128 results on '"Joseph J. Skitzki"'
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2. Manipulating adrenergic stress receptor signaling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants
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Minhyung Kim, Daniel T. Fisher, Paul N. Bogner, Umesh Sharma, Han Yu, Joseph J. Skitzki, and Elizabeth A. Repasky
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immunosuppression ,stress signalling ,vascularized composite tissue allotransplantation ,β2‐adrenergic receptors ,Medicine (General) ,R5-920 - Abstract
Abstract Background Vascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non‐life‐threatening conditions. Here we tested whether we could suppress anti‐graft immune activity by using a safe β2‐adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system‐induced signalling through AR. Methods A heterotopic hind limb transplantation model was used with C57BL/6 (H‐2b) as recipients and BALB/c (H‐2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of β2‐AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro‐inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of β2‐AR signalling in donor and recipient tissue were investigated with β2‐AR−/− strains. Results Treatment with the β2‐AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. β2‐AR agonist decreased T‐cell infiltration into the transplanted grafts and decreased memory T‐cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN‐γ, IL‐6, TNF‐α, CXCL‐1/10 and CCL3/4/5/7) were detected following β2‐AR agonist treatment, and there was a decreased expression of ICAM‐1 and vascular cell adhesion molecule‐1 in donor stromal cells. Conclusions β2‐AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress‐signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.
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- 2022
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3. A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis
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Emmanuel M. Gabriel, Minhyung Kim, Daniel T. Fisher, Catherine Mangum, Kristopher Attwood, Wenyan Ji, Debabrata Mukhopadhyay, Sanjay P. Bagaria, Matthew W. Robertson, Tri A. Dinh, Keith L. Knutson, Joseph J. Skitzki, and Michael B. Wallace
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Medicine ,Science - Abstract
Abstract Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC). During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).
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- 2021
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4. Intraoperative intravital microscopy permits the study of human tumour vessels
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Daniel T. Fisher, Jason B. Muhitch, Minhyung Kim, Kurt C. Doyen, Paul N. Bogner, Sharon S. Evans, and Joseph J. Skitzki
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Science - Abstract
Intravital microscopy has been used in laboratory animals to visualise the blood vessels in tumours. Here, the authors use this technique in melanoma patients undergoing surgery and show that vessels in situhave a larger diameter than excised tissue
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- 2016
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5. Improved Cuff Technique and Intraoperative Detection of Vascular Complications for Hind Limb Transplantation in Mice
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Minhyung Kim, MD, Daniel T. Fisher, PhD, Colin A. Powers, MD, Elizabeth A. Repasky, PhD, and Joseph J. Skitzki, MD
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Surgery ,RD1-811 - Abstract
Background. Vascularized composite tissue allotransplantation (VCA) from a cadaveric donor has now become a clinical reality and the treatment modality of choice for patients with devastating injuries, deformities, and complex tissue defects. However, many VCA patients experience severe toxicities due to the strong immunosuppression required secondary to high antigenicity of the grafts. To improve immunosuppressive protocols for VCA, feasible and reliable preclinical models are necessary. The purpose of this study was to introduce new techniques to an established preclinical VCA model to accelerate future investigations. Methods. C57BL/6 (H-2b) and BALB/c (H-2d) mice were used to perform VCA as recipients and donors, respectively. Surgery time, success rate, associated complications, and mortality were analyzed. Blood flow in grafts was interrogated with laser speckle image (LSI). Results. A nonsuture cuff technique was used with the abdominal aorta for end-to-end anastomosis. The cuff technique demonstrated efficiency for donor surgery (52 ± 10 minutes for donor vs. 45 ± 8 minutes for recipient surgery). Successful revascularization was achieved in 27 (90%) of 30 transplants. The majority of surgical complications occurred within 48 hours including artery occlusion, venous occlusion, cerebral stroke, and minor bleeding without mortality. LSI was useful in detecting intraoperative vascular complications with display patterns predictive of complication type. Conclusions. The described techniques may facilitate a more efficient heterotopic hind limb transplantation mouse model of VCA.
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- 2018
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6. Homogenous Good Outcome in a Heterogeneous Group of Tumors: An Institutional Series of Outcomes of Superficial Soft Tissue Sarcomas
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Valerie Francescutti, Sartaj S. Sanghera, Richard T. Cheney, Austin Miller, Kilian Salerno, Rachel Burke, Joseph J. Skitzki, and John M. Kane
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction. Superficial soft tissue sarcomas (S-STS) are generally amenable to wide excision. We hypothesized that local recurrence (LR) should be low, even without radiation therapy (RT), and sought to examine the contribution of depth to LR and OS. Methods. Patients with S-STS were retrospectively reviewed. Demographics, tumor features, treatment received, and outcomes were analyzed. Results. 103 patients were identified. Median age was 55 years; 53% of patients were female. Tumor site was 39% in trunk, 38% in the lower extremity, 14% in the upper extremity, and 9% in other locations. The most common histology was 36% leiomyosarcoma. Median tumor size was 2.8 cm (range 0.2–14 cm). Sixty-six percent of tumors were of intermediate/high grade. RT was administered preoperatively in 6% of patients and postoperatively in 15% of patients. An R0 resection was accomplished in 92%. At a median follow-up of 34.2 months (range 2.3–176), 9 patients had a LR (8.7%). Tumor size and grade were not associated with LR. OS was not associated with any tumor or patient variables on univariate analysis. Conclusions. LR was low for S-STS, even with large or high grade tumors and selective use of RT. Surgical resection alone may be adequate therapy for most patients. Superficial location seems to supersede other factors imparting a good prognosis for this group of tumors.
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- 2015
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7. Gynecomastia-Like Hyperplasia of Axillary Ectopic Breast Tissue in a Young Female
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Joseph Shatzel, Asher Blum, Thaer Khoury, Janine Milligan, and Joseph J. Skitzki
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Pathology ,RB1-214 - Abstract
Gynecomastia-like hyperplasia of orthotopic female breast tissue is a rare entity. We present the singularly unique case of a 22-year-old female who presented with a small axillary mass subsequently discovered to be a discrete deposit of ectopic breast tissue with gynecomastia-like hyperplasia. This case highlights the etiology, variable presentation, and evaluation of ectopic breast tissue.
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- 2013
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8. Supplementary Figure S2 from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
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Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar
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Treatment significantly affects the circulating immune compartment.
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- 2023
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9. Supplementary figure legend 1 from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
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Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar
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Representative gating strategy illustrating (A) CD4 and CD8 T cell identification (B) expression of ICOS on CD4 positive T cells (C) expression of PD-1 and Ki-67 within PD-1 positive cells and (D) expression of CD38/HLA-DR, PD-1 and KI-67 within CD8+ PD-1+ T cells is shown.
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- 2023
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10. Supplementary figure legend 2 from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
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Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar
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Treatment significantly affects the circulating immune compartment.
