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Yuhree Kim;
Georgios A. Margonis;
Jason D. Prescott;
Thuy B. Tran;
Lauren M. Postlewait;
Shishir Maithel;
Tracy S. Wang;
Jason A. Glenn;
Ioannis Hatzaras;
Rivfka Shenoy;
John E. Phay;
Kara Keplinger;
Ryan C. Fields;
Linda X. Jin;
Sharon M. Weber;
Ahmed Salem;
Jason K. Sicklick;
Shady Gad;
Adam C. Yopp;
John C. Mansour;
Quan-Yang Duh;
Natalie Seiser;
Carmen C. Solorzano;
Colleen M. Kiernan;
Konstantinos I. Votanopoulos;
Edward A. Levine;
George A. Poultsides;
Timothy M. Pawlik
OBJECTIVE:: To evaluate conditional disease-free survival (CDFS) for patients who underwent curative intent surgery for adrenocortical carcinoma (ACC). BACKGROUND:: ACC is a rare but aggressive tumor. Survival estimates are usually reported as survival from the time of surgery. CDFS estimates may be more clinically relevant by accounting for the changing likelihood of disease-free survival (DFS) according to time elapsed after surgery. METHODS:: CDFS was assessed using a multi-institutional cohort of patients. Cox proportional hazards models were used to evaluate factors associated with DFS. Three-year CDFS (CDFS3) estimates at “x” year after surgery were calculated as follows: CDFS3?=?DFS(x+3)/DFS(x). RESULTS:: One hundred ninety-two patients were included in the study cohort; median patient age was 52 years. On presentation, 36% of patients had a functional tumor and median size was 11.5?cm. Most patients underwent R0 resection (75%) and 9% had N1 disease. Overall 1-, 3-, and 5-year DFS was 59%, 34%, and 22%, respectively. Using CDFS estimates, the probability of remaining disease free for an additional 3 years given that the patient had survived without disease at 1, 3, and 5 years, was 43%, 53%, and 70%, respectively. Patients with less favorable prognosis at baseline demonstrated the greatest increase in CDFS3 over time (eg, capsular invasion: 28%–88%, Δ60% vs no capsular invasion: 51%–87%, Δ36%). CONCLUSIONS:: DFS estimates for patients with ACC improved dramatically over time, in particular among patients with initial worse prognoses. CDFS estimates may provide more clinically relevant information about the changing likelihood of DFS over time.
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Young-Seok Cho;
Gee Young Lee;
Hari Krishna Sajja;
Weiping Qian;
Zehong Cao;
Weiling He;
Prasanthi Karna;
Xiaoyuan Chen;
Hui Mao;
Andrew Wang;
Lily Yang
Molecular therapy using a small interfering RNA (siRNA) has shown promise in the development of novel therapeutics. Various formulations have been used for in vivo delivery of siRNAs. However, the stability of short double-stranded RNA molecules in the blood and efficiency of siRNA delivery into target organs or tissues following systemic administration have been the major issues that limit applications of siRNA in human patients. In this study, multifunctional siRNA delivery nanoparticles are developed that combine imaging capability of nanoparticles with urokinase plasminogen activator receptor-targeted delivery of siRNA expressing DNA nanocassettes. This theranostic nanoparticle platform consists of a nanoparticle conjugated with targeting ligands and double-stranded DNA nanocassettes containing a U6 promoter and a shRNA gene for in vivo siRNA expression. Targeted delivery and gene silencing efficiency of firefly luciferase siRNA nanogenerators are demonstrated in tumor cells and in animal tumor models. Delivery of survivin siRNA expressing nanocassettes into tumor cells induces apoptotic cell death and sensitizes cells to chemotherapy drugs. The ability of expression of siRNAs from multiple nanocassettes conjugated to a single nanoparticle following receptor-mediated internalization should enhance the therapeutic effect of the siRNA-mediated cancer therapy.
by
Ali H. Charafeddine;
Eugenia J. Kim;
Dawn M. Maynard;
Hong Yi;
Timothy A. Weaver;
Meral Gunay-Aygun;
Maria C. Russell;
William A. Gahl;
Allan D Kirk
CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation.
