MIS in pediatric solid tumor

PEDIATRIC MINIMALLY INVASIVE SURGERY IN SOLID TUMORS weeks post-op pull through Tanh Nguyen TV, M.D Department of Gerneral surgery Children’s Hospital Minimally Invasive Surgery Large Operations with Tiny Incisions MIS-Advantages * Cosmesis − open operations often leave large, unsightly incisions − with some laparoscopic instruments smaller than 2mm in size, it is often difficult to see incisions postoperatively * Analgesia • Smaller incisions associated with less pain, lower analgesic use, and quicker recovery − few controlled studies in children, especially in youngest patients * Adhesions • several studies suggest the formation of fewer intra-abdominal adhesions after laparoscopic procedures − reduces the risk of future postoperative bowel obstructions − possibly reduces postoperative pain * Decreased Ileus − Nissen, Appendectomy, Pyloromyotomy, Bowel resection, Spleen − Real or perceived? MIS - SOLID TUMORS ABDOMINAL TUMOR Neuroblastoma and adrenal tumors Renal tumors Germ cell tumors: Ovarian tumors Pancreatic tumors Liver tumors THORACIC TUMOR Thoracic neurogenic tumors Lympho-proliferative diseases Thoracic teratoma Pulmonary metastases MIS approaches for adrenal tumors A 5-year-old boy with neuroblastoma on the level of the diaphragm MIS nephrectomy in a 4year- old boy with a Wilms tumor Single incision surgery in a 12-year-old girl with a mature teratoma of the right ovary Hybrid operation with MI assisted transabdominal resection of a mature teratoma Altman type IV Whipple procedure MIS pancreatic head resection in a 10-year-old girl with a pseudopapillary tumor A 10-year-old boy with a thoracic ganglioneuroma MIS - SOLID TUMORS EVIDENCE-BASE MEDICINE?? MEDICAL EVIDENCES? MEDICAL EVIDENCES? Case series, Retrospective studies, Cohort Studies No RCTs and CCTS MIS and Oncological surgery Reports on minimally invasive surgical procedures in solid tumors are increasingly observable The emphasis of surgery in children with solid tumors lies not on the feasibility but on the strict adherence to oncological principles Specific challenges in MIS of pediatric solid tumors Small working space in large tumors Risk of tumor spillage Tactile restriction Retrieval of large tumors Management of tumors with vascular encasement Learning curve The role of surgery in Solid tumor Biopsy is required: neuroblastoma, soft tissue sarcoma Biopsy is allowed but not mandatory: liver tumors months to years Biopsy must not be performed: nephroblastoma Surgical radicality is of prognostic significance Minimal residual tumor can be accepted without impairment of the survival (Neuroblastoma) CONCLUSIONS MIS is increasingly being used as surgical approach in children with solid tumors and will have a definitive place in the future in this field MIS for tumors in children should be used with a careful patient selection after thorough decision-making processes Future Directions * Limitations of current MIS technology • No wrist • 2-dimensional images • Distance from operative field * Solution -daVinci operative system • Robot arm with degrees of freedom • True 3-dimensional images • Work station allows “total immersion” THANK YOU VERY MUCH Int. J. Med. Sci. 2011, 8 http://www.medsci.org 239 IInntteerrnnaattiioonnaall JJoouurrnnaall ooff MMeeddiiccaall SScciieenncceess 2011; 8(3):239-244 Research Paper Long Term Persistence of IgE Anti-Influenza Virus Antibodies in Pediatric and Adult Serum Post Vaccination with Influenza Virus Vaccine Tamar A. Smith-Norowitz1,5 , Darrin Wong2, Melanie Kusonruksa2, Kevin B. Norowitz1,5, Rauno Joks3,5, Helen G. Durkin2,5, Martin H. Bluth4 1. Departments of Pediatrics, S.U.N.Y. Downstate Medical Center, Brooklyn, New York 11203, USA 2. Departments of Pathology, S.U.N.Y. Downstate Medical Center, Brooklyn, New York 11203, USA 3. Departments of Medicine, S.U.N.Y. Downstate Medical Center, Brooklyn, New York 11203, USA 4. Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA 5. Center for Allergy and Asthma Research, S.U.N.Y. Downstate Medical Center, Brooklyn, New York 11203, USA  Corresponding author: Tamar A. Smith-Norowitz, Ph.D., SUNY Downstate Medical Ctr., Dept of Pediatrics, Box 49, 450 Clarkson Ave., Brooklyn, New York 11203, (718) 270-1295, (718) 270-3289 (fax), tamar.smith-norowitz@downstate.edu © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2010.12.22; Accepted: 2011.02.07; Published: 2011.03.18 Abstract The production of IgE specific to different viruses (HIV-1, Parvovirus B19, Parainfluenza virus, Varicella Zoster Virus), and the ability of IgE anti-HIV-1 to suppress HIV-1 production in vitro, strongly suggest an important role for IgE and/or anti viral specific IgE in viral