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- 2023
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11. Data from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
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Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar
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Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133
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- 2023
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12. Recombinant human Hsp110-gp100 chaperone complex vaccine is nontoxic and induces response in advanced stage melanoma patients
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Michael M. Wach, John R. Subjeck, Xiang-Yang Wang, Elizabeth Repasky, Junko Matsuzaki, Han Yu, Chong Wang, Daniel Fisher, Joseph J. Skitzki, and John M. Kane
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Male ,Cancer Research ,Skin Neoplasms ,Dermatology ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Article ,Mice ,Oncology ,Animals ,Humans ,Female ,Melanoma ,Aged ,gp100 Melanoma Antigen - Abstract
Heat shock proteins (hsp) are intracellular chaperones that possess extracellular immunostimulatory properties when complexed with antigens. A recombinant Hsp110-gp100 chaperone complex vaccine showed an antitumor response and prolonged survival in murine melanoma. A phase Ib dose-escalation study of a recombinant human Hsp110-gp100 vaccine in advanced-stage melanoma patients was performed to evaluate toxicity, immunostimulatory potential and clinical response. Patients with pretreated, unresectable stage IIIB/C/IV melanoma received the chaperone complex vaccine in a dose-escalation protocol; three vaccinations over a 43-day-period. Tumor response, clinical toxicity and immune response were measured. Ten patients (eight female, median age 70 years) were enrolled and two patients had grade 1 adverse events; minor skin rash, hyperhidrosis and fever (no grade 2 or higher adverse events). Median progression-free survival was longer for lower vaccine doses as compared to the maximum dose of 180 mcg (4.5 vs. 2.9 months; P = 0.018). The lowest dose patients (30 and 60 mcg) had clinical tumor responses (one partial response, one stable disease). CD8+ T cell interferon-γ responses to gp100 were greater in the clinically responding patients. A pattern of B cell responses to vaccination was not observed. Regulatory T cell populations and co-stimulatory molecules including cytotoxic T-lymphocyte-associated protein 4 and PD-1 appeared to differ in responders versus nonresponders. A fully recombinant human Hsp110-gp100 chaperone complex vaccine had minimal toxicity, measurable tumor responses at lower doses and produced peripheral CD8+ T cell activation in patients with advanced, pretreated melanoma. Combination with currently available immunotherapies may augment clinical responses.
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- 2021
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13. Barriers to Referral for Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Identified Using a Tailoring Grid Methodology: Interviews with Stakeholders in New York State
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Marko Simunovic, John M. Kane, Joseph J. Skitzki, and Valerie Francescutti
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medicine.medical_specialty ,Referral ,business.industry ,New York ,Hospital level ,Cytoreduction Surgical Procedures ,Hyperthermia, Induced ,Hyperthermic Intraperitoneal Chemotherapy ,Combined Modality Therapy ,Quality of evidence ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Family medicine ,medicine ,Humans ,030211 gastroenterology & hepatology ,Surgery ,Hyperthermic intraperitoneal chemotherapy ,business ,Referral and Consultation ,Inclusion (education) ,Organization level ,Peritoneal Neoplasms - Abstract
Introduction Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) has variable uptake, with referrals reliant on other physicians. To characterize barriers to referral for CS/HIPEC, we created a pragmatic “tailoring grid”, incorporating the concepts of Pathman's 4 As of awareness, agreement, adoption, and adherence and barriers acting at the individual, practice group, and organization level. Methods and Materials We invited surgeons and medical oncologists from Western New York State who potentially refer patients for CS/HIPEC to participate in tailoring grid interviews. Results Interviews of 10 surgeons and 10 medical oncologists were completed. The participants were positioned in the Pathman 4 A's with respect to referrals for CS/HIPEC as follows: (1) A 19 aware (1 not aware); (2) A 3 in agreement (17 not in agreement); (3) A 9 adopters; and (4) A 6 adherent. Among the 9 participants who had referred at least one patient for CS/HIPEC (adopters/adherent), only 2 were in agreement with the appropriateness of CS/HIPEC. Barriers to awareness of included lack of interaction with colleagues and knowledge of indications. Barriers to agreement included lack of high quality of evidence supporting CS/HIPEC such as well-designed RCTs. Barriers to adoption included lack of communication with CS/HIPEC surgeons; lack of inclusion of the procedure into algorithms and defined morbidity/mortality rates. Barriers to adherence included lack of inclusion into guidelines by major societies; perceptions that the procedure is resource-intensive; lack of defined quality measures. Conclusions The tailoring grid efficiently identified barriers to awareness, agreement, adoption and adherence for routine referral for CS/HIPEC. Barriers to increased referrals included lack of high-quality evidence supporting CS/HIPEC. Barriers more easily addressed included communication between referring and CS/HIPEC surgeons, and outcomes at the individual patient and hospital level.
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- 2021
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14. Restrictive Intraoperative Fluid Rate is Associated with Improved Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
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Jessica LaPiano, Valerie Francescutti, Kristopher Attwood, Joseph J. Skitzki, Katy Wang, June S. Peng, and John M. Kane
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Hyperthermia ,medicine.medical_specialty ,Multivariate analysis ,business.industry ,medicine.medical_treatment ,Cytoreduction Surgical Procedures ,Hyperthermic Intraperitoneal Chemotherapy ,Bowel resection ,Middle Aged ,medicine.disease ,Article ,Surgery ,Oncology ,Surgical oncology ,medicine ,Humans ,Hyperthermic intraperitoneal chemotherapy ,Risk factor ,Cytoreductive surgery ,business ,Body mass index ,Aged - Abstract
Background Management of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) has historically favored liberal fluid administration owing to lengthy duration of surgery and hyperthermia. This practice has been challenged in recent years with studies demonstrating improved outcomes with restrictive fluid administration. Methods Patients who underwent CS/HIPEC between March 2010 and September 2018 were included for analysis. Patients who received an above-median fluid rate (high-IVF) versus below-median fluid rate (low-IVF) were compared, and multivariate analyses were performed for length of stay, 90-day unplanned readmissions, and major complications. Results The 167 patients had a mean age of 56.7 ± 11.4 years and body mass index of 29.5 ± 6.9 kg/m2. The median rate of total intraoperative crystalloid and colloid was 7.4 mL/kg/h. The low-IVF group had less blood loss (183 vs. 330 mL, p = 0.002), were less likely to need intraoperative vasopressor drip (2.4% vs. 11.9%, p = 0.018), and experienced fewer cardiac complications (2.4% vs. 10.7%, p = 0.031), pneumonias (0% vs. 6.0%, p = 0.024), and Clavien-Dindo grade 3-5 complications (14.5% vs. 33.3%, p = 0.004). Multivariate analyses identified bowel resection (HR 4.65, p = 0.0008) as a risk factor for 90-day unplanned readmission, while bowel resection, intraoperative fluid rate, and estimated blood loss were associated with increased length of stay. Conclusion Higher intraoperative fluid intake was associated with multiple postoperative complications and increased length of stay, and represents a potentially avoidable risk factor for morbidity in CS/HIPEC.
