Potent antitumor effects of intra-arterial injection of fibroblasts genetically engineered to express IL-12 in liver metastasis model of rat: no additional benefit of using retroviral producer cell.

Interleukin-12 (IL-12) mediates significant antitumor effects in animal models but associated with dose-dependent toxicity in human. To achieve local expression of IL-12 at the tumor site without systemic toxicity, we performed intra-arterial administration of fibroblasts genetically engineered to produce IL-12 protein with or without retrovirus (CRIP- IL-12 or 3T3-IL-12) in liver metastasis model. Rat breast cancer cells ( MADB - 106) were injected into the portal vein of syngeneic Fisher rats on day 0, and fibroblasts were injected into the hepatic artery on day 7. On day 21, liver weight and number of liver tumors were examined. As controls, CRIP cells expressing retrovirus carrying lacZ marker gene (CRIP-lacZ) or saline (Hanks balanced salt solution, HBSS) were injected. Administration of CRIP-IL-12 significantly reduced tumor metastasis in liver measured by number of foci (CRIP- IL-12: 45.2 +/- 36.7, CRIP-lacZ: >250, HBSS: >250, P<.05) and by liver weight (CRIP-IL-12: 13.0+/-2.5 g, CRIP-lacZ: 30.4+/-8.5 g, HBSS: 26.0+/-7.6 g, P<.05). 3T3-IL-12, which produced only IL-12 protein but not IL-12 retrovirus, also had significant antitumor effects equivalent to CRIP-IL-12. Intra-arterial injection of IL-12--producing fibroblasts into the liver may be an effective therapy for liver tumors reducing systemic toxicity, and could be developed for clinical application.

A comparison of locoregional depot and systemic preparations of 9-aminocamptothecin for treatment of liver metastases in a rat tumor model: superior antitumor activity of sustained-release preparation.

BACKGROUND: Locoregional therapy of hepatic-metastatic disease may overcome the limitations of systemic therapy by allowing tumor drug dose intensification without increasing systemic toxicity. This may result in improved efficacy. We have demonstrated that the novel topoisomerase I inhibitor 9-Aminocamptothecin (9-AC) when dissolved in Ethiodol acts as a sustained release preparation, with good antitumor activity. Its benefit as a depot hepatic intraarterial (i.a.) therapy for hepatic metastases was compared to systemic therapy with an aqueous colloidal dispersion (CD) preparation of 9-AC in a rat model, since a lack of demonstrable benefit of the locoregional therapy, would argue against further clinical evaluation. METHODS: Fisher rats underwent direct intraportal injection of 2 x 10(5) MADB106 adenocarcinoma cells and were treated 6 to 7 days later with: (a) bolus i.a. 9-AC (60 micrograms) in 60 microliters of Ethiodol; (b) bolus i.a. CD/9-AC (60 micrograms) in 200 microliters water; (c) bolus i.a. Ethiodol only (60 microliters), or (d) CD/9-AC (60 micrograms) in 200 microliters water, via a mini-osmotic pump pumping at 1 microliter/hr for 7 days intraperitoneally (i.p.). Livers were harvested 10 to 12 days later, and the number of metastases on the surface were counted blindly. RESULTS: Bolus hepatic i.a. 9-AC/Ethiodol was found to be significantly superior in reducing the number of hepatic metastases, when compared to the aqueous CD preparation administered in the same manner, or by continuous infusion via mini-osmotic pump i.p. (p < 0.01). Systemic therapy was also associated with substantial toxicity. CONCLUSIONS: These results suggest that locoregional therapy of hepatic neoplasms with 9-AC/Ethiodol would be associated with clinical efficacy far exceeding that associated with its systemic administration.

Audit of general practitioner referrals to a surgical assessment unit: new methods to improve the efficacy of the acute surgical service.

