Israel Medical Association Journal

Background: Fanconi anemia complementation group C and Bloom syndrome, rare autosomal recessive disorders marked by chromosome instability, are especially prevalent in the Ashkenazi* Jewish community. A single predominant mutation for each has been reported in Ashkenazi Jews: c.711+4A→T (IVS4 +4 A→T) in FACC[1] and BLM^Ash in Bloom syndrome. Individuals affected by both syndromes are characterized by susceptibility for developing malignancies, and we questioned whether heterozygote carriers have a similarly increased risk.

Objectives: To estimate the cancer rate among FACC and BLM^Ash carriers and their families over three previous generations in unselected Ashkenazi Jewish individuals.

Methods: We studied 42 FACC carriers, 28 BLM^Ash carriers and 43 controls. The control subjects were Ashkenazi Jews participating in our prenatal genetic screening program who tested negative for FACC and BLM^Ash. All subjects filled out a questionnaire regarding their own and a three-generation family history of cancer. The prevalence rates of cancer among relatives of FACC, BLM^Ash and controls were computed and compared using the chi-square test.

Results: In 463 relatives of FACC carriers, 45 malignancies were reported (9.7%) including 10 breast (2.2%) and 13 colon cancers (2.8%). Among 326 relatives of BLM^Ash carriers there were 30 malignancies (9.2%) including 7 breast (2.1%) and 4 colon cancers (1.2%). Controls consisted of 503 family members with 63 reported malignancies (12.5%) including 11 breast (2.2%) and 11 colon cancers (2.2%).

Conclusions: We found no significantly increased prevalence of malignancies among carriers in at least three generations compared to the controls.

Background: Germline mutations in BRCA1 and BRCA2 genes account for only 20–40% of familial breast cancer cases. The CHEK2 gene encodes a checkpoint kinase, involved in response to DNA damage, and hence is a candidate gene for breast cancer susceptibility. Indeed, the CHEK2*1100delC truncating mutation was reported in a subset of mostly North European breast cancer families. The rate of the CHEK2*1100delC variant in the Ashkenazi* Jewish population was reported to be 0.3%.

Objectives: To evaluate whether CHEK2 germline mutations contribute to a breast cancer predisposition in Ashkenazi-Jewish high risk families.

Methods: High risk Ashkenazi Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were genotyped for germline mutations in the CHEK2 gene by exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis and sequencing of abnormally migrating fragments.

Results: Overall, 172 high risk women were genotyped: 75 (43.6%) with breast cancer (average age at diagnosis 49.6 ± 9.6 years, mean ± SD) and 97 asymptomatic individuals (age at counseling 48.3 ± 8.2 years). No truncating mutations were noted and four previously described missense mutations were detected (R3W 1.2%, I157T 1.2%, R180C 0.6% and S428F 5%), one silent polymorphism (E84E 20.5%) and one novel missense mutation (Y424H 1.2%). Segregation analysis of the I157T and S428F mutations (shown to affect protein function) with the cancer phenotype showed concordance for the CHK2*I157T mutation, as did two of three families with the CHK2*S428F mutation.

Conclusions: CHEK2 missense mutations may contribute to breast cancer susceptibility in Ashkenazi Jews.

Background: The imaging parameters that mandate further diagnostic workup in focal asymmetric breast densities are not clearly defined.

Objectives: To identify indications for further workup in FABD[1] by comparing mammographic and ultrasonographic findings with the pathology results of women with FABD.

Methods: Ninety-four women (97 FABD) were referred for core needle biopsy after incidental discovery of FABD on routine mammograms (n=83) or on diagnostic mammograms performed for palpable masses (n=11). Clinical data included patient’s age, use of hormone replacement therapy, family history of breast cancer, and the presence of a palpable mass. Mammograms and sonograms were evaluated for lesion size and location, associated calcifications, architectural distortion, and change from previous examinations when available. Two patient groups emerged according to the pathological findings and the data were compared.

Results: The average age, size and location of the lesions in the malignant (n=5) and benign (n=92) groups were similar. There was a significant difference (P < 0.05) for the presence of a clinically palpable mass (60% vs. 9%, respectively), a cluster of calcifications (60% vs. 12%), associated architectural distortion (exclusively in the malignant group) and a solid mass on sonography (50% vs. 9%). The malignant group had a higher rate of family history of breast cancer and HRT[2] use.

