Publications by authors named "Joseph Skitzki"

59 Publications

NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021.

J Natl Compr Canc Netw 2021 Apr 1;19(4):364-376. Epub 2021 Apr 1.

30Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

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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http://dx.doi.org/10.6004/jnccn.2021.0018DOI Listing
April 2021

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

Clin Cancer Res 2021 Mar 22. Epub 2021 Mar 22.

H. Lee Moffit Cancer Center and Research Institute, Tampa, Florida.

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/m/day i.v., 5 days per week for 4 weeks, then 10 MU/m/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 ( = 0.002 and = 0.008, respectively).

Conclusions: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4301DOI Listing
March 2021

A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis.

Sci Rep 2021 Mar 2;11(1):4946. Epub 2021 Mar 2.

Department of Gastroenterology, Mayo Clinic, Jacksonville, FL, USA.

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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http://dx.doi.org/10.1038/s41598-021-84430-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925603PMC
March 2021

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

J Immunother Cancer 2020 11;8(2)

Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA.

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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http://dx.doi.org/10.1136/jitc-2020-001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670953PMC
November 2020

Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma.

Sci Rep 2020 08 6;10(1):13245. Epub 2020 Aug 6.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

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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http://dx.doi.org/10.1038/s41598-020-70233-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413248PMC
August 2020

A Translational Hepatic Artery Infusion (HAI) Model for Hepatocellular Carcinoma in Woodchucks.

J Surg Res 2020 07 3;251:126-136. Epub 2020 Mar 3.

Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York. Electronic address:

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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http://dx.doi.org/10.1016/j.jss.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830851PMC
July 2020

NCCN Guidelines Insights: Uveal Melanoma, Version 1.2019.

J Natl Compr Canc Netw 2020 02;18(2):120-131

The University of Texas MD Anderson Cancer Center.

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.
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http://dx.doi.org/10.6004/jnccn.2020.0007DOI Listing
February 2020

Surgical Management of Primary Cutaneous Melanoma.

Surg Clin North Am 2020 Feb 28;100(1):61-70. Epub 2019 Oct 28.

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address:

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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http://dx.doi.org/10.1016/j.suc.2019.09.001DOI Listing
February 2020

Outcomes After Adjuvant Hyperthermic Intraperitoneal Chemotherapy for High-Risk Primary Appendiceal Neoplasms After Complete Resection.

Ann Surg Oncol 2020 Jan 31;27(1):107-114. Epub 2019 Jul 31.

Department of Surgery, Wake Forest Baptist Medical Center, Winston Salem, NC, USA.

Introduction: 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).

Methods: 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.

Results: 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 < 0.001).

Conclusion: While adjuvant HIPEC is both safe and feasible, there appears to be little benefit over close surveillance when outcomes are compared with historical and prospective studies, especially for perforated LGA carcinoma.
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http://dx.doi.org/10.1245/s10434-019-07634-yDOI Listing
January 2020

Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2019 04;17(4):367-402

27National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.
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http://dx.doi.org/10.6004/jnccn.2019.0018DOI Listing
April 2019

Intra-arterial Versus Intravenous Adoptive Cell Therapy in a Mouse Tumor Model.

J Immunother 2018 Sep;41(7):313-318

Departments of Surgical Oncology.

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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http://dx.doi.org/10.1097/CJI.0000000000000235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092084PMC
September 2018

Malignant adnexal tumors of the skin: a single institution experience.

World J Surg Oncol 2018 May 30;16(1):99. Epub 2018 May 30.

Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Background: Malignant adnexal tumors of the skin (MATS) are rare. We aimed to measure the survival of patients with MATS and identify predictors of improved survival.

Methods: A retrospective review of MATS treated at our institution from 1990 to 2012.

Results: There were 50 patients within the time period. Median age was 59.5 years (range 22-95); primary site was the head and neck (52%); most common histologic subtypes were skin appendage carcinoma (20%) and eccrine adenocarcinoma (20%); and the vast majority were T1 (44%). Most patients (98%) underwent surgical treatment. Chemotherapy and radiation were administered to 8 and 14% of patients, respectively. Recurrence rate was 12%. Median OS was 158 months (95% CI, 52-255). OS and recurrence-free survival at 5 years were 62.4 and 47.4% and at 10 years 56.7 and 41.5%, respectively. Five-year and 10-year disease-specific survival (DSS) was 62.9%. Age > 60 years was an unfavorable predictor of OS (HR 12.9, P < .0008) and recurrence-free survival (RFS) (HR 12.53, P < .0003). Nodal metastasis was a negative predictor of RFS (HR 2.37, P < 0.04) and DSS (HR 7.2, P < 0.03) while treatment with chemotherapy was predictive of poor DSS (HR 14.21, P < 0.03).

