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Biomedical subjects

M A Choti

Publications and source records attributed to M A Choti.

At least 19 recordsLinked to original sources

A phosphatase associated with metastasis of colorectal cancer.

To gain insights into the molecular basis for metastasis, we compared the global gene expression profile of metastatic colorectal cancer with that of primary cancers, benign colorectal tumors, and normal colorectal epithelium. Among the genes identified, the PRL-3 protein tyrosine phosphatase gene was of particular interest. It was expressed at high levels in each of 18 cancer metastases studied but at lower levels in nonmetastatic tumors and normal colorectal epithelium. In 3 of 12 metastases examined, multiple copies of the PRL-3 gene were found within a small amplicon located at chromosome 8q24.3. These data suggest that the PRL-3 gene is important for colorectal cancer metastasis and provide a new therapeutic target for these intractable lesions.

Adenoma↗

Vaccines for colorectal cancer.

Despite recent advances in the treatment of colorectal cancer, the overall survival rate for those patients with advanced locoregional disease remains less than 50%. Although adjuvant systemic chemotherapy has improved survival of these patients, more effective therapies are needed. Immunotherapy is an approach that could have a particular role in the adjuvant therapy of colorectal cancer. There is now convincing evidence that the immune system can specifically recognize and destroy malignant cells. Although both antibody- and T-cell-mediated anti-tumor responses have been documented, the cellular immune response with its direct cytotoxic mechanisms is felt to be the principal anti-tumor arm of the immune system. Analysis of the T cells that recognize tumors has led to the identification and characterization of many tumor-associated antigens including several colorectal antigens. Current approaches to developing a vaccine for colorectal cancer use our expanded understanding of these tumor-associated antigens and the conditions that allow development of an effective cellular immune response to them.

Antigens, Neoplasm↗

Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors.

PURPOSE: The purpose of our study was to develop an injectable polymeric system for the long-term localized delivery of bioactive interleukin-2 for antitumor immunotherapy. METHODS: IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure the bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were carried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor challenge were rechallenged with tumor in the opposite lobe of the brain to confirm that antitumor immunologic memory had developed. RESULTS: Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL-2 microspheres injected intratumorally were statistically more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Immunologic memory was induced following IL-2 microsphere therapy in the B16-F10 brain tumor model that was capable of protecting 42% of animals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. CONCLUSIONS: Local IL-2 therapy using novel polymeric carriers. aimed at stimulating long-lasting antitumor immunity, may provide an improved method of treating a variety of cancers.

Animals↗

Counting alleles reveals a connection between chromosome 18q loss and vascular invasion.

The analysis of loss of heterozygosity (LOH) is perhaps the most widely used technique in cancer genetics. In primary tumors, however, the analysis of LOH is fraught with technical problems that have limited its reproducibility and interpretation. In particular, tumors are mixtures of neoplastic and nonneoplastic cells, and the DNA from the nonneoplastic cells can mask LOH. We here describe a new experimental approach, involving two components, to overcome these problems. First, a form of digital PCR was employed to directly count, one by one, the number of each of the two alleles in tumor samples. Second, Bayesian-type likelihood methods were used to measure the strength of the evidence for the allele distribution being different from normal. This approach imparts a rigorous statistical basis to LOH analyses, and should be able to provide more reliable information than heretofore possible in LOH studies of diverse tumor types.

Alleles↗

Renal ablative cryosurgery in selected patients with peripheral renal masses.

OBJECTIVES: To present the preliminary results of renal ablative cryosurgery in selected patients. METHODS: Seven patients were treated, all of whom had small peripheral tumors and chose not to undergo partial or radical nephrectomy. Four patients underwent a rib-sparing flank incision; the remaining three underwent laparoscopy. All tumors were biopsied before cryoablation. Intraoperative ultrasound was used to monitor the cryolesion. RESULTS: There were no intraoperative complications. The estimated blood loss averaged 111 mL. To date, 6 of the 7 patients have undergone at least one follow-up computed tomography scan (14.2 months average follow-up); all these scans demonstrated partial resolution of the lesion. Clinically, the patients tolerated the procedure without any renal complications or significant changes in creatinine. CONCLUSIONS: This limited clinical trial has demonstrated the feasibility of treating small peripherally located renal tumors with cryosurgery with minimal morbidity and a favorable outcome. Further studies are necessary to determine the long-term efficacy of this treatment modality.

Aged↗

Antigen-specific immunotherapy for human papillomavirus 16 E7-expressing tumors grown in the liver.