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- 2021
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15. NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021
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Brian R. Gastman, Martin D. Fleming, Anthony J. Olszanski, Jeffrey A. Sosman, Samantha Guild, April K.S. Salama, Susan M. Swetter, Dominick J. DiMaio, Douglas B. Johnson, Richard W. Joseph, Ryan M. Lanning, Rohit Sharma, Joseph J. Skitzki, Anjela Galan, Alison B. Durham, Anita M. Engh, Joel M. Baumgartner, Kenneth F. Grossmann, Genevieve M. Boland, Kari Kendra, Bartosz Chmielowski, Patrick A. Ott, Mark R. Albertini, Giorgos C. Karakousis, Kim Margolin, Nicole R. McMillian, Julie R. Lange, Merrick I. Ross, Christopher A. Barker, Evan Wuthrick, John A. Thompson, Ryan C. Fields, and Ashley M. Holder
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Melanoma ,Sentinel lymph node ,medicine.disease ,Systemic therapy ,Radiation therapy ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Dissection ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Biopsy ,medicine ,Advanced disease ,Radiology ,business ,Lymph node - 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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16. Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
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Jennifer Bordeaux, Dustin McCurry, Arivarasan Karunamurthy, Lisa H. Butterfield, Rogerio I. Neves, Anil Pahuja, Matthew P. Holtzman, Beiru Chen, Jehovana Orozco Bender, Ahmad A. Tarhini, Yan Zang, Ju Young Kim, John M. Kirkwood, Yan Lin, Cindy Sander, Joseph J. Skitzki, IlaSri B. Summit, Marc S. Ernstoff, Christian Laing, Joseph J. Drabick, Yana G. Najjar, Huang Lin, Jennifer Tsau, Ghanashyam Sarikonda, Igor Puzanov, Hassane M. Zarour, Zeni Alfonso, Amy Rose, James F. Pingpank, and Diwakar Davar
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,medicine.medical_treatment ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Pembrolizumab ,Interferon alpha-2 ,Antibodies, Monoclonal, Humanized ,Antibodies ,Drug Therapy ,Clinical Research ,Internal medicine ,Monoclonal ,80 and over ,medicine ,Clinical endpoint ,Humans ,Oncology & Carcinogenesis ,Stage (cooking) ,Melanoma ,Humanized ,Neoplasm Staging ,Aged ,Cancer ,Aged, 80 and over ,business.industry ,Evaluation of treatments and therapeutic interventions ,Immunotherapy ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Confidence interval ,Discontinuation ,6.1 Pharmaceuticals ,Combination ,Drug Therapy, Combination ,Female ,Immunization ,business ,Adjuvant - Abstract
Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133
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- 2021
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17. Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma
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Kristopher Attwood, Minhyung Kim, Daniel T. Fisher, Colin A. Powers, Joseph J. Skitzki, Emmanuel Gabriel, Sanjay P. Bagaria, and Keith L. Knutson
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0301 basic medicine ,Melphalan ,Intravital Microscopy ,Cancer therapy ,medicine.medical_treatment ,Melanoma, Experimental ,lcsh:Medicine ,Article ,03 medical and health sciences ,Mice ,Phenylephrine ,0302 clinical medicine ,Bolus (medicine) ,Cell Line, Tumor ,medicine ,Animals ,Adverse effect ,lcsh:Science ,Melanoma ,Chemotherapy ,Multidisciplinary ,business.industry ,lcsh:R ,Drug Synergism ,Blood flow ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Mice, Inbred C57BL ,030104 developmental biology ,Treatment Outcome ,Blood Circulation ,Cancer research ,Feasibility Studies ,Female ,Cancer imaging ,lcsh:Q ,Saline Solution ,business ,030217 neurology & neurosurgery ,Intravital microscopy ,medicine.drug - Abstract
Despite advances in therapy for melanoma, heterogeneous responses with limited durability represent a major gap in treatment outcomes. The purpose of this study was to determine whether alteration in tumor blood flow could augment drug delivery and improve antitumor responses in a regional model of melanoma. This approach to altering tumor blood flow was termed “dynamic control.” Dynamic control of tumor vessels in C57BL/6 mice bearing B16 melanoma was performed using volume expansion (saline bolus) followed by phenylephrine. Intravital microscopy (IVM) was used to observe changes directly in real time. Our approach restored blood flow in non-functional tumor vessels. It also resulted in increased chemotherapy (melphalan) activity, as measured by formation of DNA adducts. The combination of dynamic control and melphalan resulted in superior outcomes compared to melphalan alone (median time to event 40.0 vs 25.0 days, respectively, p = 0.041). Moreover, 25% (3/12) of the mice treated with the combination approach showed complete tumor response. Importantly, dynamic control plus melphalan did not result in increased adverse events. In summary, we showed that dynamic control was feasible, directly observable, and augmented antitumor responses in a regional model of melanoma. Early clinical trials to determine the translational feasibility of dynamic control are ongoing.
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- 2020
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18. A Translational Hepatic Artery Infusion (HAI) Model for Hepatocellular Carcinoma in Woodchucks
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Joseph J. Skitzki, Sandra Sexton, Leslie Curtin, Renuka Iyer, Daniel T. Fisher, Minhyung Kim, Colin A. Powers, and Katerina Gurova
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Male ,Drug ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,media_common.quotation_subject ,Carbazoles ,Anorexia ,Gastroenterology ,Article ,Gastroduodenal artery ,03 medical and health sciences ,First pass effect ,Hepatic Artery ,Liver Neoplasms, Experimental ,0302 clinical medicine ,Internal medicine ,medicine.artery ,medicine ,Coagulopathy ,Animals ,media_common ,business.industry ,Anatomic Variation ,virus diseases ,medicine.disease ,digestive system diseases ,Artery infusion ,medicine.anatomical_structure ,Marmota ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Female ,030211 gastroenterology & hepatology ,Surgery ,Drug Screening Assays, Antitumor ,medicine.symptom ,business ,Artery - Abstract
Background Woodchucks (Marmota monax) are a well-accepted animal model for the investigation of spontaneous hepatocellular carcinoma (HCC). As HCC tumors obtain nutrient blood supply exclusively from the hepatic artery, hepatic artery infusion (HAI) has been applied to HCC. However, there is a scarcity of experimental animal models to standardize drug regimens and examine novel agents. The purpose of this study was to establish an HAI model in woodchucks. Materials and methods HAI ports were placed in the gastroduodenal artery (GDA) of 11 woodchucks. The ports were infused with either a vehicle (dextrose 5% in water) or an experimental drug, CBL0137, once a week for 3 wk. Technical success rates, anatomical variation, morbidity and mortality, and tumor responses between groups were analyzed. Results The GDA access was feasible and reproducible in all woodchucks (11/11). The average operation time was 95 ± 20 min with no increase in the levels of liver enzymes detected from either infusate. The most common morbidity of CBL0137 therapy was anorexia after surgery. One woodchuck died due to hemorrhage at the gallbladder removal site from hepatic coagulopathy. Significantly higher CBL0137 concentrations were measured in the liver compared with blood after each HAI. Tumor growth was suppressed after multiple CBL0137 HAI treatments which corresponded to greater T cell infiltration and increased tumor cell apoptosis. Conclusions HAI via GDA was a feasible and reproducible approach with low morbidity and mortality in woodchucks. The described techniques serve as a reliable platform for the identification and characterization of therapeutics for HCC.
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- 2020
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19. Surgical Management of Primary Cutaneous Melanoma
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Daniel Joyce and Joseph J. Skitzki
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medicine.medical_specialty ,Skin Neoplasms ,Biopsy ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Anatomic Location ,Melanoma ,medicine.diagnostic_test ,business.industry ,Wide local excision ,Margins of Excision ,Cosmesis ,medicine.disease ,Primary tumor ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,030211 gastroenterology & hepatology ,Surgery ,Surgical excision ,Radiology ,business - Abstract
Primary cutaneous melanomas are potentially curative with surgical excision alone. Surgical management is based on several factors determined from the initial biopsy, including primary tumor thickness, histologic features including ulceration, and anatomic location. Cosmesis, although important, should be a secondary consideration as oncologic principles take precedence. Pathology has evolved to synoptic reporting with key variables to assist in staging and risk stratification.
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- 2020
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20. Manipulating Stress Receptor Signaling to Enhance Immunosuppression and Prolong Survival of Vascularized Composite Tissue
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Joseph J. Skitzki, Paul N. Bogner, Minhyung Kim, Elizabeth A. Repasky, Daniel S. Fisher, and Umesh C. Sharma
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Stress (mechanics) ,business.industry ,medicine.medical_treatment ,Cancer research ,Medicine ,Immunosuppression ,Receptor signaling ,Composite tissue ,business - Abstract
Vascularized composite tissue allotransplantation (VCA) can replace severely damaged body parts but the unavoidable toxicity of high doses of immunosuppressive drugs, such as tacrolimus, required results in significant morbidity. Here we tested whether we could suppress immune activity in a mouse model of VCA by mimicking the natural immune suppression generated by nervous system-induced signaling of adrenergic receptors (AR) by using a safe and well-studied β-AR agonist (terbutaline). Using wild-type and β2-AR-knockout (KO) mice, we found that increased β2-AR signaling results in delayed rejection in VCA recipients, even with subtherapeutic doses of tacrolimus, and this was associated with changes in immune contexture, expression of pro-inflammatory cytokines and chemokines, and function of endothelial adhesion molecules. We propose that β-AR agonists can be used safely to mimic the natural suppression of immune responses generated by adrenergic stress signaling and thereby reduce the dose needed of other more toxic immunosuppressive drugs.