Conclusions: Younger patients had better OS and RFS. Absence of nodal metastasis translated to better RFS and DSS. Lymph node basin staging is worth considering in the workup and treatment.
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http://dx.doi.org/10.1186/s12957-018-1401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977488PMC
May 2018

Intravital microscopy in the study of the tumor microenvironment: from bench to human application.

Oncotarget 2018 Apr 13;9(28):20165-20178. Epub 2018 Apr 13.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Intravital microscopy (IVM) is a dynamic imaging modality that allows for the real time observation of biologic processes , 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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http://dx.doi.org/10.18632/oncotarget.24957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929454PMC
April 2018

Improved Cuff Technique and Intraoperative Detection of Vascular Complications for Hind Limb Transplantation in Mice.

Transplant Direct 2018 Feb 2;4(2):e345. Epub 2018 Feb 2.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY.

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-2) and BALB/c (H-2) 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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http://dx.doi.org/10.1097/TXD.0000000000000756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811274PMC
February 2018

Conditional Survival-Based "Abbreviated" Routine Cancer Surveillance for Pathologic Stage IB Melanoma.

Am Surg 2017 Nov;83(11):1256-1262

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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November 2017

Novel mouse models of hepatic artery infusion.

J Surg Res 2017 11 21;219:25-32. Epub 2017 Jun 21.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York; Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. Electronic address:

Background: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, whereas 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: C57BL/6 and BALB/c mice 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 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 with 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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http://dx.doi.org/10.1016/j.jss.2017.05.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986560PMC
November 2017

Water lavage as an adjunct to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).

Am J Surg 2017 Sep 6;214(3):462-467. Epub 2017 Jun 6.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address:

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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http://dx.doi.org/10.1016/j.amjsurg.2017.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833924PMC
September 2017

Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes.

Elife 2016 12 8;5. Epub 2016 Dec 8.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.

Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.
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http://dx.doi.org/10.7554/eLife.17375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199197PMC
December 2016

Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons.

Ann Surg Oncol 2017 Apr 29;24(4):923-930. Epub 2016 Nov 29.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1245/s10434-016-5692-3DOI Listing
April 2017

Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas.

Cancer Res 2016 11 28;76(22):6620-6630. Epub 2016 Sep 28.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York.

Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a nongenotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability. Here, we report that CBL0137 delivered by ILP in a murine melanoma model is as efficacious as melphalan, displaying antitumor activity at doses corresponding to only a fraction of the systemic MTD of CBL0137. The ability to bind DNA quickly combined with a favorable safety profile made it possible to substitute CBL0137 in the ILP protocol, using an intra-arterial infusion method, to safely achieve effective tumor suppression. Our findings of a preclinical proof of concept for CBL0137 and its administration via intra-arterial infusion as a superior treatment compared with melphalan ILP allows for locoregional treatment anywhere a catheter can be placed. Cancer Res; 76(22); 6620-30. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609527PMC
November 2016

Current Immunotherapies for Sarcoma: Clinical Trials and Rationale.

Sarcoma 2016 14;2016:9757219. Epub 2016 Sep 14.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Sarcoma tumors are rare and heterogeneous, yet they possess many characteristics that may facilitate immunotherapeutic responses. Both active strategies including vaccines and passive strategies involving cellular adoptive immunotherapy have been applied clinically. Results of these clinical trials indicate a distinct benefit for select patients. The recent breakthrough of immunologic checkpoint inhibition is being rapidly introduced to a variety of tumor types including sarcoma. It is anticipated that these emerging immunotherapies will exhibit clinical efficacy for a variety of sarcomas. The increasing ability to tailor immunologic therapies to sarcoma patients will undoubtedly generate further enthusiasm and clinical research for this treatment modality.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039267PMC
http://dx.doi.org/10.1155/2016/9757219DOI Listing
September 2016

Technical Considerations for the Generation of Adoptively Transferred T Cells in Cancer Immunotherapy.

