Spatial and temporal control of gene therapy using ionizing radiation.

Activation of transcription of the Egr-1 gene by X-rays is regulated by the promoter region of this gene. We linked the radiation-inducible promoter region of the Egr-1 gene to the gene encoding the radiosensitizing and tumoricidal cytokine, tumour necrosis factor-alpha (TNF-alpha) and used a replication-deficient adenovirus to deliver the Egr-TNF construct to human tumours growing in nude mice. Combined treatment with Ad5.Egr-TNF and 5,000 cGy (rad) resulted in increased intratumoral TNF-alpha production and increased tumour control compared with treatment with Ad5.Egr-TNF alone or with radiation alone. The increase in tumour control was achieved without an increase in normal tissue damage when compared to tissue injury from radiation alone. Control of gene transcription by ionizing radiation in vivo represents a novel method of spatial and temporal regulation of gene-based medical treatments.

Outcomes after pancreatectomy for intraductal papillary mucinous neoplasms of the pancreas: an institutional experience.

PURPOSE: To evaluate the experience with pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) at a single academic institution. METHODS: A prospective pancreatic database was reviewed and identified 43 patients with IPMN who were managed operatively. Clinicopathologic features and predictors of outcome were examined. The World Health Organization pathologic classification of IPMN was utilized. RESULTS: IPMN was diagnosed in 21% of patients who underwent pancreatic resection for solid or cystic mass lesions. Ninety-five percent of patients were symptomatic. Patients were managed with total pancreatectomy, pancreaticoduodenectomy, distal pancreatectomy, central pancreatectomy, or enucleation. Nine patients had adenomas, 14 had borderline neoplasms, 10 had carcinoma in situ, and 9 had invasive carcinoma. Overall, 23 patients (53%) had lesions with main duct involvement. Frozen section transection margins were positive for malignancy in 2 patients. With a mean follow-up of 17 months, the 5-year disease-specific survival for patients with main duct involvement was 67%. The 5-year disease-specific survival for patients with benign lesions was 100%, and 61% for patients with malignant lesions (P = .02). The presence of symptoms, increased CA 19-9, and tumor size were not predictive of malignancy. Increased serum bilirubin concentrations were predictive of malignancy (P = .03). Main duct involvement was also associated with malignancy (P < .02). CONCLUSIONS: Cancer is found in 65% of patients with IMPN involving the main duct. Based on our data, patients with symptomatic, main duct involvement, especially those with an increased serum bilirubin, should be offered resection. Alternatively, patients with side branch IPMN may be managed conservatively.

Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature.

Intratumoral injection of an adenoviral vector containing radiation-inducible DNA sequences of the Egr-1 promoter linked to a cDNA encoding tumor necrosis factor (TNF) alpha (Ad.Egr-TNF) enhances the tumoricidal action of ionizing radiation in a human epidermoid carcinoma xenograft (SQ-20B). The dominant histopathological feature in tumor-bearing animals treated with Ad.Egr-TNF and irradiation is extensive intratumoral vascular thrombosis and tumor necrosis. Thrombosis and necrosis are not observed in animals treated with either the viral construct encoding TNF-alpha or radiation and did not occur in irradiated normal tissues adjacent to tumor in animals injected with Ad.Egr-TNF. To determine if the occlusive effects of Ad.Egr-TNF and X-irradiation were specific for tumor vessels, non-tumor-bearing mice were irradiated after receiving i.m. injection of Ad.Egr-TNF at viral titers 20-100 times greater than titers injected intratumorally. No vascular thrombosis was observed in the treated normal tissues. Combined Ad.Egr-TNF and radiation produced occlusion of tumor microvessels without significant normal tissue damage. Taken together, these data suggest that the interaction between radiation inducible TNF-alpha and X-irradiation occurs selectively within the tumor vessels.

Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts.

Gene therapy combined with radiation therapy to enhance selectively radiation cytotoxicity in malignant cells represents a new approach for cancer treatment. We investigated the efficacy of adenoviral (Ad5)-directed cytosine deaminase/5-fluorocytosine (CD/5-FC) enzyme/prodrug gene therapy to enhance selectively the tumoricidal action of ionizing radiation in human cancer xenografts derived from a human squamous carcinoma cell line (SQ-20B). Tumor xenografts grown in hindlimbs of nude mice were transfected with an adenoviral vector (Ad.CMV.CD) containing the cytosine deaminase (CD) gene under the control of a cytomegalovirus (CMV) promoter. Mice were injected i.p. with 800 mg/kg of 5-FC for 12 days, and tumors were treated with fractionated radiation at a dose of 5 Gy/day to a total dose of 50 Gy. In larger tumors with a mean volume of 1069 mm3, marked tumor regression to 11% of the original tumor volume was observed at day 21 (P = 0.01). The volumetric regression of smaller tumors with a mean volume of 199 mm3, which received the same combined treatment protocol, was significant at day 12 (P = 0.014). However, unlike large tumors, regression of the smaller tumors continued until day 36 (P = 0.01), with 43% cured at day 26. No cures or significant volumetric reduction in size was observed in tumors treated with radiation alone; Ad.CMV.CD with or without radiation; or with Ad.CMV.CD and 5-FC. These results suggest that the CD/5-FC gene therapy approach is an effective radiosensitizing strategy and may lead to substantial improvement in local tumor control that would translate into improved cure rates and better survival.