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- 2021
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21. Outcomes After Adjuvant Hyperthermic Intraperitoneal Chemotherapy for High-Risk Primary Appendiceal Neoplasms After Complete Resection
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Gary N. Mann, Perry Shen, Linsay Totin, Edward A. Levine, Laura M. Enomoto, Joseph J. Skitzki, Kathleen C. Perry, M. Haroon A. Choudry, Konstantinos I. Votanopoulos, and David L. Bartlett
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Male ,medicine.medical_specialty ,Perforation (oil well) ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,Prospective cohort study ,Survival rate ,Peritoneal Neoplasms ,Retrospective Studies ,business.industry ,Retrospective cohort study ,Cytoreduction Surgical Procedures ,Hyperthermia, Induced ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Survival Rate ,Appendiceal Neoplasms ,Oncology ,Chemotherapy, Adjuvant ,Chemotherapy, Cancer, Regional Perfusion ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,030211 gastroenterology & hepatology ,Hyperthermic intraperitoneal chemotherapy ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,Cohort study - Abstract
Appendiceal neoplasms are uncommon tumors. Optimal treatment for patients with perforation or high-grade pathology after initial resection is unknown. This study evaluated patients with increased risk for peritoneal dissemination after primary resection, but no evidence of peritoneal disease, who underwent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). This multi-institutional cohort study evaluated 56 patients with high-risk (HR) appendiceal neoplasms with a peritoneal carcinomatosis index of 0 who underwent HIPEC. The patients were divided into two groups: perforated low-grade appendiceal (LGA) carcinoma and HR neoplasms, which included perforated high-grade appendiceal carcinoma, positive margins after initial resection, minimal macroscopic peritoneal disease that was previously resected or completely responded to systemic chemotherapy prior to HIPEC, goblet cell carcinoma, and adenocarcinoma with signet ring cell features. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan–Meier analysis. Thirty-eight percent of patients had perforated LGA and 68% had HR features. Five-year OS probability was 82.1% for the entire cohort, and 100% and 70.1% for patients with perforated LGA and HR features, respectively (p = 0.024). Five-year RFS probability was 79.3% for the entire cohort, and 90.0% and 72.4% for patients with perforated LGA and HR features, respectively (p = 0.025). Eight patients recurred after HIPEC and their OS was significantly worse (p
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- 2019
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22. Tertiary Lymphoid Structures as Mediators of Immunotherapy Response
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Raj G. Vaghjiani and Joseph J. Skitzki
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Cancer Research ,Oncology - Abstract
Since its first application in the treatment of cancer during the 1800s, immunotherapy has more recently become the leading edge of novel treatment strategies. Even though the efficacy of these agents can at times be predicted by more traditional metrics and biomarkers, often patient responses are variable. TLS are distinct immunologic structures that have been identified on pathologic review of various malignancies and are emerging as important determinants of patient outcome. Their presence, location, composition, and maturity are critically important in a host’s response to malignancy. Because of their unique immunogenic niche, they are also prime candidates, not only to predict and measure the efficacy of immunotherapy agents, but also to be potentially inducible gatekeepers to increase therapeutic efficacy. Herein, we review the mechanistic underpinnings of TLS formation, the data on its relationship to various malignancies, and the emerging evidence for the role of TLS in immunotherapy function.
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- 2022
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23. ASO Visual Abstract: Restrictive Intraoperative Fluid Rate Is Associated with Improved Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
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June S. Peng, Kristopher Attwood, Jessica LaPiano, John M. Kane, Katy Wang, Joseph J. Skitzki, and Valerie Francescutti
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medicine.medical_specialty ,Text mining ,Oncology ,Surgical oncology ,business.industry ,medicine ,MEDLINE ,Surgery ,Hyperthermic intraperitoneal chemotherapy ,Cytoreductive surgery ,business - Published
- 2021
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24. 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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Simon Turcotte, Sangeetha Prabhakaran, Steven A. Rosenberg, Haider Mahdi, Carol D. Morris, Howard L. Kaufman, Sara I. Pai, Yuman Fong, Michael Lim, John B. Sunwoo, Matthew M. Grabowski, Joseph J. Skitzki, Michael T. Lotze, Stephen Broderick, Pranav Murthy, Cecilia C.S. Yeung, Craig L. Slingluff, Adekunle Odunsi, David R. Byrd, Fumito Ito, Rogerio I. Neves, Lisa H. Butterfield, Brian R. Gastman, Peter E. Fecci, Genevieve M. Boland, Vernon K. Sondak, Adam C. Berger, Piyush K. Agarwal, Jyothi Sethuraman, Robert L. Ferris, Ragheed Saoud, Mokenge P. Malafa, and Stephanie L. Goff
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,tumor ,Tissue and Organ Procurement ,Best practice ,medicine.medical_treatment ,Clinical Trials and Supportive Activities ,Immunology ,review ,Review ,Subspecialty ,Medical Oncology ,Biospecimen Collection ,Tissue procurement ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Cancer immunotherapy ,Clinical Research ,Immunology and Allergy ,Medicine ,Humans ,Medical physics ,RC254-282 ,Cancer ,Pharmacology ,screening and diagnosis ,Clinical Trials as Topic ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,biomarkers ,Immunotherapy ,4.5 Resources and infrastructure (detection) ,Clinical trial ,Detection ,Orphan Drug ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunization ,immunotherapy ,business ,Cancer surgery ,guidelines as topic - 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.
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- 2020
25. Immunopathology of Bone and Connective Tissue Cancers and Immunotherapy of Sarcomas
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Sumana Narayanan and Joseph J. Skitzki
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- 2020
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26. Intra-arterial Versus Intravenous Adoptive Cell Therapy in a Mouse Tumor Model
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Joseph J. Skitzki, Emmanuel Gabriel, Asher Blum, Anthony Visioni, Minhyung Kim, Chandler Wilfong, Colin A. Powers, and Daniel T. Fisher
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0301 basic medicine ,Cancer Research ,Lymphocyte ,T-Lymphocytes ,Immunology ,Melanoma, Experimental ,Basic Studies ,Femoral artery ,intra-arterial ,Immunotherapy, Adoptive ,Cell therapy ,03 medical and health sciences ,Route of administration ,Mice ,Lymphocytes, Tumor-Infiltrating ,Cell Movement ,medicine.artery ,medicine ,Intra arterial ,melanoma ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,Mouse tumor ,adoptive cell transfer ,Pharmacology ,Tumor microenvironment ,business.industry ,Neoplasms, Experimental ,medicine.disease ,Adoptive Transfer ,3. Good health ,Tumor Burden ,Femoral Artery ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Injections, Intra-Arterial ,Cancer research ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Administration, Intravenous ,immunotherapy ,business ,Infiltration (medical) - Abstract
Supplemental Digital Content is available in the text., 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
27. Intravital microscopy in the study of the tumor microenvironment: from bench to human application
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Joseph J. Skitzki, Emmanuel Gabriel, Daniel T. Fisher, Kazuaki Takabe, and Sharon S. Evans
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0301 basic medicine ,Tumor microenvironment ,vasculature ,urogenital system ,business.industry ,Angiogenesis ,Cancer ,Review ,lymphocyte ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Oncology ,trafficking ,In vivo ,030220 oncology & carcinogenesis ,intravital microscopy ,medicine ,Cancer research ,Tumor-Associated Vasculature ,Personalized medicine ,business ,Intravital microscopy - Abstract
Intravital microscopy (IVM) is a dynamic imaging modality that allows for the real time observation of biologic processes in vivo, including angiogenesis and immune cell interactions. In the setting of preclinical cancer models, IVM has facilitated an understanding of the tumor associated vasculature and the role of effector immune cells in the tumor microenvironment. Novel approaches to apply IVM to human malignancies have thus far focused on cancer diagnosis and tumor vessel characterization, but have the potential to provide advances in the field of personalized medicine by identifying individual patients who may respond to systemically delivered chemotherapeutic drugs or immunotherapeutic agents. In this review, we highlight the role that IVM has had in investigating tumor vasculature and the tumor microenvironment in preclinical studies and discuss its current and future applications to directly observe human tumors.