BACKGROUND/AIMS: We have previously reported a recombinant vaccinia-based vaccine (vac-Sig/E7/LAMP-1) that demonstrated a significant anti-tumor effect in a subcutaneous tumor challenge model. Since the liver is one of the most common sites for tumor metastasis and organ microenvironments may modulate tumor cell responses to therapies, the aim of the present study was to evaluate the potency of vac-Sig/E7/LAMP-1 in treating E7-expressing tumors grown in the liver. METHODS: For in vivo tumor prevention experiments, mice were vaccinated intraperitoneally with vac-Sig/E7/LAMP-1 followed by intrahepatic tumor challenge. For in vivo tumor regression experiments, mice were first challenged with tumor cells and then vaccinated with vac-Sig/E7/LAMP-1 intraperitoneally. In addition, enzyme-linked immunospot assays were used to determine the frequency of E7-specific T cell precursors. RESULTS: For in vivo tumor protection experiments, tumor growth was observed in all of the mice vaccinated with wild-type vaccinia and 60% of the mice vaccinated with wild-type E7 vaccinia. All of the mice vaccinated with vac-Sig/E7/LAMP-1 remained tumor-free 30 days after tumor challenge. For the tumor regression assays, all of the mice vaccinated with vac-Sig/E7/LAMP-1 remained tumor-free 30 days after vaccination. In contrast, all of those mice receiving culture medium, wild-type vaccinia, or wild-type E7 vaccinia developed tumors in the liver. In addition, mice vaccinated with vac-Sig/E7/LAMP-1 had the highest E7-specific CD8+ T cell precursors. CONCLUSIONS: Our data suggest that vac-Sig/E7/LAMP-1 is an effective vaccine for controlling E7-expressing tumors grown in the liver and our model suggests that antigen-specific immunotherapy may represent a powerful tool for treating liver tumors with characterized tumor-specific antigens. In addition, our data indicate that the number of E7-specific CD8+ T cell precursors directly correlated with the anti-tumor effect generated by Sig/E7/LAMP-1 vaccinia.

Animals↗

Focal hepatic ablation using interstitial photon radiation energy.

BACKGROUND: Intratumoral ablative therapy is being used increasingly for the treatment of primary and secondary hepatic malignancies. The interstitial point-source photon radiosurgery system (PRS) is a novel ablative technique that uses radiation therapy similar in dosimetry to interstitial brachytherapy. STUDY DESIGN: To determine the feasibility, toxicity, and local tissue destructive capabilities of the PRS in the liver, preliminary studies in a nontumor-bearing canine model were examined. A 6-month survival study was conducted. Each animal received three radiation treatments, in the right, central, and left hepatic regions. Three low-dose treatments were delivered to each of six animals (group A), generating a 2.0-cm-diameter radiated sphere with a dose of 20 Gy at the lesion edge. Three high-dose treatments were delivered to each of six animals (group B), generating a 3.0-cm-diameter radiated sphere with 20 Gy at the lesion edge. RESULTS: The treatment reproducibly generated sharply demarcated hepatic ablative lesions proportional to the administered dose. Mean lesion diameter at 1 month was 1.6+/-0.2 cm in group A and 3.4+/-1.0 cm in group B. Lesion size was independent of intrahepatic location, including near vascular structures. PRS therapy, when applied to portal structures, resulted in hilar damage. Hilar damage appeared to be associated with arteriolar thrombosis and bile duct injury. Treatment of regions adjacent to large hepatic veins and the IVC was not associated with vessel thrombosis or stricture. CONCLUSIONS: PRS ablation is a generally well-tolerated method that results in consistent, well-demarcated, symmetric lesions of complete necrosis with minimal adjacent parenchymal injury. Application of such an approach for the treatment of liver tumors is promising.

Animals↗

Feasibility of ablating normal renal parenchyma by interstitial photon radiation energy: study in a canine model.

