Israel Medical Association Journal

Background: The incidence of malignant musculoskeletal tumors during pregnancy is very low. The paucity of data precludes the drawing of solid conclusions regarding a standard approach.

Objectives: To summarize our experience treating 13 pregnant women with malignant soft tissue or bone tumors.

Methods: We conducted a retrospective analysis of 13 cases of patients with either soft tissue or bone sarcoma that developed or progressed during pregnancy or immediately after delivery.

Results: The clinical presentation of the tumors was either a growing mass and/or increasing pain and disability. Most of the masses were located in the lower part of the body and of considerable size. Treatment given during gestation was limited to wide excision of the mass in the 28th week of gestation in one patient. All the patients reported disease progression during gestation. Vaginal delivery was possible in eight patients with no complications, cesarean section was carried out in three women, spontaneous miscarriage occurred in one and termination of pregnancy was performed in one patient.

Conclusions: The diagnostic and therapeutic approaches should be tailored specifically in every pregnant woman in whom sarcoma is suspected.
 

Background: Imaging-guided core needle biopsy is a well-established technique for the diagnosis of bone and soft tissue tumors and tumor-like lesions in specialized orthopedic oncology centers.

Objective: To present our results of computed tomography-guided core needle biopsy with assessment of the accuracy of the technique.

Methods: Between July 1998 and October 2000, 215 CT-guided core needle biopies were performed and histologically examined in the Unit of Bone and Soft Tissue Pathology, Tel Aviv Sourasky Medical Center. There were 80 soft tissue and 135 bony lesions. All biopsies were performed by the same radiologist and the histologic examination by the same pathologist.  To assess the accuracy of the procedure, we compared the diagnosis at biopsy with the diagnosis after definitive surgery (when available).

Results: Bone core needle biopsy (n = 135) showed malignancy in 89 cases (primary or recurrent bone sarcoma, lymphoma, myeloma, metastatic carcinoma or melanoma). There were 29 benign lesions. In 17 cases the result was inconclusive and an open incisional biopsy was performed. Of the 80 soft tissue biopsies, 35 were malignant (25 soft tissue sarcomas, 6 lymphomas, 4 metastatic carcinomas); 40 were benign (myositis ossificans, neurofibroma, desmoid tumor, schwannoma, hematoma and others), and 5 were inconclusive and followed by an open incisional biopsy. The core needle biopsy histologic diagnosis was compared with that of the definitive surgery and the diagnostic accuracy was 90%. Only three samples initially diagnosed as benign turned out to be malignant. No significant complications occurred during the procedures.

Conclusions: CT-guided CNB[1] of musculoskeletal lesions is a safe and effective procedure that assures sufficient and proper material for histologic examination. The accuracy of this method in our center was 90%. Tumor sampling is extremely important, especially in soft tissue sarcomas, and cores should be taken in different directions, including areas of necrosis. The processing is quick, especially for bone CNB, and diagnosis can be achieved within 24 hours. The material undergoes excellent fixation and the immunostains are reliable.

Background: Some studies have indicated a possible link between cigarette smoking and hearing loss.

Objectives: To analyze the association between smoking and hearing loss, other than that induced by noise, and to characterize the type of HL impairment found in smokers.

Methods: We conducted a retrospective cross-sectional study in 13,308 men aged 20±68 (median 34.6 years) who underwent a hearing test as part of a routine periodic examination. For each subject, age, smoking status (current, past or non-smokers) and number of cigarettes per day were noted and a hearing test was performed. The test was performed in a sealed, soundproof room by an experienced audiologist and included pure tone audiometry of 250±8,000 Hz. The audiograms were analyzed and subjects were accordingly divided into two groups: those with HL and at least one of the following impairments in at least one ear: sensorineural, conductive or mixed; and those with no hearing loss (control). Audiograms showing HL typical to noise exposure were excluded.

Results: The prevalence of any type of HL among subjects <35 years was 4.5%, compared to 10.5% among those >35 years (P < 0.0001). A significantly higher incidence of any type of HL was found in current (11.8%) and past smokers (11.7%) than in non-smokers (8.1%) (P < 0.0001). The risk increment of the smoking status for developing HL among subjects under age 35 was 43%, and 17% among those above 35 years. Both mild, flat, sensorineural impairment and conductive impairment were found to be associated particularly with smoking (odds ratio 2.2 and 1.9, respectively).

Conclusions: The incidence of HL unrelated to noise exposure is higher in smokers than in non-smokers, and in young adults the effect is greater.
 

Background: Gaucher disease results from the accumulation of glucosylceramide (glucocerebroside) in tissues of affected persons. Patients sharing the same genotype present with widely varying degrees of lipid storage and of clinical manifestations.