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- 2018
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28. Conditional Survival-Based 'Abbreviated' Routine Cancer Surveillance for Pathologic Stage IB Melanoma
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Rebecca May, Edward Cho, Joseph J. Skitzki, Michelle Lichtenthal, Moshim Kukar, Valerie Francescutti, Emmanuel Gabriel, John M. Kane, and Adrienne Groman
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Male ,medicine.medical_specialty ,Skin Neoplasms ,Every Six Months ,Sentinel lymph node ,Disease-Free Survival ,Tertiary Care Centers ,Breslow Thickness ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,Humans ,Medicine ,030212 general & internal medicine ,Melanoma ,Early Detection of Cancer ,Neoplasm Staging ,medicine.diagnostic_test ,Sentinel Lymph Node Biopsy ,business.industry ,Cancer ,Extremities ,General Medicine ,Middle Aged ,Thorax ,Prognosis ,medicine.disease ,Primary tumor ,Head and Neck Neoplasms ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Cohort ,Female ,Radiology ,Neoplasm Recurrence, Local ,business - 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
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29. Novel mouse models of hepatic artery infusion
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Minhyung Kim, Daniel T. Fisher, Joseph J. Skitzki, Emmanuel Gabriel, Andrei V. Gudkov, Alexis M. Korman, Colin A. Powers, and Sandra Sexton
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medicine.medical_specialty ,Superior pancreaticoduodenal artery ,Portal venous system ,Antineoplastic Agents ,Gastroenterology ,Article ,Mice ,03 medical and health sciences ,First pass effect ,Hepatic Artery ,Liver Neoplasms, Experimental ,0302 clinical medicine ,Cell Line, Tumor ,medicine.artery ,Internal medicine ,Animals ,Infusions, Intra-Arterial ,Medicine ,Distribution (pharmacology) ,030212 general & internal medicine ,Mice, Inbred BALB C ,business.industry ,Liver Neoplasms ,Reproducibility of Results ,Mice, Inbred C57BL ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Toxicity ,Female ,Surgery ,Fluorouracil ,Radiology ,Liver function ,business ,Perfusion ,Artery - Abstract
BACKGROUND: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, while liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. The focused arterial delivery of anticancer agents to liver tumors has been performed for decades; however, preclinical models to standardize drug regimens and examine novel agents have been lacking. The purpose of this study was to establish preclinical hepatic artery infusion (HAI) models in a mouse, and to evaluate the safety and delivery capability of the models. MATERIAL AND METHODS: Female C57BL/6 and BALB/c mice aged 8–12 wk were used to develop models of HAI via the hepatic artery (HA), superior pancreaticoduodenal artery (SPDA), or lienogastric artery (LGA). Success rates, distribution of perfusion, and associated morbidity and mortality were analyzed between groups. RESULTS: All three models were feasible and reproducible in mice, and there was no statistical difference on body weight change between models. The HA model had a 13.3% mortality from acute liver failure, and the SPDA model demonstrated significant duodenal and pancreatic toxicity. SPDA and LGA routes had the highest success rates (96.7% and 91.4%, respectively) with low mortality, better drug delivery, and preserved physiologic liver function compared to the HA model. CONCLUSIONS: The optimal route of HAI was mouse breed-specific; SPDA access in BALB/c mice, and the LGA access in C57BL/6 mice. The described techniques serve as a reproducible platform for the identification and characterization of therapeutics for diverse metastatic liver tumors.
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- 2017
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30. Water lavage as an adjunct to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC)
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Daniel T. Fisher, Emmanuel Gabriel, Kristopher Attwood, Minhyung Kim, Colin A. Powers, Anthony Visioni, Joseph J. Skitzki, and Smit Singla
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Male ,Subset Analysis ,Hyperthermia ,medicine.medical_specialty ,medicine.medical_treatment ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Gastrointestinal cancer ,Therapeutic Irrigation ,Peritoneal Neoplasms ,Retrospective Studies ,Chemotherapy ,business.industry ,Water ,Cancer ,Retrospective cohort study ,Cytoreduction Surgical Procedures ,Hyperthermia, Induced ,General Medicine ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Chemotherapy, Cancer, Regional Perfusion ,030220 oncology & carcinogenesis ,Anesthesia ,Conventional PCI ,Female ,030211 gastroenterology & hepatology ,Surgery ,Hyperthermic intraperitoneal chemotherapy ,business - 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.
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- 2017
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31. Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) in colorectal cancer: Evidence-based review of patient selection and treatment algorithms
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Allison H. Maciver, Valerie Francescutti, Patrick McKay Boland, Joseph J. Skitzki, and N. Lee
- Subjects
Oncology ,medicine.medical_specialty ,Colorectal cancer ,Patient characteristics ,Adenocarcinoma ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Infusions, Parenteral ,Peritoneal Neoplasms ,Selection (genetic algorithm) ,Evidence-Based Medicine ,business.industry ,Patient Selection ,Cytoreduction Surgical Procedures ,Hyperthermia, Induced ,General Medicine ,medicine.disease ,Evidence based review ,Primary tumor ,030220 oncology & carcinogenesis ,Level evidence ,030211 gastroenterology & hepatology ,Surgery ,Hyperthermic intraperitoneal chemotherapy ,Colorectal Neoplasms ,business ,Algorithm ,Algorithms - Abstract
Cytoreduction and heated intraperitoneal chemotherapy (CS/HIPEC) is increasingly utilized as a treatment strategy for patients with peritoneal metastases from various primary tumor sites. For this heterogenous procedure, related to patient characteristics, patient selection, and the extent of surgical completeness of cytoreduction, high level evidence (ex: multiple randomized controlled trials) is not available to support efficacy. This review of the available literature supporting application of the procedure, focusing on colorectal cancer, provides a summary of current evidence for patient selection and treatment algorithms based on patient presentation.
- Published
- 2017
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32. Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology
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Jeffrey A. Sosman, Carlo M. Contreras, Brian R. Gastman, Valerie Guild, Douglas B. Johnson, Martin D. Fleming, Anthony J. Olszanski, Morganna Freeman, Merrick I. Ross, Ryan C. Fields, Richard W. Joseph, Nicole R. McMillian, John A. Thompson, Kenneth K. Tanabe, Gregory A. Daniels, Susan M. Swetter, Christopher A. Barker, Evan Wuthrick, William E. Carson, Anita M. Engh, Dominick J. DiMaio, Sameer K. Nath, Mark R. Albertini, April K.S. Salama, Joseph J. Skitzki, Aparna Priyanath Gupta, Julie R. Lange, Anjela Galan, Patrick A. Ott, and Daniel G. Coit
- Subjects
Oncology ,medicine.medical_specialty ,Skin Neoplasms ,business.industry ,Immune checkpoint inhibitors ,medicine.medical_treatment ,MEDLINE ,Disease ,Guideline ,Medical Oncology ,Systemic therapy ,Clinical Practice ,Internal medicine ,Cutaneous melanoma ,medicine ,Humans ,business ,Adjuvant ,Melanoma - 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.
- Published
- 2019
33. 77286 Intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis
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Emmanuel Gabriel, Sanjay P. Bagaria, Tri A. Dinh, Keith L. Knutson, Wenyan Ji, Michael B. Wallace, Catherine Mangum, Minhyung Kim, Debabrata Mukhopadhyay, Daniel T. Fisher, Matthew W. Robertson, Joseph J. Skitzki, and Kristopher Attwood
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,General Medicine ,Tumor vasculature ,business ,Intravital microscopy ,Peritoneal carcinomatosis - Abstract
IMPACT: Investigation of tumor-associated blood vessels may serve as an imaging biomarker of response to systemic therapy and cancer outcomes. OBJECTIVES/GOALS: Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC) and generate clinical utility. METHODS/STUDY POPULATION: During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). RESULTS/ANTICIPATED RESULTS: Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. DISCUSSION/SIGNIFICANCE OF FINDINGS: These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).