A total of 653 referrals from general practitioners to an acute surgical service were audited prospectively over a period of 4 months. Middle-grade staff accepting these referrals were able to deal with 182 (27.9 per cent) of these cells without surgical admission. A further 189 (28.9 per cent) referrals were seen on a surgical assessment unit and were not admitted to a surgical ward. The resultant cost saving was approximately 10,000 pounds. This confirms that the ready provision of an experienced surgical opinion in combination with early assessment can reduce the number of unnecessary acute surgical admissions referred from general practitioners.

Expression of the pS2 peptide in primary breast carcinomas: comparison of membrane and cytoplasmic staining patterns.

The pS2 protein is oestrogen-regulated in breast cancer cell lines. Previous studies have shown a relationship to oestrogen receptor in primary breast carcinomas. This study examined 178 breast carcinomas for pS2 using immunohistochemistry. A high frequency (77 per cent) of positive tumours was found, using a 10 per cent cut-off point to define a positive tumour. There was no relationship with menopausal status or node status, a significant association with differentiation, a weak association with oestrogen receptor, and no association with progesterone receptor or overall survival. Two patterns of cellular localization were observed: cytoplasmic and membrane. The former showed a stronger relationship with oestrogen receptor status, although there were oestrogen receptor-negative tumours with marked pS2 staining. Membrane staining showed a stronger relationship with differentiation, with a staining pattern similar to that observed for milk fat globule membrane. The staining patterns observed may support a role for pS2 in a secretory mechanism. However, the expression and function of pS2 in breast carcinomas remain complex, and are not simply related to oestrogen regulation.

Pancreatic insufficiency secondary to abdominal radiotherapy.

Delayed post-irradiation steatorrhoea secondary to acute pancreatic insufficiency is rare. We describe a case occurring in a patient 23 years following radical abdominal radiotherapy for testicular seminoma.

Peripheral tuberculous lymphadenopathy: a review of 67 cases.

Peripheral tuberculous lymphadenopathy is the commonest form of extrapulmonary tuberculosis. Sixty-seven patients with peripheral tuberculous lymphadenopathy who presented to general surgeons and underwent lymph node biopsy between 1979 and 1989 are reviewed. Fifty-four patients (81 per cent) were of Indian subcontinent ethnic origin and 13 (19 per cent) were of white ethnic origin. The sites most commonly affected were the cervical lymph nodes. Biopsy specimens obtained by open operation were sent for microbiological examination in all but 13 cases, of whom seven were patients of white ethnic origin. Tuberculous lymphadenopathy remains an important differential diagnosis of cervical lymphadenopathy and it is essential that peripheral lymph node biopsies are examined both histologically and microbiologically.

Role of sequential leucocyte counts and C-reactive protein measurements in acute appendicitis.

The accurate clinical diagnosis of acute appendicitis is difficult, and many techniques have been suggested to improve diagnostic accuracy such as laparoscopy, ultrasonography and barium enema examination. In this study serial total leucocyte counts and serial C-reactive protein (CRP) concentrations in acute appendicitis were measured. The sensitivity and specificity of serial leucocyte counts in acute appendicitis were 92 and 100 per cent, and for CRP concentrations 69 and 75 per cent, respectively. The sensitivity and specificity of serial total leucocyte counts fulfilled the criteria for a diagnostic test. It is suggested that in patients with equivocal clinical findings, clinical observation combined with serial leucocyte counts may improve decision making.

Audit of general practitioner referrals to an acute surgical unit.

One hundred and ninety referrals from general practitioners (GPs) to an acute surgical unit were audited prospectively over a 6-month period. A total of 78 admissions were considered inappropriate of whom 23 patients were thought to have needed neither surgical admission nor opinion. The estimated expenditure resulting from admissions deemed inappropriate was 25,000 pounds. The daytime commitments of more senior staff on routine emergency duty days meant they were not easily available to deal with calls concerning acute GP referrals. These admissions reduce the efficiency of the service; this may be improved by a senior member of the team accepting and screening GP calls.