Israel Medical Association Journal

Background: Despite advances in cancer therapy the treatment of liver tumors remains a challenge. Most patients are poor candidates for surgical resection; both chemotherapy and irradiation have a low success rate and neither is without complications. New minimally invasive techniques for ablation of unresectable tumors have gained attention as effective treatment alternatives. Among these are percutaneous ethanol injection and radiofrequency ablation; both are effective for primary liver tumors and RFA is also effective for hepatic metastases.

Objective: To report our experience with PEI and RFA in the treatment of hepatic lesions.

Methods: The study included 49 lesions in 27 patients: 23 primary lesions in 13 patients treated with PEI and 26 lesions (22 secondary and 4 primary) in 14 patients treated with RFA. PEI was performed on an outpatient basis in the ultrasound suite; RFA was done in hospitalized patients (9 in the ultrasound suite and 4 in the operating room). Patients were followed with triphasic spiral computerized tomography 1 month after treatment and every 3±6 months thereafter.

Results: Complete necrosis was achieved with PEI on the first attempt in 11 of 23 primary lesions (91.3%). In 8.7% (2/23) a second series of treatments was required. Using RFA, complete necrosis was achieved in 85% of lesions (22/26) and partial necrosis in 15% (4/26). Complications included low fever (3 patients), high fever and abscess formation (1 patient), peri-tumoral necrosis (1 patient ) and portal vein thrombosis (1 patient ).

Conclusions: Our preliminary results confirm that PEI and RFA are an effective and safe option for treating hepatic tumors in patients unfit for surgery.
 

Between 1990 and 2001, altogether 28 new anticancer drugs were approved for use in Israel. The new agents include cytotoxic drugs, biologic compounds, and hormone therapies. Among the cytotoxic agents introduced, the taxanes, vinorelbine, gemcitabine, irinotecan, topotecan and temozolomide, represent important new drugs active in a range of solid malignancies including lung, breast, ovarian, bladder, pancreatic, and colon cancer as well as brain tumors. Epirubicin, idarubicin, and liposomal doxorubicin offer less toxic and in some instances more effective alternatives to older anthracylines for leukemia, breast cancer, ovarian cancer and other diseases. New oral agents are offering a chance for disease palliation without the need for burdensome intravenous access. Rituximab and trastuzumab have introduced monoclonal antibody therapy to the clinic, substantially improving the treatment of patients with lymphoma and breast cancer, respectively. The first tyrosine kinase inhibitor, a molecularly targeted therapy, imatinib, was approved for use in chronic myeloid leukemia and has also shown remarkable activity in gastrointestinal stromal tumors. A variety of aromatase inhibitors have provided less toxic and more effective hormone therapy for the treatment of breast cancer. The challenge for clinicians is to optimize the use of the new available agents for their patients' benefit, and the challenge for health policy-makers in Israel is to integrate the new anticancer pharmaceuticals into the basic health benefits package mandated for all citizens.

Background: Venous thromboembolic diseases are treated initially with low molecular weight heparin followed by oral coumarins.

Objectives: To investigate an orally available direct thrombin inhibitor for the acute treatment of venous thromboembolism as well as for prophylaxis of recurrent events.

Methods: The direct thrombin inhibitor ximelagatran was compared with subcutaneous LMW[1] heparins followed by oral warfarin in a double-blind randomized prospective multicenter trial in patients with acute VTE[2]. A pharmacokinetic study was performed in the VTE patients. For assessing the prevention of recurrent VTE, double-blind prospective randomized studies were conducted as follows: a) ximelagatran compared to warfarin for 6 months, and b) prolonged anticoagulation of ximelagatran vs. placebo for 18 months after termination of 6 months coumarin therapy.

Results: Two dose-finding studies and the pharmacokinetic analysis of ximelagatran in acute VTE were completed. About 2,500 patients were randomized to investigate 2 x 36 mg ximelagatran versus 2 x 1 mg/kg body weight enoxaparin followed by warfarin. The study hypothesized that the efficacy was equal in both treatment regimens for recurrent VTE documented by objective methods. The second study, with 1,234 patients, aimed to demonstrate a reduced incidence of recurrent thromboembolic events documented by objective methods after 18 months of treatment with 2 x 24 mg ximelagatran daily compared to placebo.

Conclusion: These large-scale clinical trials will soon yield the results of the comparison between oral ximelagatran and subcutaneous LMW heparin for treatment of acute VTE, and of warfarin for prophylaxis of recurrent events for 6 months and for a prolonged prophylaxis for another 18 months.

______________________________

[1] LMW = low molecular weight

[2] VTE = venous thromboembolism

The addition of methotrexate to treatment protocols in children with acute lymphoblastic leukemia has been found beneficial in preventing central nervous system relapse. However, MTX[1] itself may be associated with neurologic morbidities, the most significant of which is leukoencephalopathy. The present study describes the clinical spectrum of leukoencephalopathy, which ranges from a subclinical disease manifested only radiologically to a progressive, devastating encephalopathy. The interaction of MTX with other components of the treatment protocol is discussed, as is the effect of leucovorin. A summary is presented of the metabolic pathways that may be involved in the development of MTX toxicity. Researchers are still seeking a biochemical marker to aid in the determination of the amount of MTX that may be safely administered.