BACKGROUND AND PURPOSE: A miniature photon radiosurgery system (PRS) has been described as an alternative to surgical resection and external-beam radiation for tumors and may now offer an alternative for ablation of renal lesions. We evaluated the feasibility of ablation by PRS in a normal parenchyma canine model. MATERIALS AND METHODS: Twelve mongrel dogs were used in this survival study. In the left and right kidneys of each animal, a peripheral lesion and central-hilar lesion, respectively, were induced with PRS. The probes were placed in the renal parenchyma, and local radiation of 15 Gy at a radius of 1.3 cm was delivered over 10 minutes. Serum electrolytes were measured serially. Computed tomography scans were obtained, and the animals were sacrificed for pathologic correlation. In a separate study, the liver received three additional treatments of 10 to 20 minutes of radiation. RESULTS: Eleven dogs survived this 6-month study and were sacrificed as scheduled. One animal expired after 2 weeks from radiation-induced fulminant hepatic failure with normal renal function. No other complications were observed. The average lesion size was 2.5 cm in diameter. Histologic analysis confirmed coagulative necrosis with sharp demarcation from the surrounding parenchyma. CONCLUSION: Preliminary studies demonstrate the feasibility of PRS ablation of the renal parenchyma. Further tumor model testing will be important to determine the ultimate efficacy of local photon radiation energy.

Animals↗

Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial.

OBJECTIVE: To evaluate the endpoints of complications (specifically pancreatic fistula and total complications) and death in patients undergoing pancreaticoduodenectomy. SUMMARY BACKGROUND DATA: Four randomized, placebo-controlled, multicenter trials from Europe have evaluated prophylactic octreotide (the long-acting synthetic analog of native somatostatin) in patients undergoing pancreatic resection. Each trial reported significant decreases in overall complication rates, and two of the four reported significantly lowered rates of pancreatic fistula in patients receiving prophylactic octreotide. However, none of these four trials studied only pancreaticoduodenal resections, and all trials had high pancreatic fistula rates (>19%) in the placebo group. A fifth randomized trial from the United States evaluated the use of prophylactic octreotide in patients undergoing pancreaticoduodenectomy and found no benefit to the use of octreotide. Prophylactic use of octreotide adds more than $75 to the daily hospital charge in the United States. In calendar year 1996, 288 patients received octreotide on the surgical service at the authors' institution, for total billed charges of $74,652. METHODS: Between February 1998 and February 2000, 383 patients were recruited into this study on the basis of preoperative anticipation of pancreaticoduodenal resection. Patients who gave consent were randomized to saline control versus octreotide 250 microg subcutaneously every 8 hours for 7 days, to start 1 to 2 hours before surgery. The primary postoperative endpoints were pancreatic fistula, total complications, death, and length of hospital stay. RESULTS: Two hundred eleven patients underwent pancreaticoduodenectomy with pancreatic-enteric anastomosis, received appropriate saline/octreotide doses, and were available for endpoint analysis. The two groups were comparable with respect to demographics (54% male, median age 66 years), type of pancreaticoduodenal resection (60% pylorus-preserving), type of pancreatic-enteric anastomosis (87% end-to-side pancreaticojejunostomy), and pathologic diagnosis. The pancreatic fistula rates were 9% in the control group and 11% in the octreotide group. The overall complication rates were 34% in the control group and 40% in the octreotide group; the in-hospital death rates were 0% versus 1%, respectively. The median postoperative length of hospital stay was 9 days in both groups. CONCLUSIONS: These data demonstrate that the prophylactic use of perioperative octreotide does not reduce the incidence of pancreatic fistula or total complications after pancreaticoduodenectomy. Prophylactic octreotide use in this setting should be eliminated, at a considerable cost savings.

Aged↗

Local tumor recurrence following hepatic cryoablation: radiologic-histopathologic correlation in a rabbit model.

PURPOSE: To use radiologic-histopathologic correlation in an animal model to distinguish normal postoperative findings from evidence of residual tumor after cryoablation of malignant hepatic tumors. MATERIALS AND METHODS: Hepatic cryoablation was performed in 12 rabbits with VX2 tumors and in two healthy rabbits. Nonenhanced and dynamic contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging and power and color Doppler flow ultrasonography (US) were performed 7-8 days after cryoablation. Histopathologic findings were correlated with imaging findings. RESULTS: Twenty tumors of 5-20 mm (mean, 10 mm) and seven areas of normal liver were treated with cryolesions of 11-21 mm (mean, 15 mm). All cryolesions exhibited arterial phase rim enhancement at CT and MR imaging, and 13 (57%) of 23 lesions demonstrated peripheral flow at US because of granulation tissue. There was macroscopic recurrence in 15 (75%) of 20 treated tumors; 14 (93%) appeared as peripheral nodularity with low-grade enhancement. Necrotic tissue did not enhance. Intact vessels extended up to 6 mm inside cryolesion margins and caused focal internal enhancement and Doppler flow. Areas of high signal intensity on T2-weighted MR images correlated with liquefaction necrosis, granulation tissue, and tumor. CONCLUSION: In this animal model, recurrent tumor typically appeared as focal nodules at the cryolesion periphery. Rim and central foci of enhancement, Doppler flow, and increased signal intensity on T2-weighted MR images can be normal findings after hepatic cryoablation.