Conclusions: FABD usually present a benign etiology and can safely be managed by follow‑up. The presence of an architectural distortion, a cluster of malignant‑appearing or indeterminate calcifications, a sonographic mass with features of possible malignancy, or a clinically palpable mass mandates tissue diagnosis.

Background: The current methods for pre‑ and post‑chemotherapy examination of the extent of disease in the breast and lymph nodes do not provide sufficiently accurate information and, not infrequently, the surgeon has to re‑operate.

Objectives: To correlate the findings between three methods of examination (physical examination, ultrasonography, mammography), all performed by the same oncologic and radiologic team, in patients with locally advanced breast cancer or a tumor/breast tissue ratio that precludes breast-conserving surgery.

Methods: Forty patients (median age 48 years, range 24–73) with locally advanced breast cancer or with a tumor/breast ratio that precluded breast‑conserving surgery were evaluated by the same medical team and received neoadjuvant chemotherapy. Surgery was performed in all, and the pathologic specimen was correlated with the results of the other examinations.

Results: In the pre‑chemotherapy evaluation, the imaging findings of the breast correlated with the physical findings in 78% of the patients and with the axilla examination in 66.7%. In the post‑chemotherapy analysis, imaging agreed with the physical findings of the breast in 62.2% and in 76.3% of the axilla. Sonography best detected occult breast disease and axillary lymph nodes but correlated with pathology in only 58% of the patients in diagnosing breast tumor and in 65.8% in diagnosing axillary lymph nodes. Mammography correlated with breast and lymph node pathology in half the patients.

Conclusions: None of the classical methods of post‑neoadjuvant chemotherapy evaluations could adequately delineate the actual extent of the disease in the breast and axillary lymph nodes. More exacting techniques of imaging combined with the classical methods are required.

Objectives: To establish the impact of breast MRI on women undergoing testing in our institution.

Methods: We analyzed 82 cases that underwent MRI between January 2001 and April 2003. Analysis appraised the clinical impact of MRI testing in cases where medical summaries were available.

Results: Studies were categorized into five indications: a) screening in high risk women (n=7), b) search for primary disease in the presence of disease (n=5), c) monitoring of chemotherapy (n=2), d) postoperative assessment of tumor bed (n=9), and e) diagnostic/characterization of primary or recurrent breast cancer (n=59). Results were defined as negative, positive or no impact on clinical management. MRI testing had a positive impact in 62 cases, affecting measurable change in 9 cases. Benefit was seen in screening, diagnosis and postoperative cases. In 15 cases, MRI stimulated investigations.

Conclusion: MRI is a valuable tool in breast imaging and affects management. Further trials are necessary to define clearly the role of MRI and to ascertain whether in cases where beneficial impact on management is noted, there is ultimate impact on outcome. 

Objective: To determine breast-feeding patterns and the association between sociodemographic characteristics and breast-feeding in the Tel Aviv district.

Methods: The mothers of infants aged 2, 4, 6 and 12 months, attending 59 well-baby clinics in the Tel Aviv district, were interviewed by telephone. Singleton infants who weighed less than 2,000 g and multiple-gestation infants were excluded from the study. The questions covered background data, sociodemographic characteristics of the family, and breast-feeding practices. Stepwise logistic regression was used to analyze the association between breast-feeding and various sociodemographic characteristics.

Results: Altogether, 78.5% of the mothers (1,307/1,665) initiated breast-feeding. The rate of breast-feeding at 2, 4, 6 and 12 months was 55.8, 36.8, 29.9 and 11.8%, respectively. Only 35.8% of the infants at 2 months and 11.2% at 6 months were exclusively breast-fed. The mean duration of breast-feeding was 5.2 ± 0.2 months. Grand multiparas (≥5 children) had a significantly higher rate of breast-feeding than women with one to four children (P < 0.001). More likely to breast-feed for 2 weeks or longer were women married to Yeshiva students (odds ratio = 5.3), women with ≥13 years education (OR[1] = 2.1), and women on maternity leave (OR = 1.6). The predictors for breast-feeding for 6 months or longer were similar.

