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Quantitative Multiplex Immunofluorescence evaluation of the tumor microenvironment in pretreatment tumors of patients with metastatic breast cancer and serous ovarian carcinoma treated with liposomal eribulin

Marks, Douglas K; Kucharczyk, John; Kim, Pan; Chyong, Donian I; Gartrell, Robyn D; Lu, Yan; Hibshoosh, Hanina; Guo, Hua; Evans, Thomas R Jeffry; Lopez, Juanita; Kristeleit, Rebecca; Connolly, Eileen; Saenger, Yvonne; Kalinsky, Kevin
Eribulin inhibits microtubule polymerization and suppresses epithelial-mesenchymal transition. Conventional pathology approaches have not identified a precise predictive biomarker for Eribulin. We performed qmIF on pre-treatment tissue from 11 patients (6 TNBC, 5 HGSOC) treated with Eribulin-LF. T-lymphocytes were the dominant immune-subset in TME, with higher levels detected in stroma vs tumor (9% vs 2%). Greater density of CD3+ (p = 0.01) and CD3 + CD8+ (p = 0.03) cells and closer proximity between CD3 + CD8+ and tumor cells was observed in the patients with disease control (PR + SD) vs. progressive disease. QmIF identified an association between TIL infiltration and eribulin-LF sensitivity, which should evaluated further in prospective studies.
PMID: 34075851
ISSN: 1532-4192
CID: 4907312

TREATMENT OF ACUTE SUBMASSIVE PULMONARY EMBOLISM COMPLICATED BY A RIGHT HEART THROMBUS IN TRANSIT WITH TISSUE PLASMINOGEN ACTIVATOR [Meeting Abstract]

Kucharczyk, John; Ciancarelli, James; Spiegler, Peter
ISI:000500199202160
ISSN: 0012-3692
CID: 4601262

Targeting Toll-Like Receptors for Cancer Therapy

Braunstein, Marc J; Kucharczyk, John; Adams, Sylvia
The immune system encompasses a broad array of defense mechanisms against foreign threats, including invading pathogens and transformed neoplastic cells. Toll-like receptors (TLRs) are critically involved in innate immunity, serving as pattern recognition receptors whose stimulation leads to additional innate and adaptive immune responses. Malignant cells exploit the natural immunomodulatory functions of TLRs, expressed mainly by infiltrating immune cells but also aberrantly by tumor cells, to foster their survival, invasion, and evasion of anti-tumor immune responses. An extensive body of research has demonstrated context-specific roles for TLR activation in different malignancies, promoting disease progression in certain instances while limiting cancer growth in others. Despite these conflicting roles, TLR agonists have established therapeutic benefits as anti-cancer agents that activate immune cells in the tumor microenvironment and facilitate the expression of cytokines that allow for infiltration of anti-tumor lymphocytes and the suppression of oncogenic signaling pathways. This review focuses on the clinical application of TLR agonists for cancer treatment. We also highlight agents that are undergoing development in clinical trials, including investigations of TLR agonists in combination with other immunotherapies.
PMID: 30229471
ISSN: 1776-260x
CID: 3301732

Outcomes of Patients With Late-Relapse Metastatic Renal Cell Carcinoma Treated With Targeted Therapies: A Single Institution Experience

Kucharczyk, John; Mandalapu, Kamal; Satti, Suma; Matrana, Marc R
Background/UNASSIGNED:Late relapse with presentation of metastatic disease >5 years after nephrectomy with curative intent is a known behavior of renal cell carcinoma (RCC), but data on outcomes, especially regarding targeted therapies, are limited. In this study, we analyze clinicopathologic features and response to targeted therapy in patients with late-relapse metastatic RCC (mRCC). Methods/UNASSIGNED:We retrospectively reviewed clinical data on consecutive patients treated with targeted therapy for mRCC diagnosed >5 years after nephrectomy with curative intent. Results/UNASSIGNED:A total of 24 patients (100% clear cell histology, median age 72 years, 83% males, all with prior nephrectomies) met inclusion criteria; 71% had favorable risk, and 25% had intermediate risk by International Metastatic Renal Cell Carcinoma Database Consortium criteria. The estimated median overall survival for all patients was 60.5 months, and the 3-year overall survival rate was 71.78% (95% confidence interval, 47.98%-84.77%). All patients were treated with targeted therapy; first-line treatments included pazopanib (46%), sorafenib (25%), sunitinib (17%), and cytokine (13%), with no significant difference in time to treatment failure between therapies. Median time on first-line therapy was 19.7 months; 67% of patients received second-line treatment. Metastases were detected at considerable rates in sites considered historically uncommon, such as the pancreas, adrenal glands, and soft tissue. Conclusion/UNASSIGNED:Patients with late-relapse mRCC treated with targeted therapy had prolonged survival that compared favorably to historical controls, and metastases in uncommon sites were noted.
PMCID:5718445
PMID: 29230117
ISSN: 1524-5012
CID: 4604692

