Stephen R. Grobmyer

Emerging implications of nanotechnology on cancer diagnostics and therapeutics

Nanotechnology is multidisciplinary field that involves the design and engineering of objects <500 nanometers (nm) in size. The National Cancer Institute has recognized that nanotechnology offers an extraordinary, paradigm‐changing opportunity to make significant advances in cancer diagnosis and treatment. In the last several decades, nanotechnology has been studied and developed primarily for use in novel drug‐delivery systems (e.g. liposomes, gelatin nanoparticles, micelles). A recent explosion in engineering and technology has led to 1) the development of many new nanoscale platforms, including quantum dots, nanoshells, gold nanoparticles, paramagnetic nanoparticles, and carbon nanotubes, and 2) improvements in traditional, lipid‐based nanoscale platforms. The emerging implications of these platforms for advances in cancer diagnostics and therapeutics form the basis of this review. A widespread understanding of these new technologies is important, because they currently are being integrated into the clinical practice of oncology. Cancer 2006.

Surgical treatment and outcomes of patients with primary inferior vena cava leiomyosarcoma.

BACKGROUND The inferior vena cava (IVC) is a rare site for primary soft tissue sarcoma. There are limited data in the literature regarding surgical management of the IVC and longterm survival of these patients. STUDY DESIGN From 1982 to 2002, a total of 25 patients with primary IVC leiomyosarcoma was treated as inpatients and followed in a prospective database at Memorial Sloan-Kettering. Presenting symptoms, tumor characteristics, operative management, postoperative morbidity, and disease-specific survival were assessed for each patient. RESULTS The 25 patients with primary IVC leiomyosarcoma accounted for 0.5% of all adult patients with soft tissue sarcoma treated during this time. The median patient age was 56 years (range 41 to 79 years). The three most common presenting symptoms were abdominal pain (52%), distention (20%), and deep venous thrombosis (12%). Of the patients, 21 (84%) underwent complete resection of the tumor. The IVC was managed in one of three ways: ligation (n = 11), primary/patch repair (n = 8), and expanded polytetrafluoroethylene tube grafting (n = 2). Among patients undergoing IVC ligation and primary/patch repair (n = 19), 11% had severe postoperative edema and none had worsening renal function. Local recurrence occurred in 33% of patients and distant recurrence occurred in 48% of patients. Patients undergoing complete resection had 3-year and 5-year disease-specific survival rates of 76% and 33%, respectively. There were no 3-year survivors among patients with incomplete resections. CONCLUSIONS Complete resection of primary IVC leiomyosarcomas is feasible and associated with improved survival. The IVC can be managed by primary repair or ligation with a low risk of severe postoperative edema.

Gold nanoparticles as a contrast agent for in vivo tumor imaging with photoacoustic tomography

Photoacoustic tomography (PAT) is a rapidly emerging non-invasive imaging technology that integrates the merits of high optical contrast with high ultrasound resolution. The ability to quantitatively and non-invasively image nanoparticles has important implications for the development of nanoparticles as in vivo cancer diagnostic and therapeutic agents. In this study, the ability of systemically administered poly(ethylene glycol)-coated (PEGylated) gold nanoparticles as a contrast agent for in vivo tumor imaging with PAT has been evaluated. We demonstrate that gold nanoparticles (20 and 50 nm) have high photoacoustic contrast as compared to mouse tissue ex vivo. Gold nanoparticles can be visualized in mice in vivo following subcutaneous administration using PAT. Following intravenous administration of PEGylated gold nanoparticles to tumor-bearing mice, accumulation of gold nanoparticles in tumors can be effectively imaged with PAT. With gold nanoparticles as a contrast agent, PAT has important potential applications in the image guided therapy of superficial tumors such as breast cancer, melanoma and Merkel cell carcinoma.

Chemotherapy Is Associated With Improved Survival in Adult Patients With Primary Extremity Synovial Sarcoma

Purpose:To determine if ifosfamide-based chemotherapy (IF) offers a survival benefit to adult patients with primary extremity synovial sarcoma. Patients and Methods:Prospectively collected patient data from 2 institutions was used to identify all adult patients (≥16 years) with ≥5 cm, deep, primary, extremity, synovial sarcoma that underwent surgical treatment of cure from 1990 to 2002. A total of 101 patients were identified and the median follow-up for survivors was 58 months. Clinical, pathologic, and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS), and local recurrence-free survival (LRFS). Results:Sixty-eight (67%) patients were treated with IF and 33 (33%) patients received no chemotherapy (NoC) for the primary tumor. The characteristics of the IF-treated patients [median tumor size = 7.2 cm; monophasic n = 46 (68%)] were similar to NoC patients [median tumor size = 7 cm; monophasic n = 23 (70%)]. The 4-year DSS of the IF-treated patients was 88% compared with 67% for the NoC patients (P = 0.01). Smaller size (HR = 0.3 per 5-cm decrease, P < 0.0001) and treatment with IF (HR = 0.3 compared with NoC, P = 0.007) were independently associated with an improved DSS. Treatment with IF was independently associated with an improved DRFS (HR = 0.4, P = 0.03) but not associated with an improved LRFS (P = 0.39). Conclusion:Ifosfamide-based chemotherapy was associated with an improved DSS in adult patients with high-risk, primary, extremity, synovial sarcoma and should be considered in the treatment of such patients.

Malignant peripheral nerve sheath tumor: Molecular pathogenesis and current management considerations

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare tumors that often occur in patients with neurofibromatosis 1. Surgical resection represents the mainstay of treatment. Radiation and chemotherapy have a role in selected patients with MPNST. Accurate pathologic diagnosis remains a challenge in many cases of MPNST. There are many recent advances in the understanding of the molecular pathogenesis of MPNST which represent the best opportunities to develop new strategies for management of patients with MPNST. J. Surg. Oncol. 2008;97:340–349.

