Israel Medical Association Journal

Background: The contribution of the abnormal DNA mismatch repair system to non-small cell lung cancer tumorigenesis is controversial and has not been reported in Jewish Israeli patients. Similarly, the involvement of 3p deletions in NSCLC[1] in the same population has not been assessed.

Objectives: To assess the contribution of the DNA-MMR[2] system to NSCLC pathogenesis by analyzing microsatellite instability, and evaluate loss of heterozygosity at 3p rates in Israeli NSCLC patients.

Methods: Paired DNA from tumorous and non-tumorous tissue was extracted, and genotyping for MSI[3] determination was carried out using the five Bethesda markers and for determining LOH[4] two 3p markers were used. Genotyping was performed using polymerase chain reaction amplification and size separation on an ABI semiautomatic DNA sequencer, and the allelic patterns of tumorous and non-tumorous tissue were compared.

Results: Forty-four NSCLCs from 35 smokers and 9 non-smokers were analyzed, with 26 of the 44 (59%) at stage I disease. Using five microsatellite markers (D17S250, D5S346, D2S123, BAT-25, BAT-26) (known as Bethesda markers) for MSI determination, 6 of the 44 tumors (13.6%) exhibited MSI in at least one marker. Similarly, genotyping for LOH at chromosome 3p was performed using two markers (D3S4103, D3S1234) located at 3p14.2 l. With D3S4103, 33 of the 44 patients successfully analyzed were homozygous and therefore non-informative with respect to LOH. Using D3S1234, 33 of 36 patients (91.7%) were heterozygous, and 23 of these individuals' tumors (69.7%) displayed LOH. Unexpectedly, 4 of 33 tumors (12.1%) genotyped by D3S4103, and 16 of 36 tumors (44.5%) genotyped by D3S1234 showed a pattern of MSI, even though only one of these tumors showed a similar pattern when genotyped with the five consensus markers. Overall, 23 of 44 tumors (52.3%) demonstrated MSI on at least one marker, and 5 of these 23 tumors (21.7%) had MSI on two or more markers.

Conclusions: MSI using 3p markers and not the Bethesda markers occurs at a high rate and in early stages in Jewish NSCLC patients.

Background: Metastatic melanoma is an aggressive and highly malignant cancer. The 5 year survival rate of patients with metastatic disease is less than 5% with a median survival of only 6–10 months. Drugs like dacarbazin (DTIC) as a single agent or in combination with other chemotherapy agents have a response rate of 15–30%, but the duration of response is usually short with no impact on survival. Interleukin-2-based immunotherapy has shown more promising results. The National Institutes of Health recently reported that lymphodepleting chemotherapy, followed by an adoptive transfer of large numbers of anti-tumor specific tumor-infiltrating lymphocytes, resulted in an objective regression in 51% of patients.

Objectives: To introduce the TIL[1] technology to advanced metastatic melanoma patients in Israel.

Methods: We generated TIL cultures from tumor tissue, choosing those with specific activity against melanoma and expanding them to large numbers.

Results: TIL cultures from nine patients were established and examined for their specific activity against the patients' autologous tumor cells. Twelve TIL cultures derived from 5 different patients showed the desired anti-tumor activity, making those 5 patients potential candidates for the therapy.

Conclusions: Pre-clinical studies of the TIL technology in a clinical laboratory set-up were performed successfully and this modality is ready for treating metastatic melanoma patients at the Sheba Medical Center's Ella Institute.

Background: The suspicion of child abuse and neglect may arise from manifestations such as physical or psychosomatic symptoms, eating disorders, suicidal behavior, impaired parental functioning, etc. Thus the arrival of an abused or neglected child at the hospital provides an opportunity for detecting the problem and beginning a process of change. Optimal utilization of this potential depends on the awareness, diagnostic ability and cooperation of the staff.

Objectives: To assess knowledge about hospital policy, attitudes and actual behavior of hospital staff in cases of SCAN[1].

Methods: The questionnaire was adapted and distributed to a convenience sample of personnel at a children’s hospital. The questionnaire included items on knowledge of hospital policy regarding SCAN, attitudes towards inquiring about cases that appear suspicious, and behaviors in cases in which the respondent was involved. The comparison of responses to specific questions and among members of different professions was analyzed by chi-square test.