Anaphylactic reactions to isosulfan blue dye during sentinel lymph node biopsy for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an alternative to axillary dissection for many breast cancer patients. Cases of anaphylactic reaction to the isosulfan blue dye used during SLNB have recently been reported. No study on the incidence of serious anaphylactic reactions during SLNB for breast cancer has been reported. METHODS: We reviewed 639 consecutive SLNBs for breast cancer performed at our institution. Sentinel lymph node biopsy was performed using both isosulfan blue dye and technetium-99m sulfur colloid. Cases of anaphylaxis were reviewed in detail. RESULTS: Overall, 1.1% of patients had severe anaphylactic reactions to isosulfan blue requiring vigorous resuscitation. No deaths or permanent disability occurred. In patients with anaphylaxis, hospital stay was prolonged by a mean of 1.6 days. In 1 patient, the anaphylactic reaction required termination of the operation. CONCLUSIONS: Prompt recognition and aggressive treatment of anaphylactic reactions to isosulfan blue are critical to prevent an adverse outcome. Lymphatic mapping with blue dye should be performed in a setting where personnel are trained to recognize and treat anaphylaxis.

Detection and prevention of colon cancer by colonoscopy.

It is widely accepted that most carcinomas of the colon and rectum develop through the adenoma-to-carcinoma sequence. A recent review characterizes the various relationships between colorectal polyps and carcinoma. Tierney and Associates list several studies that show the frequent coexistence of adenomatous polyps with carcinoma of the colon or rectum. The incidence of polyps in patients with carcinoma of the colon and rectum ranges from 12.9% to 62%. Retrospective reports show a lower incidence of polyps in patients with carcinoma of the colon or rectum (13.7% to 23%). However, colon segments resected for carcinoma of the colon have a significant incidence of associated adenomatous polyps (15% to 28%). In patients with carcinoma of the colon or rectum undergoing preoperative fiberoptic colonoscopy there is a percentage of polyps larger than 5mm in diameter ranging between 36% and 62%. There is also a higher rate of both synchronous and metachronous carcinomas in patients in whom polyps coexist with the primary malignant lesion. The rate of metachronous carcinomas in patients with associated polyps at the time the first tumor was discovered is reported to be twice as great as for patients who did not have polyps (2.6% versus 1.14%, respectively). Synchronous malignant lesions were detected in 11% of patients with polyps but in only 0.7% of patients without polyps. In patients with multiple polyps coexistent with the original carcinoma, synchronous malignant lesions are found in 14.6% of patients and metachronous malignant lesions developed in 12.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

Multimodality management of localized pancreatic cancer.

Despite improvements in surgical management, only a minority of patients enjoy long-term survival following pancreaticoduodenectomy for adenocarcinoma of the pancreas. Adjuvant therapy consisting of 5-fluorouracil and irradiation has improved median and 5-year survival rates; however, at least one third of eligible patients do not receive postoperative adjuvant therapy because of delayed recovery following pancreaticoduodenectomy. This has led to the development of treatment schedules incorporating the delivery of systemic therapy and/or chemoradiation prior to surgery. This article briefly outlines the history of adjuvant therapy for adenocarcinoma of the pancreas and reviews the available literature on neoadjuvant therapy for localized pancreatic cancer including investigational therapies under clinical trial evaluation.

Diazepam versus midazolam (versed) in outpatient colonoscopy: a double-blind randomized study.

Midazolam is a new parenteral benzodiazepine premedication for endoscopy. Consecutive patients were randomized to receive either intravenous midazolam or diazepam as premedication for outpatient total colonoscopy by one endoscopist. Fifty-five patients received diazepam (0.15 mg/kg) and 50 received midazolam (0.07 mg/kg). Both patient and endoscopist were blind to the study drug used. The two groups were similar with respect to age, sex, and indication for colonoscopy. Patients were rated by the endoscopist for degree of cooperation, sedation, and pain during examination. There was significantly more oversedation in the midazolam group than in the diazepam group (p less than 0.05). Immediate procedure recall was less in midazolam patients (p less than 0.005), but on repeat interview the next day there was no difference between the two groups concerning recall of the endoscopy. There was no significant difference between the two groups in the incidence of arm pain. We conclude that in a clinical setting, midazolam does not appear to offer any significant advantage over diazepam, except for cost. Midazolam carries an increased risk of oversedation when it is administered on a milligram per kilogram basis and should instead be titrated individually.