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- 2021
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34. Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC)
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Adrienne Groman, Jill Nestico, Nathalie C. Zeitouni, Anthony Jarkowski, Ryan Hare, Kilian Salerno May, Karen L Vona, John M. Kane, Nikhil I. Khushalani, Joseph J. Skitzki, and Peter A. Loud
- Subjects
Male ,Oncology ,Cancer Research ,Skin Neoplasms ,Databases, Factual ,Treatment outcome ,Cetuximab ,Kaplan-Meier Estimate ,Systemic therapy ,Cohort Studies ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Aged, 80 and over ,Middle Aged ,Prognosis ,Treatment Outcome ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Female ,Cohort study ,Adult ,medicine.medical_specialty ,Cutaneous squamous cell carcinoma ,New York ,Locally advanced ,Cancer Care Facilities ,Risk Assessment ,Disease-Free Survival ,Drug Administration Schedule ,03 medical and health sciences ,Internal medicine ,Confidence Intervals ,Carcinoma ,medicine ,Humans ,Neoplasm Invasiveness ,Survival analysis ,Aged ,Neoplasm Staging ,Retrospective Studies ,Dose-Response Relationship, Drug ,business.industry ,Retrospective cohort study ,medicine.disease ,Survival Analysis ,Dermatology ,Cisplatin ,business - Abstract
Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy.Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method.Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy.Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.
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- 2016
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35. Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons
- Author
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Allison H. Maciver, Joseph J. Skitzki, Valerie Francescutti, Eisar Al-Sukhni, John M. Kane, and Jesus Esquivel
- Subjects
Adult ,medicine.medical_specialty ,Perioperative Care ,03 medical and health sciences ,0302 clinical medicine ,Cytoreduction Surgical Procedures ,Monitoring, Intraoperative ,Surveys and Questionnaires ,Antineoplastic Combined Chemotherapy Protocols ,Preoperative Care ,Humans ,Medicine ,Anesthesia ,Blood Transfusion ,Infusions, Parenteral ,Practice Patterns, Physicians' ,Antibiotic prophylaxis ,Early Ambulation ,Peritoneal Neoplasms ,Physical Therapy Modalities ,Aged ,Postoperative Care ,Venous Thrombosis ,Intraoperative Care ,Perioperative management ,Nutritional Support ,business.industry ,General surgery ,International survey ,Hyperthermia, Induced ,Perioperative ,Antibiotic Prophylaxis ,Middle Aged ,Surgery ,Oncology ,030220 oncology & carcinogenesis ,Perioperative care ,Fluid Therapy ,030211 gastroenterology & hepatology ,Hyperthermic intraperitoneal chemotherapy ,Analgesia ,business ,Cytoreductive surgery ,Hospitals, High-Volume - Abstract
Cytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers.Surgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care.Ninety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics.Perioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.
- Published
- 2016
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36. NCCN Guidelines Insights: Melanoma, Version 3.2016
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Vijay Trisal, April K.S. Salama, Marshall M. Urist, Gregory A. Daniels, Daniel G. Coit, Merrick I. Ross, Nicole R. McMillian, Kenneth K. Tanabe, Dominick J. DiMaio, Joseph J. Skitzki, John A. Thompson, Brian R. Gastman, Christopher K. Bichakjian, Ryan C. Fields, Alain Algazi, Douglas B. Johnson, Martin D. Fleming, Anthony J. Olszanski, Richard W. Joseph, Rene Gonzalez, Patrick A. Ott, Valerie Guild, William E. Carson, Susan M. Swetter, Miguel A. Materin, Aparna Priyanath Gupta, Julie R. Lange, Mary C. Martini, Javier F. Torres-Roca, Anita M. Engh, and Robert H.I. Andtbacka
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,MEDLINE ,Antineoplastic Agents ,Systemic therapy ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Combined Modality Therapy ,In patient ,Molecular Targeted Therapy ,Melanoma ,Neoplasm Staging ,business.industry ,Treatment regimen ,Immunotherapy ,medicine.disease ,Treatment Outcome ,Novel agents ,030220 oncology & carcinogenesis ,Retreatment ,business - 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.
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- 2016
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37. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology
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Anita M. Engh, Ryan C. Fields, F. Stephen Hodi, Nicole R. McMillian, Martin D. Fleming, Anthony J. Olszanski, Robert H.I. Andtbacka, John A. Thompson, Miguel A. Materin, Kenneth K. Tanabe, April K.S. Salama, Daniel G. Coit, Valerie Guild, Joseph J. Skitzki, Rene Gonzalez, Marc Ernstoff, Dominick J. DiMaio, Merrick I. Ross, Susan M. Swetter, Javier F. Torres-Roca, William E. Carson, Julie R. Lange, Christopher K. Bichakjian, Jeffrey A. Sosman, Vijay Trisal, Mary C. Martini, Richard W. Joseph, Allan C. Halpern, Gregory A. Daniels, Marshall M. Urist, and Alain Algazi
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Oncology ,medicine.medical_specialty ,business.industry ,Melanoma ,MEDLINE ,Ipilimumab ,Disease ,medicine.disease ,Clinical Practice ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adjuvant therapy ,Humans ,Stage (cooking) ,Talimogene laherparepvec ,business ,medicine.drug - 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.