Animals↗

1999 ARRS Executive Council Award. Contrast-enhanced CT of small hypovascular hepatic tumors: effect of lesion enhancement on conspicuity in rabbits. American Roentgen Ray Society.

OBJECTIVE: The purpose of this study was to evaluate the effect of lesion enhancement on the conspicuity of small hypovascular hepatic tumors in an animal model. MATERIALS AND METHODS: Seven VX2 hepatic tumors in five rabbits were imaged. Dynamic contrast-enhanced CT was performed at a single level centered over the lesions at 5-sec intervals for 119 sec after injection of 2 ml/kg i.v. contrast material at 2 ml/sec. Attenuation was measured over time within regions of interest in the tumor and normal liver, aorta, inferior vena cava, and portal vein. Lesion conspicuity, defined as the difference between the attenuation of the uninvolved liver and neoplasm, was calculated. RESULTS: The mean diameter of the tumors on CT was 10 mm (range, 6-15 mm). The tumors appeared as low-attenuation lesions with progressive enhancement during the arterial phase and early portal phase. Peak mean lesion attenuation was 60 +/- 27 H (enhancement, 23 H) at 64 sec. Peak mean lesion conspicuity was 80 +/- 18 H at 39 sec, occurring 10 sec before the peak mean hepatic attenuation of 135 +/- 15 H (enhancement, 67 H) at 49 sec. Relative lesion conspicuity paralleled relative enhancement of the liver throughout the imaging period. CONCLUSION: Although low-level tumor enhancement during the arterial phase and early portal phase reduced the conspicuity of small hypovascular tumors in this animal model, our results support the use of maximum liver enhancement as a marker for peak lesion conspicuity.

Animals↗

Detection of hepatic lesions in candidates for surgery: comparison of ferumoxides-enhanced MR imaging and dual-phase helical CT.

OBJECTIVE: The purpose of this study was to compare the use of phased array MR imaging of the liver at 1.5 T with and without ferumoxides with dual-phase helical CT for the detection of hepatic lesions in candidates for hepatic surgery. SUBJECTS AND METHODS: Patients with known or suspected hepatic lesions who were eligible for surgery underwent dual-phase helical CT at 20 and 70 sec after the start of contrast material injection and phased array MR imaging using fast spin-echo T2-weighted imaging and gradient-echo T1-weighted imaging before and after ferumoxides infusion of 0.56 mg of iron per kilogram of body weight. Three observers who were unaware of the surgical findings separately reviewed the CT scans and unenhanced and enhanced MR images of 24 patients who completed the protocol. The observers' findings were compared with results obtained at surgery using intraoperative sonography and having histopathologic confirmation. Statistical analysis was performed using a segment-by-segment analysis. RESULTS: Eighty-two lesions were found at surgery. The sensitivity of CT, unenhanced MR imaging, and enhanced MR imaging for blinded observers was 60.4%, 62.0%, and 68.2%, respectively. The specificity was 89.2%, 81.9%, and 81.6%, respectively. Five lesions in three patients were not detected preoperatively using any of the techniques. MR imaging found additional lesions not detected on CT in four patients; CT detected one additional lesion not seen on MR imaging. CONCLUSION: Ferumoxides-enhanced MR imaging of the liver shows a trend toward increased sensitivity compared with dual-phase helical CT. Specificity of helical CT was superior to that of enhanced MR imaging for most observers.

Case-Control Studies↗

Management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is responsible for a significant amount of morbidity and mortality throughout the world. In many countries, including the United States, a definite increase in the incidence of HCC has been reported recently, largely attributable to the increasing incidence of hepatitis C infection. Unfortunately, the current management of HCC is confusing due to the large number of treatment options available. The difficulty of managing a patient with HCC is compounded by the lack of well-designed, randomized clinical trials comparing the various treatment modalities. Nevertheless, many exciting management options are currently available that may prove valuable in the treatment of this disease. Partial hepatic resection or, in some instances, liver transplantation offers the best chance for cure. However, various ablative therapies, including percutaneous ethanol injection, radiofrequency ablation, and cryosurgery, may produce a survival benefit. In the future, systemic chemotherapy and transarterial chemoembolization, employed either alone or as adjuncts to ablation or resection, may play an increasing role in palliating or down-staging a patient with advanced HCC. This overview of the state-of-the-art management of HCC attempts to guide the practicing physician in selecting the best treatment plan for an individual with HCC.