Objectives: To determine whether variation in the glucosylceramide synthase (UDPGlucose ceramide glucosyltransferase) gene, which encodes the enzyme that regulates the synthesis of glucocerebroside, could account for the variability and clinical manifestations.

Methods: Patients homozygous for the 1226G (N370S) mutation, the most common in the Ashkenazi Jewish population, were investigated. The exons and flanking sequences of the gene were sequenced using DNA derived from five very mild Gaucher disease patients and four patients with relatively severe Gaucher disease. Results: One polymorphism was found in the coding region, but this did not change any amino acids. Seven other polymorphisms were found in introns and in the 5' untranslated region. Some of these were single nucleotide polymorphisms; others were insertions. The mutations appear to be in linkage equilibrium and none were found with a significantly higher frequency in either severe or mildly affected individuals.

Conclusions: Mutations in the glucosylceramide synthase gene do not appear to count for the variability in expression of the common Jewish Gaucher disease mutation.
 

Background: Chronic childhood autoimmune hemolytic anemia is an uncommon disorder that is associated with significant morbidity. Treatment with high dose steroids, splenectomy and frequent blood transfusions results in a myriad of complications including growth failure, bone demineralization, Cushing’s syndrome, immunosuppression, and transfusional hemosiderosis.

Objectives: To investigate the efficacy of the monoclonal anti-CD20 antibody, rituximab, in treating children with AIHA[1].

Methods: Four children with chronic AIHA, including two with prior splenectomy, who were dependent on high dose steroids and refractory to other immunosuppressive regimens were treated with four to six weekly doses of rituximab at a dose of 375 mg/m².

Results: All four patients became transfusion-independent and were taken off prednisone completely. Adverse effects included infusion-related reactions that were mild, and infectious complications of Pneumocystis carinii pneumonia and varicella pneumonia.

Conclusions: Treatment with rituximab appears promising for refractory AIHA; it may obviate the need for prednisone and may result in sustained disease remissions in some patients.

Background: Granulocyte colony-stimulating factor has had a major impact on the management of severe chronic neutropenia – a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF[1] with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia (termed Kostmann’s syndrome herein) and Shwachman-Diamond syndrome have developed myelodysplastic syndrome and acute myeloid leukemia, which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS[2] or AML[3] as part of their natural history.

Objective and Methods: To address this, the Severe Chronic Neutropenia International Registry used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics.

Results: As of January 2001, of the 383 patients with congenital forms of neutropenia in the Registry, 48 had MDS or AML (crude rate, about 12.5%). No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from Kostmann’s syndrome patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. The latter in murine models produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival.

Conclusions: Since Kostmann’s syndrome and Shwachman-Diamond syndrome are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of Kostmann’s syndrome patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an innocent bystander that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. Only careful long-term follow-up of the cohort of patients receiving G-CSF will provide the answer.

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[1] G-CSF = granulocyte colony-stimulating factor

[2] MDS = myelodysplastic syndrome

[3] AML = acute myeloid leukemia

Background: Cigarette smoking is a well-known risk factor for the development of endothelial dysfunction and the progression of atherosclerosis. Oxidative stress and inflammation have recently been implicated in endothelial dysfunction.

Objectives: To assess the concomitant contribution of polymorphonuclear leukocytes to systemic oxidative stress and inflammation in cigarette smokers.

Methods: The study group comprised 41 chronic cigarette-smoking, otherwise healthy males aged 45.0 ± 11.5 (range 31–67 years) and 41 male non-smokers aged 42.6 ± 11.3 (range 31–65) who served as the control group. The potential generation of oxidative stress was assessed by measuring the rate of superoxide release from separated, phorbol 12-myristate 13-acetate-stimulated PMNL[1] and by plasma levels of reduced (GSH) and oxidized (GSSG) glutathione. Inflammation was estimated indirectly by: a) determining the in vitro survival of PMNL, reflecting cell necrosis; b) in vivo peripheral PMNL counts, reflecting cell recruitment; and c) plasma alkaline phosphatase levels, indicating PMNL activation and degranulation.

Results: PMA[2]-stimulated PMNL from cigarette smokers released superoxide at a faster rate than PMNL from the controls. Smokers had decreased plasma GSH[3] and elevated GSSG[4] levels. In vitro incubation of control and smokers' PMNL in sera of smokers caused necrosis, while control sera improved smoker PMNL survival. Smokers' PMNL counts, although in the normal range, were significantly higher than those of controls. Plasma ALP[5] levels in smokers were significantly higher than in controls and correlated positively with superoxide release and PMNL counts.

