Israel Medical Association Journal

Sex steroid hormones (estrogens, progestagens and androgens) have been associated with healthy and neoplastic pancreatic biology, although the precise significance of the findings has not been well established. Receptors for the three different types of SSH are expressed in normal and tumoral pancreatic tissue with varying profiles related to cell origin (exocrine or endocrine), to type of neoplasm. and probably even to tumoral behavior. The activity of specific enzymes involved in the synthesis and transformation of SSH are increased in some neoplastic pancreatic tissues, which may influence the circulating concentrations of these hormones, such as the low serum testosterone: dihydrotestosterone ratio described in male patients with pancreatic carcinoma. Different patterns of age and gender-related incidence and growth of neoplasms have been identified. Experimental studies have shown that pancreatic carcinogenesis is promoted or inhibited by SSH. At present, the data supporting hormonal manipula­tion for the treatment of these tumors are non-conclusive. Normal and tumoral pancreatic tissues may be regarded as a target for SSH and an additional site of biosynthesis. The influence of these hormones on physiological activities is not well known but should be further explored. The study of SSH in pancreatic neoplasms will provide clues about its origin, development, tumoral behavior, prognosis and more specific hormonal therapy. We review here the evidence favoring the role of SSH and their possible clinical implications in pancreatic function.

Background: Case-control and prospective studies indicate that an elevated plasma homocysteine level is a powerful risk factor for atherosclerotic vascular diseases. Certain medications can induce hyperhomocystinemia, such as methotrexate, trimethoprim and anti-epileptic drugs. There are few reports indicating an interaction between lipid-lowering drugs (cholestyramine and niacin) and homocysteine. Recently, an interaction was shown between fenofibrate and benzafibrates (a fibric acid derivative) and homocysteine plasma levels.

Objectives: To evaluate the effects of different fibrates on plasma homocysteine levels and to measure the reversibility of this effect.

Methods and Results: We investigated the effects of ciprofibrate and bezafibrate on homocysteine levels in patients with type IV hyperlipidemia and/or low high density lipoprotein levels. While a 57% increase in homocysteine was detected in the ciprofibrate-treated group (n=26), a 17% reduction n homocysteine was detected in the group treated with bezafibrate (n=12). The increase in homocysteine in the ciprofibrate-treated group was sustained for the 12 weeks of treatment and was partially reversible after 6 weeks of discontinuing the ciprofibrate therapy.

Conclusions: These results indicate that an increase In plasma homocysteine levels following administration of flbrates is not a class effect, at least in its magnitude. Moreover, it is reversible upon discontinuation of the treatment.
 

Background: Alkaline tide is the transient increase in blood and urine pH following stimulation of gastric acid secretion. It is attributed to HC0₃ release from parietal cells in parallel with H+ secretion. The enzyme carbonic anhydrase is thought to be responsible for HC0₃ production from CO₂ and 0H in the parietal cell.

Objective: To examine the effect of pretreatment with the carbonic anhydrase inhibitor, acetazolamide, on the alkaline tide phenomenon.

Methods: Ten patients with dyspepsia and demonstrable alkaline tide were tested on three separate days. The pH and base excess were determined in arterialized venous blood before and 45 minutes after an intramuscular injection of pentagastrin. The pH of the urine was measured before and 120 mm after pentagastrin injection. Measurements were performed after pentagastrin alone on day 1 following pretreatment with acetazolamide 60 mm before pentagastrin on day 2, and after the administration of acetazolamide alone on day 3.

Results: Following the administration of pentagastrin alone, the blood base excess increased by 1.61 +0.2 mEq/L (mean + standard deviation) and the calculated alkaline tide at 45 mm was 33.99 ±4.49 mEq. On day 2 with prior adminis­tration of acetazolamide, base excess decreased by 0.21 + 0.39 mEq/L, and the calculated alkaline tide was -3.28±7.57 mEq, which was significantly lower than on day 1 (P=0 0001). On day 3, following acetazolamide alone, the base excess values decreased by 0.53~0.2 mEq/L and the alkaline tide was -10.05 +3.33 mEq there was no significant difference compared with day 2 (P= 0.44).

Conclusion: Pretreatment with acetazolamide abolished the alkaline tide induced by pentagastrin. This finding supports the view that carbonic anhydrase has a major role in the alkaline tide phenomenon.

Background: Classic Kaposi's sarcoma is a rare tumor with an indolent behavior. Local therapy is not applicable in disseminated cutaneous disease. Patients with advanced disease are usually treated with systemic chemotherapy.

Objectives: To assess the effectiveness and toxicity of  single-agent vinblastine in the treatment of disseminated and recurrent Kaposi's sarcoma.

Methods: Ten patients with wide cutaneous spread of classic Kaposis sarcoma were treated with single-agent vinblastine, 6 mg/m² intravenously once every 2 weeks. Vinblastine was continued for 2 months after achieving a maximal response.

Results: The male:female ratio was 2.3:1, and median age 64 years (range 50-79 years). The median number of involved nodules in the skin was 34. The overall response rate was 90%, 5 with complete response (50%) and 4 with partial response (40%). Complete responders had a longer duration of response than partial responders: 41.2 vs. 14.8 months. The median survival of all patients was 33 months. Side effects were minimal and tolerable.