Carcinoma, Hepatocellular↗

NCCN Practice Guidelines for Colorectal Cancer.

The NCCN Colorectal Cancer Guidelines panel believes that a multidisciplinary approach is necessary for the management of the patient with colorectal cancer. The panel endorses the concept that treatment of patients in a clinical trial has priority over standard or accepted therapy. The recommended surgical procedure for resectable colon cancer is an en bloc resection; laparoscopic surgery should be done only in the context of a clinical trial. For patients with stage III disease, 5-FU-based adjuvant therapy is recommended. A patient who has metastatic disease in the liver or lung should be considered for surgical resection if he or she is a candidate for surgery and if surgery can extend survival. Surgery should be followed by adjuvant chemotherapy. The panel advocates a conservative post-treatment surveillance program for colon and rectal carcinoma patients. Serial CEA determinations are appropriate if the patient is a candidate for aggressive surgical resection, should recurrence be detected. Abdominal and pelvic CT scans should be utilized only when there are clinical indications of possible recurrence. Patients whose disease progresses during 5-FU-based therapy should be treated with irinotecan or encouraged to participate in a phase I or phase II clinical trial.

Colorectal Neoplasms↗

Treatment of liver metastases from colon carcinoma with autologous tumor vaccine expressing granulocyte-macrophage colony-stimulating factor.

BACKGROUND AND OBJECTIVES: In preclinical studies, tumor cells genetically altered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate systemic antitumor immunity. Clinically relevant immunotherapeutic approaches for the treatment of colorectal cancer should address efficacy within the liver, a common site of metastatic disease. We investigated the effect of irradiated colon cancer cells engineered to produce GM-CSF on protecting from and treating established liver metastases. METHODS: Using a model of liver metastasis by intrahepatic injection of CT-26 murine colon carcinoma cells in syngeneic BALB/c mice, GM-CSF-producing irradiated cells were given as an intradermal vaccine either 14 days prior to hepatic challenge or in animals with early established tumor (days 5 and 10). The presence of tumor, tumor volume, and survival were endpoint determinants. RESULTS: Animals receiving GM-CSF-producing vaccination demonstrated significant protection from subsequent hepatic challenge of viable tumor cells, even at the highest challenge doses. In animals with early established tumors, a significant response was seen with prolongation in survival. CONCLUSIONS: We conclude that GM-CSF autologous tumor vaccination was effective for the treatment of hepatic colorectal metastases in this murine model. These findings provide support for immunotherapeutic approaches for metastatic liver cancer.

Animals↗

Management of hepatic metastases.

Although the liver is the most common site of metastatic disease from a variety of tumor types, isolated hepatic metastases most commonly occur from colorectal cancer and, less frequently, from neuroendocrine tumors, gastrointestinal sarcoma, ocular melanoma, and others. Complete evaluation of the extent of metastatic disease, both intrahepatically and extrahepatically, is important before considering treatment options. Based on a preponderance of uncontrolled studies for hepatic metastatic colorectal carcinoma, surgical resection offers the only potential for cure of selected patients with completely resected disease, with 5-year survival rates of 25% to 46%. Systemic and hepatic arterial infusion chemotherapy may be useful treatment options in patients with unresectable disease and possibly as an adjuvant treatment after liver resection. Other techniques of local tumor ablation, including cryotherapy and radiofrequency ablation, although promising, remain unproved. Management of hepatic metastases from neuroendocrine tumors and other noncolorectal primary tumors should be individualized based on the patient's clinical course, extent of disease, and symptoms.

Antidotes↗

Complex gastrointestinal surgery: impact of provider experience on clinical and economic outcomes.