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- 2016
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38. Intraoperative intravital microscopy permits the study of human tumour vessels
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Paul N. Bogner, Daniel T. Fisher, Joseph J. Skitzki, Minhyung Kim, Jason B. Muhitch, Sharon S. Evans, and Kurt C. Doyen
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Intravital Microscopy ,medicine.medical_treatment ,Science ,General Physics and Astronomy ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Malignant disease ,Article ,Microcirculation ,03 medical and health sciences ,Mice ,In vivo ,Cell Line, Tumor ,Medicine ,Animals ,Humans ,Melanoma ,Multidisciplinary ,business.industry ,General Chemistry ,Blood flow ,Immunotherapy ,3. Good health ,030104 developmental biology ,Drug delivery ,cardiovascular system ,Immunohistochemistry ,Blood Vessels ,business ,Intravital microscopy - Abstract
Tumour vessels have been studied extensively as they are critical sites for drug delivery, anti-angiogenic therapies and immunotherapy. As a preclinical tool, intravital microscopy (IVM) allows for in vivo real-time direct observation of vessels at the cellular level. However, to date there are no reports of intravital high-resolution imaging of human tumours in the clinical setting. Here we report the feasibility of IVM examinations of human malignant disease with an emphasis on tumour vasculature as the major site of tumour-host interactions. Consistent with preclinical observations, we show that patient tumour vessels are disorganized, tortuous and ∼50% do not support blood flow. Human tumour vessel diameters are larger than predicted from immunohistochemistry or preclinical IVM, and thereby have lower wall shear stress, which influences delivery of drugs and cellular immunotherapies. Thus, real-time clinical imaging of living human tumours is feasible and allows for detection of characteristics within the tumour microenvironment., Intravital microscopy has been used in laboratory animals to visualise the blood vessels in tumours. Here, the authors use this technique in melanoma patients undergoing surgery and show that vessels in situ have a larger diameter than excised tissue
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- 2016
39. Abstract LB-396: Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of CXCL9 synergizes with IL-12 gene therapy (TAVO) to elicit robust anti-tumor immunity
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Erica Browning, Anandaroop Mukhopadhyay, Jon Salazar, David A. Canton, Reneta Hermiz, Daniel T. Fisher, Lauren Svenson, Christopher G. Twitty, Joseph J. Skitzki, Jack Y. Lee, Bianca Nguyen, Mia Han, and Daniel O'Connor
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Cancer Research ,Tumor microenvironment ,business.industry ,Electroporation ,T cell ,Genetic enhancement ,Antigen presentation ,stomatognathic diseases ,medicine.anatomical_structure ,Immune system ,stomatognathic system ,Oncology ,Interleukin 12 ,Cancer research ,Medicine ,business ,CD8 - Abstract
Clinical and preclinical studies have demonstrated that plasmid IL-12 (tavokinogene telseplasmid; TAVO) delivered intratumorally via electroporation drives IFN-γ expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our IL-12/anti-PD-1 clinical trial has identified that clinical responses are closely tied to intratumoral CXCR3 levels. While all patients had a similar frequency of activated CD8+ T cells in the periphery, responding patients had a significant increase of intratumoral CXCR3 transcripts post-treatment (p=0.03) compared to nonresponding patients (p=0.4), underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. Since the IFN-γ/CXCL9/CXCR3 axis is known to increase sensitivity to anti-PD-1 therapies, we hypothesized that combining intratumoral TAVO with a DNA-encoded locally secreted CXCL9 (cognate ligand for CXCR3) would further augment/restore this axis and ‘license' a robust anti-PD-1 response beyond the treated lesion. An appropriate CXCL9 gradient can productively modulate frequencies of tumor infiltrating tumor-reactive CXCR3+ T cells. We have previously demonstrated that intratumoral electroporation of plasmid IL-12 and CXCL9 elicits a robust antitumor immune response evidenced by increased systemic antigen-specific CD8+ T cells and improved regression of both treated and contralateral CT26 tumors. In the current study, we demonstrate that an enhanced CXCL9 gradient via intratumoral electroporation leads to efficient trafficking of CXCR3+ CD8+ T cells into CT26 tumors. We further explored how DNA-encodable IL-12/CXCL9 can work together to improve checkpoint inhibitor response. We demonstrated that intratumoral TAVO rapidly drives a population of CXCR3+ CD8+ T cells in the lymph node and importantly, depletion of these CXCR3+ immune cells abrogated an IL-12-mediated anti-tumor response. Furthermore, upon electroporation of IL-12 and CXCL9, transcriptomic analysis of the tumor microenvironment revealed an enrichment of genes associated with immune-related pathways (IFN-γ signaling, interleukin signaling, GPCR signaling), antigen presentation machinery, and TCR signaling, indicating that this combination therapy augments anti-tumor immunity. Lastly, leveraging the partially responsive anti-PD-1 CT26 tumor model, we demonstrated that intratumoral electroporation of plasmid IL-12 with CXCL9 significantly improved anti-PD1 response, providing a strong rationale for filing an Investigational New Drug application based on this intratumoral DNA-encodable combination approach.Intratumoral CXCL9 with IL12 Citation Format: Anandaroop Mukhopadhyay, Bianca Nguyen, Jack Y. Lee, Mia Han, Jon Salazar, Reneta Hermiz, Lauren Svenson, Erica Browning, Daniel J. O'Connor, David A. Canton, Daniel Fisher, Joseph Skitzki, Christopher G. Twitty. Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of CXCL9 synergizes with IL-12 gene therapy (TAVO) to elicit robust anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-396.
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- 2020
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40. Malignant adnexal tumors of the skin: a single institution experience
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Wei Tan, Valerie Francescutti, Kilian E. Salerno, Nikhil I. Khushalani, Joseph J. Skitzki, John M. Kane, and Tolutope Oyasiji
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Male ,Skin Neoplasms ,Survival ,medicine.medical_treatment ,Eccrine Glands ,Gastroenterology ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Surgical oncology ,Single institution ,Lymph node ,Skin ,Aged, 80 and over ,Malignant ,Nodal metastasis ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Combined Modality Therapy ,Survival Rate ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Female ,Neoplasms, Adnexal and Skin Appendage ,Adult ,medicine.medical_specialty ,Eccrine carcinoma ,lcsh:Surgery ,lcsh:RC254-282 ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Carcinoma ,Humans ,Neoplasm Invasiveness ,Aged ,Retrospective Studies ,Tumors ,Chemotherapy ,business.industry ,Research ,Adnexal ,lcsh:RD1-811 ,medicine.disease ,Adnexal tumors ,Treatment ,Sweat Gland Neoplasms ,Surgery ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - 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
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- 2018
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41. Improved Cuff Technique and Intraoperative Detection of Vascular Complications for Hind Limb Transplantation in Mice
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Joseph J. Skitzki, Colin A. Powers, Daniel T. Fisher, Minhyung Kim, and Elizabeth A. Repasky
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Transplantation ,medicine.medical_specialty ,Laboratory Method ,business.industry ,medicine.medical_treatment ,Abdominal aorta ,lcsh:Surgery ,Immunosuppression ,lcsh:RD1-811 ,030230 surgery ,Anastomosis ,Revascularization ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine.artery ,Cuff ,medicine ,Artery occlusion ,business ,Complication - Abstract
Background Vascularized composite tissue allotransplantation (VCA) from a cadaveric donor has now become a clinical reality and the treatment modality of choice for patients with devastating injuries, deformities, and complex tissue defects. However, many VCA patients experience severe toxicities due to the strong immunosuppression required secondary to high antigenicity of the grafts. To improve immunosuppressive protocols for VCA, feasible and reliable preclinical models are necessary. The purpose of this study was to introduce new techniques to an established preclinical VCA model to accelerate future investigations. Methods C57BL/6 (H-2b) and BALB/c (H-2d) mice were used to perform VCA as recipients and donors, respectively. Surgery time, success rate, associated complications, and mortality were analyzed. Blood flow in grafts was interrogated with laser speckle image (LSI). Results A nonsuture cuff technique was used with the abdominal aorta for end-to-end anastomosis. The cuff technique demonstrated efficiency for donor surgery (52 ± 10 minutes for donor vs. 45 ± 8 minutes for recipient surgery). Successful revascularization was achieved in 27 (90%) of 30 transplants. The majority of surgical complications occurred within 48 hours including artery occlusion, venous occlusion, cerebral stroke, and minor bleeding without mortality. LSI was useful in detecting intraoperative vascular complications with display patterns predictive of complication type. Conclusions The described techniques may facilitate a more efficient heterotopic hind limb transplantation mouse model of VCA.
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- 2018
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42. real time observation of tumor-host interaction during ovarian cancer cytoreductive surgery using intravital microsocopy
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Joseph J. Skitzki, Daniel T. Fisher, Kelly L. Singel, Kunle Odunsi, Anm Nazmul H. Khan, Tiffany R. Emmons, Peter J. Frederick, S.B. Lele, Brahm H. Segal, Emese Zsiros, M. Kim, Jaron Mark, and E. Alqassim
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Obstetrics and Gynecology ,Cytoreductive surgery ,business ,Ovarian cancer ,medicine.disease ,Host (network) - Published
- 2019
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43. A murine model of targeted infusion for intracranial tumors
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Joseph J. Skitzki, Tara A. Barone, Chandler Wilfong, Anatoli S. Gleiberman, Julie A. Alosi, Natalia Fedtsova, Robert J. Plunkett, Andrei V. Gudkov, and Minhyung Kim
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Mice, Nude ,Antineoplastic Agents ,Tumor response ,Article ,Cell Line ,Mice ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,Internal medicine ,medicine.artery ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Humans ,Infusions, Intra-Arterial ,Neurologic Examination ,Brain Neoplasms ,business.industry ,Brain ,Drug administration ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Neurology ,Novel agents ,Murine model ,030220 oncology & carcinogenesis ,Drug delivery ,Neurology (clinical) ,Internal carotid artery ,Glioblastoma ,business ,030217 neurology & neurosurgery ,Large animal - Abstract
Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery (ICA) to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.