Conclusions: Vinblastine is very effective in the treatment of extensive classic Kaposi's sarcoma, and results in a high response rate, long survival and disease-free survival with tolerable toxicity.

Background: Despite years of research and clinical experience with acute appendicitis, the rate of complications in the pediatric age group continues to be high.

Objective: To characterize the profile of the child with appendicitis complicared by perforation or intraabdominal abscess.

Methods: Between 1 January 1985 and 31 December 1997 in our department, 581 children under the age of 14 years were clinically diagnosed as suffering from "acute appendici­tis". The final diagnoses were: white appendix in 28 cases (4.8%), acute non-complicated appendicitis in 472 (81%), and complicated appendicitis in 81 (13.9%), including 51 cases of free perforation (8.7%) and 30 cases of intraabdominal abscess (5.2%). We retrospectively reviewed the charts of all children with complicated appendicitis and those of 70 randomly selected children with non-complicated appendicitis, and compared patient age, gender, weight percentile, past medical history, and course of the illness.

Results: The children with complicated appendicitis were significantly younger (R~4.8*10~⁷), they had higher oral and rectal temperatures (P=7.9*10-⁸), higher platelet count (P=0.0008) and lower hemoglobin level (P=0.004). No difference was found in white blood count (P=0.41). Total delay from symptom onset to surgery was 33 hours (SD 23) in the non-complicated group, 60 hours (SD 38) in the perforated appendicitis group, and 176 hours (SD 107) in the intra­abdominal abscess group (P=4.6*10-⁸). No difference in intra­hospital delay was found.

Conclusions: Children with complicated appendicitis are characterized by younger age, longer delay from symptom onset to correct diagnosis, and typical laboratory findings. Delays in diagnosis can be avoided by first considering the diagnosis of acute appendicitis in the differential diagnosis when examining any child with abdominal pain.

Background: Asthma, allergic rhinitis, and atopic derma­titis are leading causes of chronic diseases in developed countries, with at least one allergic condition troubling 10 to 20% of the general population. The few studies performed in Israel determined the prevalence of allergic conditions in selected populations (schoolchildren and soldiers) no study representative of the general population has previously been done.

Objectives: To determine the prevalence of allergic conditions in the general population in Israel and the differences between ethnic and socioeconomic groups.

Method: Using a computer-assisted telephone interview, a telephone questionnaire was conducted in a representative sample of the general Israeli population.

Results: Of the population studied, 140/a claimed to have bronchial asthma, 14% allergic rhinitis, and 6% other allergic conditions. Prevalence rates were higher in the Israeli Arab population and in those with low income and low education levels. Of those with allergic conditions, 58% were treated by a primary physician, 32% were not treated at all, and only 10% were treated by a different specialist physician.

Conclusions: The prevalence of allergic conditions in this study concurs with that found by other studies in developed countries. Allergic conditions are higher in the Israeli Arab population and in those with low income and low education level.

Paraneoplastic syndromes are disorders associated with cancer but without a direct effect of the tumor mass or its metastases on the nervous system. Small cell carcinoma of lung associated with paraneoplastic sensory neuronopathy and/or paraneoplastic encephalomyelitis with the presence of anti-Hu antibodies has been termed “anti-Hu syndrome. Anti-­Hu associated PSN-PEM is an immune disorder in which both cell-mediated and humoral mechanisms are involved. Patients are consiaered affected by Anti-Hu associated PSN-PEM when they develop clinical signs and symptoms of CNS dysfunction and/or sensory neuropathy not caused by metas­tases or other disorders, and serum or cerebrospinal fluid is positive for Hu abs. SCLC is found in more than 90% of patients with cancer and positive Hu abs. Individual patients with Hu abs associated to SCLC may suffer PSN-PEM, Iimbic encephalitis, brainstem encephalopathy, opsoclonus-myoclo­nus, paraneoplastic cerebellar degeneration or myelopathy. Hu abs have a specificity of 99% and sensitivity of 82% in detecting paraneoplastic neurological syndromes. There are two types of treatment: the first is to treat the cancer, the second is to suppress the immune reaction with the use of corticosteroids, cyclophosphamide, azathioprine, plasma ex­change, intravenous immunoglobulin and immunoadsorption however, treatment of paraneoplastic syndromes is generally unsatisfactory.

Trophic factors such as nerve and fibroblast growth factors are important modulators of 13 cell physiology. These two factors induce the extension of neurite-Iike processes in primary cultures of adult rat 13 cells. Moreover, both NGF and FGF enhance glucose-induced insulin secretion. Since â cells synthesize NGF and pancreatic islet cells produce FGFs, it is possible that autocrine/paracrine interactions may be major regulators of insulin secretion, and impairment of these interactions could lead to pathological states such as diabetes mellitus.

Background: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense pre­clinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothetial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer.

Objective: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature.

Methods: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir). was evaluated.

Results: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain.

Conclusion: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.