BACKGROUND: Commonly performed elective gastrointestinal surgical procedures are carried out with low morbidity and mortality in hospitals throughout the United States. Complex operative procedures on the alimentary tract are performed with a relatively low frequency and are associated with higher mortality. Volume and experience of the surgical provider team have been correlated with better clinical and economic outcomes for one complex gastrointestinal surgical procedure, pancreaticoduodenectomy. This study evaluated whether provider volume and experience were important factors influencing clinical and economic outcomes for a variety of complex gastrointestinal surgical procedures in one state. STUDY DESIGN: Complex high-risk gastrointestinal surgical procedures were defined as those with statewide in-hospital mortality of > or = 5%, frequency of greater than 200 per year in the state, and requiring special surgical skill and expertise. Six procedures met these criteria. Using publicly available discharge data, all patients discharged from Maryland hospitals from July 1989 to June 1997 with a primary procedure code for one of the six study procedures were selected. Hospitals were classified into one of six groups based on the average number of study procedures per year: 10 or less; 11 to 20; 21 to 50; 51 to 100; 101 to 200; and 201 or more procedures per year. A hospital was included if at least one procedure was performed there during the study period. No providers fell within the 51 to 100, and 101 to 200 groups, so all analyses were performed for the remaining four volume groups that were classified, respectively, as minimal (10 or fewer procedures), low (11 to 20 procedures), medium (21 to 50 procedures), and high-volume groups (201 or more procedures). Poisson regression was used to assess the relationship between in-hospital mortality and hospital volume after case-mix adjustment. Multiple linear regression models were used to assess differences in average length-of-stay and average total hospital charges among hospital volume groups. We further analyzed mortality, length-of-stay, and charges at the procedural level to understand these subgroups of complex gastrointestinal patients. We also examined the relationship between provider volume and outcomes for malignant versus benign diagnosis groups. RESULTS: Complex gastrointestinal surgical procedures were performed on 4,561 patients in Maryland from July 1989 through June 1997. The study population averaged 61.6 years of age, was 55% male, 71% Caucasian, and had predominantly Medicare as a payment source. After case-mix adjustment, patients who underwent complex gastrointestinal surgical procedures at the medium-, low-, and minimal-volume provider groups had a 2.1, 3.3, and 3.2 times greater risk of in-hospital death, respectively, than patients at the high-volume provider (p < 0.001 for all comparisons); longer lengths-of-stay, 16.1, 15.7, and 15.5 days at the low-, medium-, and minimal-volume groups, respectively, versus 14.0 days for the high-volume provider (p < 0.001 for all comparisons). Similarly, adjusted charges at the high-volume provider were, on average, 14% less than those of the low-volume group, which had the next lowest charges. Although mortality rates differed by procedure type, for each procedure, mortality increased as provider volume decreased, following the pattern found in the aggregate analysis. After case-mix adjustment, the risk of in-hospital death for patients with malignant diagnoses was significantly higher for the medium-, low-, and minimal-volume groups compared with patients at the high-volume provider, relative risk of 3.1, 4.0, and 4.2, respectively, (p < 0.001 for all comparisons). CONCLUSIONS: This study demonstrates that increased hospital experience is associated with a marked decrease in hospital mortality. The decreased mortality at the high-volume provider was also associated with shorter lengths-of-stay and lower hospital char

Clinical Competence↗

Gene gun-mediated DNA vaccination induces antitumor immunity against human papillomavirus type 16 E7-expressing murine tumor metastases in the liver and lungs.

DNA vaccination has emerged as an attractive approach for tumor immunotherapy. The aim of this study was to evaluate the potency of DNA vaccines in preventing and treating the liver and lung metastases of a human papillomavirus-16 (HPV-16) E7-expressing murine tumor (TC-1). We used the gene gun method to vaccinate C57BL/6 mice intradermally with DNA vaccines containing the HPV-16 E7 gene, the E7 gene linked to the sorting signals of the lysosome-associated membrane protein-1 (Sig/E7/ LAMP-1), or the 'empty' plasmid vector. The in vivo antitumor immunity was analyzed in both tumor prevention and tumor regression experiments. In addition, cytotoxic T lymphocyte (CTL) assays, enzyme-linked immunospot assay and enzyme-linked immunoabsorbent assay were used to assess the E7-specific T cell-mediated and humoral immunity. Mice vaccinated with Sig/E7/LAMP-1 DNA generated the strongest E7-specific CTL activities, the highest numbers of E7-specific CD8+ cell precursors and the highest titers of E7-specific antibodies. While both E7 DNA and Sig/E7/LAMP-1 DNA generated potent antitumor immunity in the liver and lung metastases models, the Sig/E7/LAMP-1 DNA was more potent under stringent conditions. DNA vaccination with E7-expressing plasmids was effective in controlling liver and lung metastases of an E7-expressing murine tumor. Our data suggest that antigen-specific DNA vaccination can potentially be applied to control liver and lung metastases of tumors with defined tumor-specific antigens.

Animals↗