Gene therapy for human bypass grafts.

Autologous saphenous vein is the conduit of choice for the bypass of arterial occlusive disease, be it in the peripheral arterial tree or in the coronary system. This technique is limited by primary graft failure rates approaching 20% in the first year for peripheral arterial disease and 50% at 10 years for coronary artery bypass grafting. The PREVENT trial describes a novel, safe and effective means of ex vivo transfection of harvested vein grafts with an E2F decoy oligonucleotide, with 70-74% decreases in the level of proliferating cell nuclear antigen (PCNA) and c-myc mRNA expressed by the smooth muscle cells in the vein. This translated into a statistically significant reduction in primary graft failure when used to bypass peripheral arterial occlusions in a high-risk human patient population.

Efficacy of 5 MU of interferon in combination with ribavirin for naïve patients with chronic hepatitis C virus: a randomized controlled trial.

BACKGROUND: In chronic hepatitis C the schedule of interferon (IFN), 3 MU thrice weekly (tiw) plus ribavirin (1000-1200 mg/daily) needs further evaluation, as IFN dosages >3 MU achieve better responses. AIMS: To compare the efficacy of 5 MU tiw of IFN with (96 patients) or without ribavirin (96 patients) for 12 months in naïve patients, to evaluate the effect of baseline features on the response to therapy, and to determine a reliable point in time during treatment to predict non-response. RESULTS: Sustained virologic response was 20.8% (95% CI 13-29) with IFN monotherapy and 54.2% (95% CI 44-64) with combination (P = 0.0001), the relapse rate 39.4% (95% CI 23-56) and 9% (95% CI 1-16) (P = 0.0007), and the combined rate of sustained biochemical and virologic response 22.7% (95% CI 14-31) and 60.5% (95% CI 50-71) (P = 0.0001), respectively. Patients given combination therapy were more likely to respond regardless of baseline features. Apart from genotype non-1, predictive factors for IFN monotherapy were ineffective in predicting response to combination therapy. Using logistic regression analysis, IFN-ribavirin was the strongest predictor of response (X2 = 21.3; P = 0.0001). Viral persistence at month 3 of therapy was a more accurate predictor than aminotransferase values for non-response to IFN monotherapy but not to combination therapy (positive predictive values of 98 and 82%, respectively). CONCLUSION: In this study, 5 MU of IFN combined with a standard dose of ribavirin has yielded the highest rate of sustained response reported to date. Further dose finding studies are warranted.

Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb?

This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials. Evidence for the use of gene therapy to limit neointimal hyperplasia and confer myocardial protection was presented, and it was found that augmenting local nitric oxide (NO) production using gene transfer (GT) of NO synthase or interruption of cell cycle progression through a genetic transfer of cell cycle regulatory genes limited vascular smooth muscle hyperplasia in animal models and infra-inguinal bypass patients. The results of application of vascular endothelial growth factor (VEGF) GT strategies for therapeutic angiogenesis in critical limb and myocardial ischemia in pilot clinical trials was reviewed. In addition, experimental evidence was presented that genetic manipulation of peptide systems (i.e., the renin-angiotensin II system and the kallikrein-kinin system) was effective in the treatment of systemic cardiovascular diseases such as hypertension, heart failure, and renal failure. Although, as of yet, there are no well controlled human trials proving the clinical benefits of gene therapy for cardiovascular diseases, the data presented here in animal models and in human subjects show that genetic targeting is a promising and encouraging modality, not only for the treatment and long-term control of cardiovascular diseases, but for their prevention as well.

Stump appendicitis.

There has been a recent increase in interest in stump appendicitis with the rapid development of laparoscopic appendectomy. The objective of this study is to determine the frequency, management, and prevention of stump appendicitis in a retrospective review of 2185 cases of appendectomy and right colectomy at the Massachusetts General Hospital from 1960 to 1998. Three patients with stump appendicitis were identified. Patients presented with epigastric or periumbilical pain that radiated to the right lower quadrant. All had focal abdominal signs and a mild to moderate leukocytosis, and all underwent right colectomy. Pathology noted appendiceal stumps 5 mm deep. Two additional patients with chronic abdominal pain had cecal filling defects on barium enema. Endoscopically, these appendiceal stumps were 7 mm deep with impacted fecaliths and pathologic changes consistent with early inflammation. The stumps were resected by snare electrocautery. Stump appendicitis is a very rare entity. Its incidence may be minimized with accurate visualization of the appendiceal base and creation of an appendiceal stump less than 3 mm in depth. There is no correlation between simple ligation or inversion of the stump and stump appendicitis. There should not be a sudden increase in the incidence of this entity if laparoscopic appendectomy is performed properly.