Emerging Immunotargets in Metastatic Renal Cell Carcinoma

Kucharczyk, John; Matrana, Marc R; Santoni, Matteo; Massari, Francesco; Scarpelli, Marina; Cheng, Liang; Lopez-Beltran, Antonio; Cascinu, Stefano; Montironi, Rodolfo; Holger, Moch
Renal cell carcinoma (RCC) is one of the most immunoresponsive human cancers. High-dose IL-2 and Interferon-α were once the principle therapies for metastatic RCC, however they had harsh-tolerance profiles and limited response rates. In the last decade, targeted therapies have supplanted cytokine therapy due to higher response rates and more favorable toxicity profiles. Emerging immunotherapies targeting the PD-1 receptor and PD-L1 ligand have shown promising results. Likewise, other novel targeted immunotherapies are currently under evaluation. The safety profiles and response rates of new generation immunotherapies are encouraging and justify the progression of clinical trials. However, longer follow-up data are needed to confirm these promising results. In addition, it is still unclear if an optimal sequence or combinations of new immunotherapies paired with current targeted therapies will emerge.
PMID: 26648075
ISSN: 1873-5592
CID: 4604682

Early experience and operative technique of robotic-assisted partial nephrectomy

Kucharczyk, John R; Basto, Marnique; Landau, Adam; Graves, Reid; Everaerts, Wouter; Birch, Emma; Murphy, Declan; Moon, Daniel
BACKGROUND:The adoption of robotic-assisted partial nephrectomy (RAPN) is increasing in Australia; however, to date no Australian RAPN series has been reported. This paper describes a single-surgeon initial experience with RAPN and evaluates perioperative, pathological and oncological outcomes. METHODS:Data on the first 50 consecutive patients to undergo RAPN by a single surgeon were reviewed. Demographic, perioperative, tumour characteristics and Clavien complications were collected in addition to oncological follow-up and renal function monitoring. RESULTS:Mean age was 58.2 ± 10.4 years, body mass index was 28.8 ± 4.5 kg/m(2) and Charlson Co-morbidity Index was 4.6 ± 1.2. Tumour diameter was 31 ± 13 mm and RENAL score was 6.8 ± 1.5. Average total operative time was 151 ± 32.7 min, estimated blood loss was 171.1 ± 185.8 mL, warm ischaemia time was 17.8 ± 6.7 min and length of hospital stay was 3 ± 0.9 days. There were seven Clavien complications and no deaths. Estimated glomerular filtration rate did not decrease significantly post-operatively (P = 0.8); and there was 14.6% upstaging of chronic kidney disease scoring although no patient required dialysis. There were no positive malignant surgical margins, and to date no patient has evidence of disease recurrence. Of 50 patients, 54% had a minimum follow-up of 6 months and 28% had a minimum follow-up of 1 year. CONCLUSION/CONCLUSIONS:We report the largest RAPN study in Australia or New Zealand to date. Initial results suggest that RAPN can be safely introduced into the Australian public and private health systems, and has been effective in oncologic control and renal function preservation.
PMID: 24820851
ISSN: 1445-2197
CID: 4604672

Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass

Saeidi, Nima; Meoli, Luca; Nestoridi, Eirini; Gupta, Nitin K; Kvas, Stephanie; Kucharczyk, John; Bonab, Ali A; Fischman, Alan J; Yarmush, Martin L; Stylopoulos, Nicholas
The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography-computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-D-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB.
PMID: 23888041
ISSN: 1095-9203
CID: 4604662

Probing the mechanisms of the metabolic effects of weight loss surgery in humans using a novel mouse model system