Conclusions: Although the rate of breast-feeding initiation in central Israel was 78.5%, only 29.9% of the mothers continue to breast-feed for 6 months. Already at a young age, an appreciable number of breast-fed infants receive infant formula. Breast-feeding promotion should focus on less educated women, homemakers, and families with one to four children.

Objectives: To examine the effect of postoperative loco-regional radiotherapy on local and regional recurrence and survival in breast cancer patients with four or more involved lymph nodes or extracapsular tumor extension.

Methods: This controlled clinical trial included 258 breast cancer patients with four or more involved nodes or ECE[1]. Eighty-nine patients in the control group had modified radical mastectomy and received adjuvant chemotherapy with melphalan and 5FU, but no radiation therapy. The 169 patients in the study group (87 with MRM[2] and 82 with lumpectomy and axillary dissection) received various adjuvant chemotherapy regimes and radiation therapy to the chest wall/breast, supraclavicular region and full axilla.

Results: With an average follow-up of more than 5 years, loco-regional radiation significantly reduced local and regional disease recurrence. The median disease-free survival was significantly longer in radiated patients (59.2 months and 63.3 months in the MRM and L+AXLND[3] groups, respectively, vs. 28.4 months in the control group; P < 0.01). There was no difference in the rate of systemic recurrence and overall survival. The median overall survival was 71.2 and 67.5 months in the study groups (MRM and L+AXLND, respectively) and 70.5 months in the control group (P = 0.856).

Conclusions: Radiotherapy to the breast/chest wall and to the draining lymphatics, in addition to surgery and adjuvant therapy, significantly reduced the risk of local and regional recurrence in high risk breast cancer patients with four or more involved lymph nodes or ECE.

Israel has a National Screening Program for early detection of breast cancer. The need to continue and even expand this program was recently stressed in light of the high risk in the population. However, the optimal modalities for breast cancer screening are controversial, especially for women at risk. Mammography, the established screening method, is critically examined, and molecular imaging techniques, such as magnetic resonance spectroscopy and spectroscopic imaging are explored, especially for primary breast cancer detection. MRS[1] and MRSI[2] are currently limited by their reliance on the conventional framework for data analysis in biomedical imaging, i.e., the fast Fourier transform. Recent mathematical advances in signal processing via the fast Pade transform can extract diagnostically important information, which until now has been unavailable with in vivo MRS. A clinical MRS signal illustrates the rapid and stable convergence provided by FPT[3], yielding accurate information about key metabolites and their concentrations at short acquisition times. We suggest that the next step would be to apply the FPT to in vivo MRS/MRSI signals from patients with breast cancer and to compare these to findings for normal breast tissue. The potential implications of such an optimized MRS/MRSI for breast cancer screening strategies are discussed, especially for younger women at high risk.

Background: Hyperthermia combined with radiation therapy was shown to be more effective in local recurrent breast cancer than radiotherapy alone, but it use is limited due to technical difficulties, stringent reimbursement policies and because it is time consuming.

Objectives: To report our experience with a simple and convenient XRT+HT[1] delivery system.

Methods: XRT was delivered through either electron or photon beams (total dose 30–40 Gy in previously irradiated fields or 50–70 Gy in non-irradiated fields). Hyperthermia was delivered by a dedicated HT device operating at 915 MHz. The heating session lasted 45 minutes. The maximal tumor surface temperature was set at 45°C and modified according to patient comfort. No intratumoral (invasive) thermometry was used. At least two HT sessions were scheduled to each HT field during the entire XRT treatment period. Tumor response was evaluated every 3 months after completion of treatment. The overall survival was measured from XRT+HT initiation until the last follow‑up.

Results: Fifteen women underwent 114 HT treatments delivered through 28 HT fields. Twenty-four HT fields (15 patients) were previously irradiated. There was complete infield response in 10 fields (6 patients), partial response in 8 fields (4 patients), no response or progressive disease in 4 fields (3 patients), and no parameters in 6 fields (5 patients). Eighteen (64%) fields had complete or partial response. Seven patients had outfield recurrence despite wide XRT+HT fields. Ulceration was the only major side effect (three patients, three fields).

Conclusions: The combined HT+XRT delivery system, with no invasive thermometry, is a simple and effective method for treating local recurrent breast cancer.