Atrial fibrillation and tumor emboli as manifestations of metastatic leiomyosarcoma to the heart and lung.

Leiomyosarcoma is a malignant tumor of the smooth muscle that rarely occurs in the gastrointestinal tract. High-grade leiomyosarcomas of the rectosigmoid usually metastasize to the liver and lungs. Although it is unusual, metastases to the heart have been reported. When this occurs, the metastatic tumor usually seeds in the right atrium and pulmonary artery. We report on and discuss a patient who had atrial fibrillation, peripheral emboli, and thrombocytopenia resulting from a low-grade rectosigmoid leiomyosarcoma metastatic to the pulmonary vein and left atrium. Atrial fibrillation is not a common manifestation of malignant neoplasms that have spread to the heart. Surgical removal of the tumor terminated the arrhythmia and thrombocytopenia.

Surgical management of phyllodes tumors.

HYPOTHESIS: Although phyllodes tumors have minimal metastatic potential, we hypothesized that they have a proclivity for local recurrence and should be excised with a wide margin. We reviewed the clinical and radiological appearance of phyllodes tumors and analyzed the role of surgical treatment in their management. DESIGN: Medical records, imaging studies, pathology reports, and interventions were reviewed. SETTING: A large tertiary care teaching hospital. PATIENTS: Between 1980 and 1997, 40 patients with phyllodes tumors were identified through the tumor registry at the Massachusetts General Hospital, Boston. MAIN OUTCOME MEASURES: Surgical resection margins, rates of local recurrence, incidence of distant metastases, and survival. RESULTS: All 40 patients were female, with a mean age of 41 years. Each patient had a palpable mass or a mammographic finding that was indistinguishable from a fibroadenoma on examination. Tumor size ranged from 5 mm to 28 cm. Local recurrence correlated with excision margins (P<.05), but not with tumor grade or size. Local recurrence occurred in 5 patients, each of whom had positive margins or margins less than 1 cm after excision. After reexcision with a 1-cm margin, these individuals remained free of recurrence. One patient developed metastatic disease after total mastectomy and died after chemotherapy. CONCLUSIONS: Phyllodes tumors mimic fibroadenomas and are often excised with close margins. Primary excision or reexcision with a 1-cm margin is recommended. Mastectomy is indicated for patients with large lesions. Lymph node metastases are unusual and occur secondary to necrotic tumor. Chemotherapy is based on guidelines for the treatment of sarcomas, not breast adenocarcinoma.

Gastrointestinal malignancies in patients with celiac sprue.

BACKGROUND: Celiac sprue is a malabsorption disease, which carries an increased risk of gastrointestinal malignancy, often underestimated. The purpose of this study was to examine the management of patients with gastrointestinal neoplasms complicating celiac disease. PATIENTS AND METHODS: The pathology database at our institution was searched from 1986 to present; and the literature from 1966 to 1997 was reviewed to identify reports of celiac sprue complicated by malignancy. A total of 82 cases were available for analysis. RESULTS: Two thirds of patients had carried the diagnosis of celiac sprue for a mean of approximately 10 years. The remaining one third were diagnosed with celiac disease and gastrointestinal malignancy simultaneously. Jejunal T-cell lymphoma was the most common malignancy. There was also an increased frequency of small intestinal adenocarcinoma and squamous cell carcinoma of the esophagus. Prognosis was generally poor, related to the histologic type and stage of the disease. CONCLUSIONS: Gastrointestinal malignant neoplasms, especially small bowel lymphomas, can occur in patients with celiac sprue. Patients with known celiac disease who present with exacerbation of symptoms should be promptly investigated for occult gastrointestinal malignancies, and considered for early surgical exploration.