Kucharczyk, John; Nestoridi, Eirini; Kvas, Stephanie; Andrews, Robert; Stylopoulos, Nicholas
BACKGROUND:Gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective treatment for severe obesity. RYGB is associated with a remarkable decrease in the rate of death from obesity-related complications, such as diabetes mellitus, coronary artery disease, and cancer. Dissecting the mechanisms of RYGB effects could augment our understanding about the pathogenesis of obesity and its complications. OBJECTIVES AND METHODS/OBJECTIVE:In this study, we describe in detail a mouse model of RYGB that closely reproduces the surgical steps of the human procedure. RESULTS:We show that RYGB in mice has the same effects as in human patients, proving the high translational validity of this model system. We present an intraoperative video to facilitate the widespread use of this complex and difficult method. CONCLUSIONS:The study of the mechanisms of RYGB using this model system can greatly facilitate our understanding about the effects of RYGB in human patients. The reverse engineering of the physiological mechanisms of RYGB could lead to discovery of new, effective, and less invasive treatments.
PMID: 22504136
ISSN: 1095-8673
CID: 4604652

Resting energy expenditure and energetic cost of feeding are augmented after Roux-en-Y gastric bypass in obese mice

Nestoridi, Eirini; Kvas, Stephanie; Kucharczyk, John; Stylopoulos, Nicholas
Although the prevalence of obesity has increased dramatically throughout the world during the last 25 yr, its long-term control remains poor. Currently, only gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is associated with substantial and sustained weight loss and resolution or significant improvement of diabetes mellitus and other metabolic obesity-induced complications. Clinical observations and recent studies have suggested that RYGB induces its effects by changing the physiology of weight regulation. Understanding the underlying mechanisms of these profound and sustainable effects could facilitate the development of novel and less invasive treatments against obesity and its complications. To study the physiological mechanisms of RYGB, we have developed a mouse RYGB model that replicates the human operation. The aims of this study were to develop a roadmap for assessing energy expenditure (EE) in animal models of weight loss surgery and to examine the effects of RYGB on EE. We first measured EE by indirect calorimetry in groups of animals that underwent RYGB or a sham operation. Calorimetry data were analyzed using three different methods: normalization by total body mass, allometric scaling, and analysis of covariance modeling. RYGB in mice induced a significant increase in EE that was independent of the method used. An energy balance analysis was then performed, which also confirmed that RYGB-treated animals have higher energy maintenance needs. Finally, we determined the EE components that account for the observed increase in EE, and we found that resting EE and postprandial thermogenesis are the major contributors to this increase.
PMID: 22416083
ISSN: 1945-7170
CID: 4604642

Laparoscopic bowel injury in retroperitoneal surgery: current incidence and outcomes

Schwartz, Michael J; Faiena, Izak; Cinman, Nadya; Kucharczyk, John; Meriggi, Jenna S; Waingankar, Nikhil; Richstone, Lee; Kavoussi, Louis R
PURPOSE: Laparoscopic bowel injury is associated with significant morbidity and mortality when unrecognized. We assessed the incidence and outcomes of bowel injury in a contemporary cohort of patients, and reviewed the literature to examine the impact of experience with time on the incidence and consequences of bowel injury. MATERIALS AND METHODS: Between 2006 and 2009 we performed 1,073 laparoscopic surgeries on the upper urinary tract, adrenal gland and retroperitoneal lymph nodes. Patients incurring bowel injury were identified retrospectively. We reviewed complications and management. In a separate literature survey we identified 21 studies on laparoscopic bowel injury from 1993 to 2009. We analyzed etiology, incidence and management. RESULTS: Bowel injury occurred in 8 cases (0.75%), including 6 and 2 identified intraoperatively and postoperatively, respectively. Mechanisms included Veress needle and trocar placement, dissection and thermal injury. Intraoperative management included oversewing the injury, bowel resection and observation. No patient with intraoperatively recognized bowel injury sustained a postoperative adverse event. Patients with unrecognized injury presented in delayed fashion and required multiple procedures to manage the injury. No deaths occurred in this series. Urology series of bowel injury showed a combined 0.65% incidence in 14,447 laparoscopic procedures with 46.7% of injuries unrecognized at surgery. While the incidence of bowel injury has increased with time, the percent of unrecognized bowel injury has dramatically decreased from the early (70.4%) to the more recent (36.9%) laparoscopic era. CONCLUSIONS: The incidence of laparoscopic bowel injury has increased in the last 17 years. However, morbidity and mortality have decreased due to immediate recognition and repair.
PMID: 20639022
ISSN: 0022-5347
CID: 492202