__________________________

Background: The implementation of treatment guidelines is lacking worldwide.

Objectives: To examine whether follow-up in a specialized lipid clinic improves the achievement rate of the treatment guidelines, as formulated by the National Cholesterol Education Program and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Methods: The study group included patients who were referred to the lipid clinic because of hyperlipidemia. At each of five visits over a 12 month period, lipid levels, liver and creatine kinase levels, body mass index, and adherence to diet and medications were measured, and achievement of the NCEP[1] target level was assessed.

Results: A total of 1,133 patients (mean age 61.3 years, 60% males) were studied. Additional risk factors for atherosclerosis included hypertension (41%), type II diabetes mellitus (21%), smoking (17%), and a positive family history of coronary artery disease (32%). All patients had evidence of atherosclerotic vascular disease (coronary, cerebrovascular or peripheral vascular diseases). The low density lipoprotein target of <100 mg was present in only 22% of patients before enrollment, with improvement of up to 57% after the follow-up period. During follow-up, blood pressure control was improved (from 38% at the time of referral to 88% after 12 months, P < 0.001), as was glycemic control in diabetic patients (HgA₁C improved from 8.2% to 7.1% after 12 months, P < 0.001). Improved risk factor control was due to increased compliance to medication treatment (from 66% at enrollment to more than 90% after 12 months), as well as careful attention to risk factor management that translated into a change in the treatment profile during the follow-up. There was an increase in the use of the following medications: aspirin from 68% to 96%, statins from 42% to 88%, beta blockers from 20% to 40%, and angiotensin-converting enzyme inhibitors from 28% to 42%; while calcium channel blocker use decreased from 40% to 30% in patients during follow-up.

Conclusion: Follow-up of patients in a specialized clinic enhances the achievement of LDL[2]-cholesterol treatment goals as well as other risk factor treatment goals, due to increased patient compliance and increased use of medications.

________________________________________________

Background: The treatment of patients with recurrent ovarian carcinoma after failure of first and second-line chemotherapy is still debated. Chemical agents used for third and fourth-line therapy usually yield poor results with severe toxic side effects.

Objective: To summarize our experience with goserelin in the treatment of patients with recurrent ovarian cancer.

Methods: From September 1996 to June 1999 we administered goserelin, 3.6 mg subcutaneously every 4 weeks, to 15 patients with advanced and recurrent epithelial ovarian cancer (median age 59.0, median performance status 3.0).

Results: Seven of 15 eligible patients relapsed after platinum-based chemotherapy (3 of them also received paclitaxel and another 2 received tamoxifen). Four patients relapsed after carboplatin and paclitaxel, one of whom was treated with topotecan thereafter. Two patients relapsed after single-agent paclitaxel. Two patients with advanced disease and poor performance status without previous treatment received only goserelin. There was one complete response (6.7%) and 1 partial response (6.7%) lasting 8 and 14 months respectively (overall response rate 13.4%). In addition, the disease stabilized in three patients (20%) for a median of 7.5 months. In 10 patients the disease progressed. There was no significant toxicity. Median survival of all patients was 5.8 months.

Conclusion: Goserelin was helpful in one-third of our patients with advanced and refractory ovarian cancer. It is an easy and non-toxic option for treating very ill or previously heavily treated patients.
 

Atropine is the drug of choice for treatment of organophosphate (OP) nerve agent and insecticide intoxication and has been used for this indication for several decades. Adverse reactions to atropine may occur, and are of two types: toxic and allergic. Toxic reaction, the most common form, results from the anti-muscarinic effects of the drug. Since it is most probably related to interpersonal variation in sensitivity to atropine, toxic effects may appear at the usual therapeutic doses. The second type, allergic reaction, includes local manifestations, usually after the administration of eyedrops, and systemic reaction in the form of anaphylaxis. Since most patients manifest only a mild reaction, allergy testing is not performed and the prevalence of allergy to atropine is therefore not known. Severe allergic reaction to atropine is rare, as evidenced by the small number of case reports in the literature despite the drug's extensive use. Alternative anti-muscarinic drugs recommended for OP poisoning include glycopyrrolate and scopolamine. Glycopyrrolate is a peripheral anti-muscarinic drug that has been studied in comparison to atropine for many clinical indications, while scopolamine is an anti-muscarinic drug with both peripheral and central effects. An acceptable alternative regimen for patients with proven allergy to atropine is a combination of glycopyrrolate with centrally active drugs such as benzodiazepines or scopolamine.