Pancreatic anastomotic failure after pancreaticoduodenectomy

BACKGROUND Pancreatic anastomotic failure has historically been regarded as one of the most feared complications after pancreaticoduodenectomy. METHODS We reviewed our recent experience (59 cases), March 1994 to December 1998, with pancreaticoduodenectomy and compared preoperative and intraoperative characteristics as well as outcomes in those patients who experienced (n = 10) versus those who did not experience a postoperative pancreatic leak (n = 49). Information was retrospectively collected from hospital records, office records, and interviews with patients. RESULTS The clinical leak rate in this series was 8.5%. There were no significant differences in preoperative or intraoperative characteristics comparing those with versus those without a postoperative pancreatic leak. Only 1 of 10 patients with a postoperative pancreatic leak required reoperation to manage the leak. Those with a pancreatic leak had more other postoperative complications (median 2 versus 0 complications per patient, P = 0.01) and longer hospital duration compared with those without a leak (median 13 versus 23 days, P<0.01). Overall mortality in the series was 3.4%; no mortalities occurred as a result of a pancreatic leak. CONCLUSIONS In the 1990s pancreatic anastomotic leak remains a potentially lethal problem after pancreaticoduodenectomy. Pancreatic leakage after pancreaticoduodenectomy is associated with other postoperative complications and a longer hospital stay.

Perihepatic Lymph Node Assessment in Patients Undergoing Partial Hepatectomy for Malignancy

Objective:To assess the value of preoperative imaging studies and the intraoperative assessment of perihepatic lymph nodes in patients undergoing partial hepatectomy for malignancy. Summary Background Data:Perihepatic lymph node status is an important prognostic factor for patients undergoing hepatic resection for 1o and metastatic cancer. The value of preoperative imaging studies and intraoperative assessment of perihepatic nodes is unknown. Methods:Perihepatic lymph nodes were sampled in 100 patients undergoing resection for 1o and metastatic hepatic malignancy. At the time of sampling, participating surgeons assigned a clinical suspicion score (scale, 1–5: 1 = clinically negative, 5 = clinically positive). Preoperative CT scans and PET scans were reviewed in a blinded fashion by 2 radiologists. Clinical assessment, CT, and PET scan results were analyzed in the context of the pathologic status of the lymph nodes. Results:A mean of 3.2 ± 0.2 nodes were sampled per patient. Fifteen patients had metastatic disease in perihepatic lymph nodes; 13 had suggestive findings on preoperative CT or PET, and 2 were clinically positive at exploration. Clinical assessment had a high negative predictive value (NPV) = 99% but a low positive predictive value (PPV) = 39%. Similarly, CT scans had a high NPV = 95% and a low PPV = 30%. PET scans had a NPV = 88% and a PPV of 100%. Of the 48 patients with both negative preoperative CT and PET scans, only 1 (2.1%) had metastatic nodal disease, and this was suspected based on the clinical assessment. Of the patients with negative CT and PET scans and a negative clinical assessment (n = 39), none had involved perihepatic nodes. Conclusions:In patients with 1o and metastatic liver cancer, the incidence of truly occult metastatic disease to perihepatic lymph nodes is low. Routine sampling of perihepatic lymph nodes will therefore have a low yield in patients without some evidence of disease on preoperative CT or PET scans or at the time of exploration.

Elevation of IL-18 in human sepsis

Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine that shares biochemical features with IL-1β and acts in part by inducing interferon-gamma (IFN-γ). Endotoxic bacterial lipopolysaccharide (LPS) (1 or 2 ng/kg) was insufficient to increase plasma IL-18 in five healthy adults measured 3, 12, and 24 hr following challenge. In contrast, in the first 96 hr of admission to the surgical intensive care unit, mean maximal serum IL-18 was elevated (1122 ± 259 pg/ml) in nine septic patients compared to six healthy adults (191 ± 42 pg/ml), P < 0.01). Serum IL-18 concentrations in septic patients did not correlate with other measured inflammatory mediators: tumor necrosis factor, IL-6, IL-10, or secretory leukocyte protease inhibitor. Therefore, IL-18 circulates in healthy adults and is a component of the human systemic inflammatory response. Further, stimuli other than LPS may induce IL-18 production in vivo in human sepsis.

Esophageal cancer—the five year survivors

Esophageal cancer in the United States carries a poor prognosis with overall 5 year survival rate of approximately 10%. Due to this dismal outcome, data analyzing factors predictive of survival for greater than 5 years are not available.

Gold-Speckled Multimodal Nanoparticles for Noninvasive Bioimaging

In this report the synthesis, characterization, and functional evaluation of a multimodal nanoparticulate contrast agent for noninvasive imaging through both magnetic resonance imaging (MRI) and photoacoustic tomography (PAT) is presented. The nanoparticles described herein enable high resolution and highly sensitive three-dimensional diagnostic imaging through the synergistic coupling of MRI and PAT capabilities. Gadolinium (Gd)-doped gold-speckled silica (GSS) nanoparticles, ranging from 50 to 200 nm, have been prepared in a simple one-pot synthesis using nonionic microemulsions. The photoacoustic signal is generated from a nonuniform, discontinuous gold nanodomains speckled across the silica surface, whereas the MR contrast is provided through Gd incorporated in the silica matrix. The presence of a discontinuous speckled surface, as opposed to a continuous gold shell, allows sufficient bulk water exchange with the Gd ions to generate a strong MR contrast. The dual imaging capabilities of the particles have been demonstrated through in silicio and in vitro methods. The described particles also have the capacity for therapeutic applications including the thermal ablation of tumors through the absorption of irradiated light.