Background: Gastrointestinal dysfunction is very common in diabetic patients. We assessed the changes in the colonic enteric nervous system using colectomy specimens and intestinal biopsies from diabetic subjects and age-matched controls.
Methods: In control and diabetic colons, we determined the total ganglion area (hematoxylin-eosin staining), changes in neuronal markers-PGP 9.5, peripherin, nNOS, NPY, ChAT and VIP (by immunostaining), apoptosis (cleaved caspase-3 staining) and reduced glutathione levels (HPLC). Superoxide dismutase (SOD) mRNA was determined in enteric ganglia isolated by laser capture micro dissection. Isometric muscle recording was used to assess contraction and relaxation responses of colonic circular muscle strips. Apoptosis in enteric neurons under hyperglycemia in vitro was determined by cleaved caspase-3 Western blotting and protective effects of lipoic acid were evaluated.
Key Results: Diabetic subjects had higher incidence of lower gastrointestinal symptoms like constipation and diarrhea at baseline prior to surgery. Diabetic ganglia displayed significant decrease in ganglion size due to enhanced apoptosis and loss of peripherin, nNOS, NPY and ChAT neurons. Reduced glutathione levels in the diabetic colon (HbA1C>7%) were significantly less than the control, indicating increased oxidative stress. Colonic circular muscle strips from diabetic subjects showed impaired contraction and relaxation responses compared to the healthy controls. Hyperglycemia-induced cleaved caspase-3 in enteric neurons was reversed by lipoic acid.
Conclusions: Our data demonstrate loss of enteric neurons in the colon due to increased oxidative stress and apoptosis which may cause the motility disturbances seen in human diabetes. Antioxidants may be of therapeutic value for preventing motility disorders in diabetes.
Molecular therapy using small interfering RNA (siRNA) shows great promise in the development of novel therapeutics for cancer. Although various approaches have been developed for in vivo delivery of siRNAs into tumors, stability of siRNA in blood circulation, and low efficiency of siRNA delivery into tumor cells are the major obstacles for further translation into cancer therapeutics. In this protocol, we describe methods of the production of shRNA expressing DNA nanocassettes by PCR amplification of double-stranded DNA fragments containing a U6 promoter and a shRNA gene. Those DNA nanocassettes can be conjugated to the polymer coating of nanoparticles that are targeted to cellular receptors highly expressed in tumor cells, such as urokinase plasminogen activator receptor (uPAR), for targeted delivery and receptor mediated internalization of shRNA expressing DNA nanocassettes. Methods for in vitro and in vivo evaluation of target specificity and gene-knockdown effect are also provided.
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Hannah M Knochelmann;
Connor J Dwyer;
Aubrey S Smith;
Jacob S Bowers;
Megan M Wyatt;
Michelle H Nelson;
Guillermo Rangel O Rivera;
Joshua D Horton;
Carsten Krieg;
Kent Armeson;
Gregory Lesinski;
Mark P Rubinstein;
Z Li;
Chrystal Paulos
The accessibility of adoptive T-cell transfer therapies (ACT) is hindered by the cost and time required for product development. Here we describe a streamlined ACT protocol using Th17 cells expanded only 4 days ex vivo. While shortening expansion compromised cell yield, this method licensed Th17 cells to eradicate large tumors to a greater extent than cells expanded longer term. Day 4 Th17 cells engrafted, induced release of multiple cytokines including IL6, IL17, MCP-1, and GM-CSF in the tumor-bearing host, and persisted as memory cells. IL6 was a critical component for efficacy of these therapies via its promotion of long-term immunity and resistance to tumor relapse. Mechanistically, IL6 diminished engraftment of FoxP3þ donor T cells, corresponding with robust tumor infiltration by donor effector over regulatory cells for the Day 4 Th17 cell product relative to cell products expanded longer durations ex vivo. Collectively, this work describes a method to rapidly generate therapeutic T-cell products for ACT and implicates IL6 in promoting durable immunity of Th17 cells against large, established solid tumors.
