximately 50% of the donor cells recovered from these sites after 5 days. Finally, donor T cells entering metastases both early (within 1-2 days) and late (after 2 days) suppressed tumor growth, but the early recruits accounted for most of the therapeutic response. Thus, cultured TDLN cells migrate directly into tumor-bearing organs and seed the recirculating pool of lymphocytes after infusion. Small fractions of the later differentiate in lymphoid organs and migrate into the lungs but appear less effective than effector cells in the initial bolus.
- Published
- 2004
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124. Intratumoral IL-12 and TNF-alpha-loaded microspheres lead to regression of breast cancer and systemic antitumor immunity.
- Author
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Sabel MS, Skitzki J, Stoolman L, Egilmez NK, Mathiowitz E, Bailey N, Chang WJ, and Chang AE
- Subjects
- Animals, Female, Mice, Mice, Inbred BALB C, Neoadjuvant Therapy, Antineoplastic Agents administration & dosage, Breast Neoplasms therapy, Immunotherapy methods, Interleukin-12 administration & dosage, Microspheres, Tumor Necrosis Factor-alpha administration & dosage
- Abstract
Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response., Methods: BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-alpha, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon gamma (IFNgamma) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis., Results: Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF-alpha leading to increased infiltration by polymorphonuclear cells and CD8+ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN-gamma production, was highest with IL-12 and TNF-alpha. This treatment resulted in resistance to tumor rechallenge., Conclusions: A single intratumoral injection of IL-12 and TNF-alpha-loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8+ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.
- Published
- 2004
- Full Text
- View/download PDF
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