Conclusions: Our study shows that PMNL in smokers are primed in vivo, contributing concomitantly to systemic oxidative stress and inflammation that predispose smokers to endothelial dysfunction, and explains in part the accelerated atherosclerosis found in smokers.

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[1] PMNL = polymorphonuclear leukocytes

[2] PMA = phorbol 12-myristate 13-acetate

[3] GSH = reduced glutathione

[4] GSSG = oxidized glutathione

[5] ALP = alkaline phosphatase

Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients.

Objective: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls.

Methods: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212-sporadic and 56 carriers of either a BRCA1:or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent auloradiography,

Results: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only {3/536, 0.6%).

Conclusions: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.
 

Background: Human parvovirus B19 is responsible for a variety of clinical syndromes, such as erythema infectiosum, non-immune hydrops fetalis, transient aplastic anemia, and arthropathies. HPV is also suspected of playing a role in the pathogenesis of various chronic inflammatory and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Kawasaki disease and multiple sclerosis.

Objectives: To study the age distribution and clinical presentation of patients hospitalized for human parvovirus B19 infection.

Method: We reviewed the case records of all pediatric patients with serologic evidence of HPV infection who were admitted during a 20 month period to a major community hospital

Results: Of 128 children tested for HPV, 48 had evidence of acute infection based on the presence of immunoglobulin M antibodies; 8 patients who also had positive IgM for other viruses were excluded, thus 40 case records were studied. The mean age of the patients was 5.21 years, but 22 patients were under 4: The clinical presentations included 25 patients with fever, either recurrent or prolonged, accompanied in some by enlarged spleen, liver and lymph nodes, skin rash and arthropathy; the remaining patients were investigated for anemia, skin rash, joint complaints and hepatitis. In addition; HPV infection was documented in several well-defihed clinical conditions, such as SLE, vasculitic skin lesions, acute lymphoblastic leukemia, pure red cell aplasia, and optic neuritis.

Conclusions: In a group of 40 pediatric patients exhibiting anti-HPV IgM antibodies, a younger age and less common clinical presentations were observed, furthermore 5 patients had clinical syndromes in which the causative role of HPV infection was not clear.

Background: Acarbose has become an important adjuvant therapy for diabetic patients. Many of these patients are also treated with digoxin for congestive heart failure or chronic atrial fibrillation

Objective: To evaluate a possible drug interaction between acarbose and digoxin.

Methods: An open-label, analyst-blind, randomized, crossover, two-period study was conducted in 11 healthy subjects. In period I, each subject received one single oral dose of 0.75 mg digoxin. In period ll, they were given acarbose tablets., 60 mg-3 times a day for 12 days. On day 8, one hour after acarbose administration, a single oral dose of 0.75 mg digoxin was administered. The study periods were separated by a 3 week washout interval: Serum. digoxin levels., over. time, in the two periods were compared by standard techniques;

Results: There were no differences in the pharmacokinetic parameters of digoxin in the two periods, apart from a significant increase in the mean maximum serum concentration (Cmax) when digoxin was given with acarbose (5.97 compared to 4.67 g/L, P = 0.02). Simulated steady-state peak levels of digoxin (Cmax,ss) achieved with a daily dose of 0.25 mg digoxin, in the presence.and absence of acarbose, were 2.89 and 2.40 g/L respectively (P =0.05); Simulated steady-state trough (Cmin,ss) and average (Cave,ss) concentrations were similar and within the therapeutic window.

Conclusion: There was no significant pharmacokinetic interaction between digoxin and acarbose at current therapeutic doses in the healthy volunteers. This interaction should be further studied with higher doses of acarbose and at steady-state conditions.
 

Fanconi anemia is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancy. FA cells are sensitive to DNA cross-linking agents. Complementation analysis of FA cells using somatic cell fusion has facilitated the identification of eight complementation groups, suggesting that FA is a genetically heterogeneous disorder. Six genes (FANCA, FANCC, FANCD2, FANCE, FANGF, FANCG) have been cloned so far. The majority of affected patients belong to FA group A. Of the 32 unrelated Israeli patients with FA that we studied, 6 carried the FANCC mutations and 15 the FANCA mutations. Among the Jewish patients, ethnic-related mutations were common. Recent cumulative evidence suggests that the FA proteins are repair proteins. FANCC, FANCA and FANCG bind and interact in a protein complex found in the cytoplasm and nucleus of normal cells. FANCD2 exists in two isoforms; the long active form, FANCD2-L, is absent from FA cells of all complementation groups. FANCD2 co-localized with BRCA1 in unclear foci, probably as part of a large genomic surveillance complex. Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-g hypersensitivity and show progressive apoptosis. The definition of the molecular basis of FA in many affected families now enables prenatal diagnosis.