Results: Eighty-two staff members completed the questionnaires. Most of the respondents were aware of hospital policy regarding suspected abuse (86.6%), with fewer regarding suspected neglect (77.2%). Physicians were the least aware of these policies, as compared to medical students, nurses and social workers. Although most considered the issue of SCAN a responsibility of members of their own profession, 35.4% considered it primarily the responsibility of the welfare or judicial systems. Over 40% felt uncomfortable discussing suspicions with the child and nearly half felt uncomfortable discussing them with parents. The most often reported reason for this was the sense that they lacked skills or training for dealing with the issue. Despite this, when asked about actual behavior, 94.7% responded that they do try to clarify the circumstances related to the suspicious symptoms. Respondents were more likely to contact the hospital social worker than community resources (91.5% vs. 47.2%).

Conclusions: The findings highlight the need to encourage awareness, discourse and training of medical personnel about issues related to SCAN in order to maximize their potential contribution to identifying children at risk.

Background: Persistent creatine kinase elevation is occasionally encountered in subjects without any clinical manifestation of a neuromuscular disorder or any condition known to be associated with increased serum CK[1] levels. It is still unresolved whether extensive investigations and specifically a muscle biopsy should be performed in clinically normal individuals with elevated CK levels.

Objective: To study the muscle pathology of patients with asymptomatic or minimally symptomatic hyperCKemia.

Methods: The clinical and laboratory data of patients with persistent hyperCKemia and normal neurologic examination were reviewed and their muscle biopsies evaluated.

Results: The study group included 40 patients aged 7–67 years; the male to female ratio was 3:1. Nineteen patients were completely asymptomatic, 20 had mild non-specific myalgia, and 1 had muscle cramps. Electromyography was performed in 27 patients and showed myopathic changes in 7 (26%). Abnormal muscle biopsy findings (e.g., increased variation in fiber size, increased number of central nuclei and occasional degenerating fibers) were detected in 22 of the 40 patients (55%). No fat or glycogen accumulation was detected. Immunohistochemistry demonstrated abnormal dystrophin staining in 3 patients (8%), resembling the pathologic changes of Becker muscular dystrophy. No abnormal findings were detected on immunohistochemical staining for merosin, dysferlin, caveolin 3, or alpha and gamma sarcoglycans. The EMG[2] findings did not correlate with the pathologic findings.

Conclusions: Abnormal muscle biopsies were found in 55% of patients with asymptomatic or minimally symptomatic hyperCKemia. Specific diagnosis of muscular dystrophy, however, was possible in only 8% of the patients.

Evidence that crystalline silica is associated with an increased rate of lung cancer led the International Agency for Research on Cancer to conclude in 1997 that crystalline silica is a known human carcinogen. In Israel too, crystalline silica is considered as such. The decision raised a debate in the scientific arena, and a few scientists have questioned the basis upon which causality was determined. We review the literature regarding the level of evidence of crystalline silica carcinogenicity.

Three decades have elapsed since the inception of Level I trauma centers as the final link in the trauma system "chain of survival".

Tumor necrosis factor-associated fever syndrome is an autosomal dominant disorder caused by mutations of the TNFRSF 1A gene encoding the 55 kD TNF receptor (p55 TNF-RI).

"Surviving severe injury depends very heavily upon the time it takes to receive trauma services. The risk of death increases three fold after one hour without the uniqe surgical care of a trauma center. This is often referred to as the 'golden hour'..."

Multidetector-row computed tomography has been validated as a useful non-invasive diagnostic method in patients with various cardiac diseases.

A 61 year old woman with chronic untreated hypertension presented for routine examination without any complaints.

Background: During the last decade, Israel, a country with low tuberculosis rates, absorbed some 900,000 new immigrants from TB[1]-endemic countries.

Objectives: To analyze the specific impact of our screening procedures on active TB among children in Israel.

Methods: We conducted a retrospective analysis of epidemiologic and clinical data of all children (aged 0–17) with TB notified to the Ministry of Health between 1990 and 1999.

Results: There were 479 children with TB (male/female ratio 1.36). Most cases (81.8%) were foreign born, predominantly (88.2%) immigrants from Ethiopia and, therefore, huge differences existed in TB incidence rates according to countries of origin. Some 80% were diagnosed within 3 years of arrival, mainly due to active case-finding. Pulmonary TB, with infiltrates on chest X-ray, was found in 49.5%. Extra-pulmonary TB sites were: intra-thoracic lymphadenitis (31.1%), extra-thoracic lymphadenitis (12.5%), bones (3.6%), pleura (1.3%), meninges (1%), and others (1%). Seventy percent had a tuberculin skin test reaction ≥10 mm in size. Two (non-immigrant) children died of TB meningitis.

Conclusions: Most of the pediatric TB cases occurred in recent immigrants and were diagnosed within 3 years of immigration. These data support our policy of active case-finding among new immigrants from Ethiopia and extensive contact evaluation for all TB cases.