Cancers (Basel) 2016 Sep 20;8(9). Epub 2016 Sep 20.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits. Preclinical investigations and human trials have utilized natural killer (NK) cells, dendritic cells (DC), macrophages, T-cells or B-cells for ACT with the most intense research focused on T-cell ACT. T-cells are exquisitely specific to the target of its T-cell receptor (TCR), thus potentially reducing the amount of collateral damage and off-target effects from treatment. T-cells also possess a memory subset that may reduce the risk of recurrence of a cancer after the successful treatment of the primary disease. There are several options for the source of T-cells used in the generation of cells for ACT. Perhaps the most widely known source is T-cells generated from tumor-infiltrating lymphocytes (TILs). However, studies have also employed peripheral blood mononuclear cells (PBMCs), lymph nodes, and even induced pluripotent stem cells (IPSCs) as a source of T-cells. Several important technical considerations exist regarding benefits and limitations of each source of T-cells. Unique aspects of T-cells factor into their ability to be efficacious in ACT including the total number of cells available for ACT, the anti-tumor efficacy on a per cell basis, the repertoire of TCRs specific to tumor cells, and their ability to traffic to various organs that harbor tumor. Current research is attempting to unlock the full potential of these cells to effectively and safely treat cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040988PMC
http://dx.doi.org/10.3390/cancers8090086DOI Listing
September 2016

Key gaps in pathologic reporting for appendiceal mucinous neoplasms: time for universal synoptic reporting?

Ann Diagn Pathol 2016 Oct 17;24:52-4. Epub 2016 Aug 17.

Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.

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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http://dx.doi.org/10.1016/j.anndiagpath.2016.06.004DOI Listing
October 2016

NCCN Guidelines Insights: Melanoma, Version 3.2016.

J Natl Compr Canc Netw 2016 08;14(8):945-58

From Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; UCSF Helen Diller Family Comprehensive Cancer Center; Huntsman Cancer Institute at the University of Utah; University of Michigan Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; UC San Diego Moores Cancer Center; Fred & Pamela Buffett Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The University of Tennessee Health Science Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; University of Colorado Cancer Center; Aim at Melanoma; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Yale Cancer Center/Smilow Cancer Hospital; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The University of Texas MD Anderson Cancer Center; Duke Cancer Institute; Roswell Park Cancer Institute; Stanford Cancer Institute; Massachusetts General Hospital Cancer Center; Moffitt Cancer Center; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; and National Comprehensive Cancer Network.

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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http://dx.doi.org/10.6004/jnccn.2016.0101DOI Listing
August 2016

Unlocking tumor vascular barriers with CXCR3: Implications for cancer immunotherapy.

Oncoimmunology 2016 May 11;5(5):e1116675. Epub 2016 Feb 11.

Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY, USA.

Promising cancer immunotherapeutics depend on mobilization of cytotoxic T cells across tumor vascular barriers through mechanisms that are poorly understood. Recently, we discovered that the CXCR3 chemokine receptor uniquely functions as the master-regulator of cytotoxic CD8(+) T cell extravasation and tumor control despite the multiplicity of chemokines available in the tumor landscape.
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http://dx.doi.org/10.1080/2162402X.2015.1116675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910745PMC
May 2016

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2016 Apr;14(4):450-73

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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http://dx.doi.org/10.6004/jnccn.2016.0051DOI Listing
April 2016

Intraoperative intravital microscopy permits the study of human tumour vessels.

Nat Commun 2016 Feb 17;7:10684. Epub 2016 Feb 17.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

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.
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http://dx.doi.org/10.1038/ncomms10684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757793PMC
February 2016

Homogenous Good Outcome in a Heterogeneous Group of Tumors: An Institutional Series of Outcomes of Superficial Soft Tissue Sarcomas.

Sarcoma 2015 8;2015:325049. Epub 2015 Nov 8.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

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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http://dx.doi.org/10.1155/2015/325049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655067PMC
December 2015

Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer.

PLoS One 2015 23;10(11):e0143370. Epub 2015 Nov 23.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.

Purpose: While surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA) induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre-resectional RFA) in a preclinical mouse model.

Experimental Design: Therapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma.

Results: Treatment with pre-resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen). Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity.

Conclusion: Improved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant treatment for cancer patients with high-risk of local and systemic recurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143370PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657935PMC
June 2016