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- 2015
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44. The Role of Regional Therapies for in-Transit Melanoma in the Era of Improved Systemic Options
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Joseph J. Skitzki and Emmanuel Gabriel
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Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Review ,Disease ,030230 surgery ,lcsh:RC254-282 ,Systemic therapy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Intensive care medicine ,Response rate (survey) ,in-transit melanoma ,business.industry ,Melanoma ,In transit melanoma ,regional cancer therapy ,Widespread Disease ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,3. Good health ,Oncolytic virus ,Surgery ,Oncology ,030220 oncology & carcinogenesis ,immunotherapy ,business - 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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45. Key gaps in pathologic reporting for appendiceal mucinous neoplasms: time for universal synoptic reporting?
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Eisar Al-Sukhni, Joseph J. Skitzki, Charles LeVea, John M. Kane, and Valerie Francescutti
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Statistics as Topic ,education ,Perforation (oil well) ,Classification scheme ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Retrospective Studies ,Pathology, Clinical ,business.industry ,Retrospective cohort study ,General Medicine ,Prognosis ,Optimal management ,Appendiceal neoplasms ,Dissection ,030104 developmental biology ,Appendiceal Neoplasms ,Research Design ,030220 oncology & carcinogenesis ,Histopathology ,business - 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.
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- 2016
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46. A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma
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Yana G. Najjar, Dustin McCurry, Igor Puzanov, Joseph J. Drabick, Cindy Sander, Matthew P. Holtzman, Diwakar Davar, John M. Kirkwood, Yan Lin, Marc S. Ernstoff, Amy Rose, Joseph J. Skitzki, Huang Lin, James F. Pingpank, Rogerio I. Neves, and Ahmad A. Tarhini
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pembrolizumab ,Phase i study ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Combination immunotherapy ,business ,030215 immunology ,Advanced melanoma - Abstract
9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.
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- 2019
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47. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models
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John F. Gibbs, Ritesh Patil, Myron S. Czuczman, Cory Mavis, Juan J Gu, George Deeb, Francisco J. Hernandez-Ilizaliturri, Natalie M Czuczman, and Joseph J. Skitzki
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Boron Compounds ,Cancer Research ,Time Factors ,Cell cycle checkpoint ,Cell Survival ,Cell ,Glycine ,Antineoplastic Agents ,Apoptosis ,Article ,Antibodies, Monoclonal, Murine-Derived ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Humans ,Pharmacology (medical) ,Doxorubicin ,B-cell lymphoma ,Pharmacology ,B-Lymphocytes ,Dose-Response Relationship, Drug ,Bortezomib ,Cell growth ,business.industry ,Cell Cycle ,Drug Synergism ,Cell cycle ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Caspases ,Cancer research ,Proteasome inhibitor ,Drug Screening Assays, Antitumor ,Rituximab ,business ,Proteasome Inhibitors ,medicine.drug - Abstract
To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma.
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- 2013
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48. Targeting the Heat Shock Response in Cancer
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Sartaj S. Sanghera and Joseph J. Skitzki
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business.industry ,Cancer ,medicine.disease ,medicine.disease_cause ,Small molecule ,Mediator ,Oncology ,Cancer cell ,Cancer research ,Medicine ,Surgery ,In patient ,Heat shock ,business ,Carcinogenesis - Abstract
The elucidation of the heat shock response (HSR) as a mediator of cellular stress has created a framework for understanding how these processes may promote tumorigenesis. Furthermore, the identification of specific components of the HSR and how they are co-opted by cancer cells has led to the discovery of new therapeutic targets. A wide range of small molecule inhibitors of the HSR are in various stages of development for clinical application in patients with cancer. The introduction of these novel small molecule inhibitors offers the opportunity for synergy with existing therapies and the potential for highly targeted treatments.
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- 2013
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49. Consensus Guidelines from The American Society of Peritoneal Surface Malignancies on Standardizing the Delivery of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Patients in the United States
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Jesus Esquivel, Paul F. Mansfield, Jason M. Foster, Daniel M. Labow, T. Blazer, Robert M. Barone, Joseph J. Skitzki, Richard E. Royal, John H. Stewart, J. Spellman, Robert P. Sticca, Benjamin D.L. Li, James F. Pingpank, Laura A. Lambert, George I. Salti, H.R. Alexander, Edward A. Levine, Reynaldo Garcia, A. Bastidas, N. J. Espat, Lawrence E. Harrison, F. Attiyeh, Armando Sardi, K. Y. Chung, Richard A. Hoefer, Andrew M. Lowy, R. Adbel-Misih, Colette R. Pameijer, M. Quinones, Garrett M. Nash, Quyen D. Chu, E. Ong, Keith Fournier, Kiran K. Turaga, Michael D. Goodman, Perry Shen, Nader Hanna, John M. Kane, Matthew P. Holtzman, Michael A. Morse, David L. Bartlett, L. Dominguez-Parra, and Nicholas J. Petrelli
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Societies, Scientific ,medicine.medical_specialty ,Consensus ,Peritoneal surface ,Colorectal cancer ,medicine.medical_treatment ,Surgical oncology ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Combined Modality Therapy ,Peritoneal Neoplasms ,Chemotherapy ,business.industry ,General surgery ,Cancer ,Hyperthermia, Induced ,medicine.disease ,Oxaliplatin ,Surgery ,Oncology ,Chemotherapy, Cancer, Regional Perfusion ,Practice Guidelines as Topic ,Hyperthermic intraperitoneal chemotherapy ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC.A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests.Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin.This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.
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- 2013
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50. The benefit of intraperitoneal chemotherapy for the treatment of colorectal carcinomatosis
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Louis Rivera, Mukund Seshadri, Kristopher Attwood, Marta Camoriano, Valerie Francescutti, John M. Kane, Michelle Haslinger, Minhyung Kim, and Joseph J. Skitzki
- Subjects
Hyperthermia ,Cancer Research ,Pathology ,medicine.medical_specialty ,Cell Survival ,medicine.medical_treatment ,Mitomycin ,Urology ,hyperthermic intraperitoneal chemoperfusion ,carcinomatosis ,intraperitoneal ,chemotherapy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Carcinoma ,Animals ,Infusions, Parenteral ,Dosing ,Saline ,mouse ,Mice, Inbred BALB C ,Oncogene ,business.industry ,Mitomycin C ,Cancer ,General Medicine ,Articles ,Hyperthermia, Induced ,medicine.disease ,Molecular medicine ,3. Good health ,Tumor Burden ,Disease Models, Animal ,Oncology ,030220 oncology & carcinogenesis ,Chemotherapy, Cancer, Regional Perfusion ,030211 gastroenterology & hepatology ,Female ,business ,Colorectal Neoplasms - Abstract
The clinical practice of hyperthermic intraperitoneal chemoperfusion (HIPEC) for carcinomatosis has lacked preclinical justification. A standardized mouse model was created to evaluate the independent effects of intraperitoneal chemotherapy. Diffuse colorectal carcinomatosis was generated in mice prior to intraperitoneal lavage with mitomycin C (MMC) at clinically comparable dosing for variable lengths of time. Tumor volumes, MMC tissue concentrations and survival were measured in comparison to saline lavage and intravenous MMC. Magnetic resonance imaging revealed a direct correlation between tumor volume, MMC dose and exposure time and survival. Intravenous MMC demonstrated a rapid clearance from the blood, lower peritoneal tissue concentrations, less tumor growth inhibition and decreased survival compared to intraperitoneal administration. Intraperitoneal chemotherapy inhibited tumor growth independent of cytoreduction or hyperthermia, demonstrated improved peritoneal tissue concentration and was associated with increased survival. These data support the clinical utility of the intraperitoneal chemotherapy component of HIPEC.
- Published
- 2013
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