pathogenesis. Nevertheless, the presence and persistence of IgE anti-Influenza virus antibodies has not been studied. Total serum IgE and specific IgE and IgG anti-Influenza virus antibodies were studied in children (N=3) (m/f 14-16 y/o) and adults (N=3) (m/f, 41-49 y/o) 2-20 months after vac-cination with Influenza virus (Flumist® or Fluzone®), as well as in non-vaccinated children (N=2). (UniCAP total IgE Fluoroenzymeimmunoassay, ELISA, Immunoblot). We found that serum of vaccinated children and adults contained IgE and IgG anti-Influenza virus antibodies approaching two years post vaccination. Non-vaccinated children did not make either IgE or IgG anti-Influenza antibodies. Similar levels of IL-2, IFN-γ, IL-4, and IL-10 cytokines were detected in serum of vaccinated compared with non vaccinated subjects (p>0.05), as well as between vaccinated adults compared with vaccinated children and non vaccinated subjects (p>0.05). Vaccinated children and adults continue to produce IgE anti-Influenza virus anti-bodies long term post vaccination. The long term production of IgE anti-Influenza virus an-tibodies induced by vaccination may contribute to protective immunity against Influenza. Key words: IgE, Influenza virus, Influenza virus vaccine INTRODUCTION Previous studies in our laboratory have investi-gated the role of IgE and the immune response to specific viruses including: Parvovirus B19 in children [1], HIV-1 in HIV-1 BioMed Central Page 1 of 13 (page number not for citation purposes) Journal of Translational Medicine Open Access Research Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors Hemant Sarin* 1,2 , Ariel S Kanevsky 2 , Haitao Wu 3 , Alioscka A Sousa 1 , Colin M Wilson 3 , Maria A Aronova 1 , Gary L Griffiths 3 , Richard D Leapman 1 and Howard Q Vo 1,2 Address: 1 National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA, 2 Radiology and Imaging Sciences Program, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA and 3 Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA Email: Hemant Sarin* - sarinh@mail.nih.gov; Ariel S Kanevsky - kanevskya@mail.nih.gov; Haitao Wu - wuh3@mail.nih.gov; Alioscka A Sousa - sousaali@mail.nih.gov; Colin M Wilson - wilsoncm@mail.nih.gov; Maria A Aronova - aronovaa@mail.nih.gov; Gary L Griffiths - griffithsgl@mail.nih.gov; Richard D Leapman - leapmanr@mail.nih.gov; Howard Q Vo - voho@mail.nih.gov * Corresponding author Abstract Background: The existence of large pores in the blood-tumor barrier (BTB) of malignant solid tumor microvasculature makes the blood-tumor barrier more permeable to macromolecules than the endothelial barrier of most normal tissue microvasculature. The BTB of malignant solid tumors growing outside the brain, in peripheral tissues, is more permeable than that of similar tumors growing inside the brain. This has been previously attributed to the larger anatomic sizes of the pores within the BTB of peripheral tumors. Since in the physiological state in vivo a fibrous glycocalyx layer coats the pores of the BTB, it is possible that the effective physiologic pore size in the BTB of brain tumors and peripheral tumors is similar. If this were the case, then the higher permeability of the BTB of peripheral tumor would be attributable to the presence of a greater number of pores in the BTB of peripheral tumors. In this study, we probed in vivo the upper limit of pore size in the BTB of rodent malignant gliomas grown inside the brain, the orthotopic site, as well as outside the brain in temporalis skeletal muscle, the ectopic site. Methods: Generation 5 (G5) through generation 8 (G8) polyamidoamine dendrimers were labeled with gadolinium (Gd)-diethyltriaminepentaacetic acid, an anionic MRI contrast agent. The respective Gd-dendrimer generations were visualized in vitro by scanning transmission electron microscopy. Following intravenous infusion of the respective Gd-dendrimer generations (Gd-G5, N = 6; Gd-G6, N = 6; Gd-G7, N = 5; Gd-G8, N = 5) the blood and tumor tissue pharmacokinetics of the Gd-dendrimer generations were visualized in vivo over 600 to 700 minutes by dynamic contrast-enhanced MRI. One additional animal was imaged in each Gd-dendrimer generation group for 175 minutes under continuous anesthesia for the creation of voxel-by-voxel Gd concentration maps. Results: The estimated diameters of Gd-G7 dendrimers were 11 ± 1 nm and those of Gd-G8 dendrimers were 13 ± 1 nm. The BTB of ectopic RG-2 gliomas was more permeable than the BTB RESEARCH Open Access Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors BingHe Xu 1† , YiLong Wu 2† , Lin Shen 3 , DingWei Ye 4 , Annette Jappe 5 , Azzeddine Cherfi 5 , Hui Wang 6 , RuiRong Yuan 7* Abstract Background: This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safe ty, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors. Methods: A total of 24 patients with advance d breast cancer (n = 6), gastric cancer (n = 6), non-small cell lung cancer (n = 6), or renal cell carcinoma (n = 6) who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued. Results: Everolimus was absorbed rapidly; median T max was 3 h (range, 1-4) and 2 h (range, 0.9-6) in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7%) and fatigue (16.7% and 33.3%) in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83%) and 6 (50%) patients in the 5 and 10 mg/day groups, respectively. Conclusions: Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consist ent with previous studies. Trial registration: Chinese Health Authorities 2008L09346 Background The mammalian target of rapamycin (mTOR), a highly conserved serine-threonine kinase, is a central regulator of critical cell processes via the PI3K-AKT pathway. mTOR signaling is mediated through phosphorylation of downstream substrates p70 ribosomal S6 kinase 1 and eukaryotic initiation factor 4E binding protein 1 result- ing in increased translation of proteins promoting cell proliferation and cellular metabolism [1,2]. mTOR also promotes angiogenesis via enhanced hypoxia-inducible factor-1 and growth factor protein tra nslation and increased endothelial and smooth muscle cell prolifera- tion [3,4]. The PI3K/AKT/mTOR-signalling pathway has been shown t o be d ysregulated in a variety of human malig nancies [5-8], making mTOR inhibiti on a rationale in anticancer therapy. Everolimus, an orally available mTOR inhibitor, binds to immunophilin FK506-binding protein 12 to inhibit mTOR activity [4,9]. Everolimus is approved currently in the United States, Europe, and Japan for the treat- ment of patients with metastatic renal cell carcinoma (RCC) whose disease has progressed on sunitinib or sor- afenib [10]. The pivotal phase II I study of everolimus * Correspondence: yuanru@umdnj.edu † Contributed equally 7 Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA; New Jersey Medical School (UMDNJ), Newark, NJ, USA Full list of author information is available at the end of the article Xu et al. Journal of Hematology & Oncology 2011, 4:3 http://www.jhoonline.org/content/4/1/3 JOURNAL OF HEMATOLOGY & ONCOLOGY © 2011 Xu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 mg daily demonstrated significantly prolonged pro- gression-free survival compared BioMed Central Page 1 of 20 (page number not for citation purposes) Theoretical Biology and Medical Modelling Open Access Research A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors Steffen Eikenberry Address: Department of Mathematics and Statistics, Arizona State University, Tempe, AZ 85287, USA Email: Steffen Eikenberry - seikenbe@asu.edu Abstract Background: Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments. Methods: A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration. Results: The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy. Conclusion: Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors. Published: 9 August 2009 Theoretical Biology and Medical Modelling 2009, 6:16 doi:10.1186/1742-4682-6-16 Received: 22 January 2009 Accepted: 9 August 2009 This article is available from: http://www.tbiomed.com/content/6/1/16 © 2009 Eikenberry; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Theoretical Biology and Medical Modelling 2009, 6:16 http://www.tbiomed.com/content/6/1/16 Page 2 of 20 (page number not for citation purposes) Background Doxorubicin (adriamycin) is a first line anti-neoplastic agent used against a number of solid tumors, leukemias, and lymphomas [1]. There are many proposed mecha- nisms by which doxorubicin (DOX) may induce cellular death, including DNA synthesis inhibition, DNA alkyla- tion, and free radical generation. It is known to bind to nuclear DNA and inhibit topoisomerase II, and this may be the principle mechanism [2]. Cancer cell mortality has been correlated with both dose and exposure time, and El- Kareh and Secomb have argued that it is ... principles Specific challenges in MIS of pediatric solid tumors Small working space in large tumors Risk of tumor spillage Tactile restriction Retrieval of large tumors Management of tumors... Oncological surgery Reports on minimally invasive surgical procedures in solid tumors are increasingly observable The emphasis of surgery in children with solid tumors lies not on the feasibility... significance Minimal residual tumor can be accepted without impairment of the survival (Neuroblastoma) CONCLUSIONS MIS is increasingly being used as surgical approach in children with solid tumors