Recent events have significantly increased concern about the use of biologic and chemical weapons by terrorists and other countries. Since weapons of mass destruction could result in a huge number of casualties, optimizing our diagnostic and therapeutic skills may help to minimize the morbidity and mortality. The national demands for training in medical aspects of nuclear, biologic and chemical warfare have increased dramatically. While Israeli medical preparedness for non-conventional warfare has improved substantially in recent years especially due to extensive training programs, a standardized course and course materials were not available until recently. We have developed a core curriculum and teaching materials for a 1 or 2 day modular course, including printed materials.

Background: Organophosphates (OP) are frequently used as insecticides in the household and in agricultural areas, thus posing a risk for accidental exposure.

Objectives: To describe the characteristics, clinical course and outcome of 97 patients admitted to emergency rooms with a diagnosis of acute OP poisoning.

Methods: The clinical details of 97 patients were collected from 6 different hospitals in Israel. Diagnosis of intoxication was based on clinical findings, butyrylcholinesterase levels and, in several cases, the material brought to the hospital. Demographic, intoxication and clinical data were analyzed.

Results: The study group comprised 64 men and 33 women whose age range was 1–70 years old (mean 19.8 ± 17.1); more than one-third of the patients were less than 10 years old. Accidental exposure was the cause of intoxication in 51.5% of the patients, and suicide in 20.6% of exposures. Intoxication occurred at home in most patients (67%), and the route of intoxication was oral in 65% of them. The patients arrived at the hospital 20 minutes to 72 hours after intoxication. Nine patients were asymptomatic; 53 presented with mild intoxication, 22 with moderate, and 13 had severe intoxication, 5 of whom died. There was a direct correlation between the degree of inhibition of butyrylcholinesterase levels and the severity of intoxication. Treatment included decontamination and antidotal medication. Duration of hospitalization ranged between 1 and to 14 days (average 2.9 days).

Conclusions: Organophosphates may cause severe morbidity and mortality. Medical staff should therefore be aware of the clinical manifestations and the antidotal treatment for this poisoning.
 

The chemical warfare agent sulfur mustard affects primarily the eyes, skin and respiratory tract. Of these, ocular injury is the most immediate and distressing. Learning to recognize ocular injury enables the treating physician to provide early and suitable treatment, which will reduce complications and allow the victim a rapid recovery.

Background: The mortality rate for cholecystectomy for acute cholecystitis in the elderly is 10% in low risk patients and increases threefold in high risk patients. Ultrasound-guided percutaneous transhepatic cholecystostomy may serve as a rapid and relatively safe tool to relieve symptoms of sepsis and decrease gallbladder distension.

Objective: To determine the safety and effectiveness of PTC[1] in the treatment of acute cholecystitis in elderly debilitated high risk patients.

Methods: The study sample included 10 patients aged 63–88 (mean 77.6 years) with clinical and sonographic signs of acute cholecystitis for more than 48 hours (fever, white blood cells > 12,000/mm³, positive Murphy sign and distended gallbladder) who underwent ultrasound guided PTC. All had severe underlying disease (coronary heart disease, renal failure, chronic obstructive pulmonary disease, and others) that places them at high risk for surgical intervention.

Results: Eight patients showed rapid regression of the clinical symptoms following PTC drainage. One patient, with bacterial endocarditis, was febrile for 5 days after catheter insertion, but with rapid resolution of the biliary colic and sepsis. One patient died from perforation of the gallbladder and small bowel. PTC catheters were withdrawn 3–25 days after the procedure, and the patients remained free of biliary symptoms. Two patients underwent successful elective cholecystectomy 3 weeks later.

Conclusion: PTC may be a safe and effective treatment for high risk elderly patients with acute cholecystitis. It can be followed by elective cholecystectomy if the underlying condition improves, as soon as the patient stabilizes and no sepsis is present, or by conservative management in high surgical-risk patients.

Intractable forms of autoimmune diseases follow a rapid course, with a significantly shortened life expectancy sometimes comparable to that of malignant diseases. Immunoablative therapy, including high dose cytotoxic agents and hematopoietic autologous stem cell rescue, was recently introduced as an aggressive approach to treat autoimmune diseases that have a rapid course and are resistant to conventional therapy. The most frequent indication for this type of treatment is multiple sclerosis, seconded by systemic sclerosis. The results of immunoablative treatment with documented responses in both diseases are encouraging. The data are mature enough to begin comparative randomized studies of immunoablative versus conventional treatment to validate the benefit of the aggressive approach. A randomized trial involving SSc[1] was recently launched (ASTIS) and a trial involving MS[2] is under preparation. Considerably less experience with immunoablative treatment has been gained in systemic lupus erythematosus, rheumatoid arthritis, and other disorders with an autoimmune pathophysiology. Autologous hematopoietic stem cell transplantation in humans offers more long-lasting immunosuppression than reeducation of lymphocytes. In fact, allogeneic transplantation may replace the whole immune system. However, this attractive approach is still associated with considerable morbidity and mortality and is not yet justified for treatment of automimmune diseases. Non-myeloablative allogeneic transplantation and sub-myeloblative high dose cyclophosphamide without stem cell support are alternative approaches that could be explored in pilot studies.

_______________________________