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Jeong-Ik Park;
Ki-Hun Kim;
Hong-Jin Kim;
Daniel Cherqui;
Olivier Soubrane;
David A Kooby;
Chinnusamy Palanivelu;
Albert Chan;
Young Kyoung You;
Yao-Ming Wu;
Kuo-Hsin Chen;
Goro Honda;
Xiao-Ping Chen;
Chung-Ngai Tang;
Ji Hoon Kim;
Yang Seok Koh;
Young-In Yoon;
Kai Chi Cheng;
Tran Cong Duy Long;
Gi Hong Choi;
Yuichiro Otsuka;
Tan To Cheung;
Taizo Hibi;
Dong-Sik Kim;
Hee Jung Wang;
Hironori Kaneko;
Dong-Sup Yoon;
Etsuro Hatano;
In Seok Choi;
Dong Wook Choi;
Ming-Te Huang;
Sang Geol Kim;
Sung-Gyu Lee
The application of laparoscopy for liver surgery is rapidly increasing and the past few years have demonstrated a shift in paradigm with a trend towards more extended and complex resections. The development of instruments and technical refinements with the effective use of magnified caudal laparoscopic views have contributed to the ability to overcome the limitation of laparoscopic liver resection. The Endoscopic and Laparoscopic Surgeons of Asia (ELSA) Visionary Summit 2017 and the 3rd Expert Forum of Asia-Pacific Laparoscopic Hepatectomy organized hepatobiliary pancreatic sessions in order to exchange surgical tips and tricks and discuss the current status and future perspectives of laparoscopic hepatectomy. This report summarizes the oral presentations given at the 3rd Expert Forum of Asia-Pacific Laparoscopic Hepatectomy.
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Robert HI Andtbacka;
Frances A. Collichio;
Thomas Amatruda;
Neil Senzer;
Jason Chesney;
Keith Delman;
Lynn Spitler;
Igor Puzanov;
Sanjiv Agarwala;
Mohammed Milhem;
Kevin Harrington;
Mark Middleton;
Ai Li;
Mark Shilkrut;
Robert Coffin;
Howard Kaufman
T-VEC is an oncolytic immunotherapy derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM, a randomized Phase III trial of T-VEC vs GM-CSF in patients with unresected melanoma with regional or distant metastases met the primary objective of an improvement in durable response rate (response lasting continuously for ≥6 months) with T-VEC versus GM-CSF (16% vs 2%, respectively; P<0.001). Most common adverse events with T-VEC were fatigue, chills, and pyrexia. No ≥grade 3 adverse events occurred in ≥3% of patients in either arm (Andtbacka et al., J Clin Oncol 2013,32[suppl]:LBA9008). At the primary analysis (PA) of secondary OS endpoint, with median follow-up of 44 (range, 32-59) months and 189 events in the T-VEC arm and 101 events in the GM-CSF arm, median (95%CI) OS was 23.3 (19.5-29.6) months for T-VEC and 18.9 (16.0-23.7) months for GM-CSF (hazard ratio [HR]=0.79; 95%CI = 0.62-1.00; P = 0.051) (Kaufman et al., J Clin Oncol 2014,32[suppl]:9008a). A planned analysis of OS at 3 years from the last randomization is presented here.
Gastric adenocarcinoma (GAC) is one of the most commonly diagnosed cancers worldwide. Two standard approaches for treatment of resectable GAC include adjuvant 5-fluorouracil-based chemoradiotherapy [per Intergroup 0116 (INT-0116) trial and perioperative epirubicin, cisplatin, fluorouracil (ECF) chemotherapy per Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial]. Controversy remains regarding the most appropriate treatment strategy to decrease recurrence rates and improve survival following surgery. The purpose of this study was to analyze how patterns of care for patients with GAC treated at Emory University Hospital changed following publication of the MAGIC trial in 2006.