Itzhak Pappo

The Possible Association between IVF and Breast Cancer Incidence

BackgroundThe possible association between ovulation-inducing drugs and breast cancer development has been debated. Our aim was to evaluate the incidence of breast cancer in a cohort of women exposed to in vitro fertilization (IVF).MethodsA retrospective cohort analysis was performed by linkage of the computerized database of all women treated at the IVF Unit at Assaf Harofeh Medical Center between 1986 and 2003, and the Israeli National Cancer Registry. The standardized incidence ratio (SIR) was computed as the ratio between the observed number of breast cancer cases and the expected cases, adjusted for age and continent of birth, in the general population. Tumor characteristics of the IVF patients were studied by reviewing original medical records.Results35 breast carcinomas were diagnosed among 3,375 IVF-treated women, compared to 24.8 cases expected (SIR = 1.4; 95% CI 0.98–1.96). Age ≥40 years at IVF treatment (SIR = 1.9; 95% CI 0.97–3.30), hormonal infertility (SIR = 3.1; 95% CI 0.99–7.22), and ≥4 IVF cycles (SIR = 2.0; 95% CI 1.15–3.27) were found to be risk factors to develop breast cancer compared to the general population. Multivariate analysis revealed that women who underwent ≥4 IVF cycles compared to those with one to three cycles were at risk to develop breast cancer, although not significantly (SIR = 1.9; 95% CI 0.95–3.81). Of IVF-treated women 85% had ER(+) tumors and 29% had positive family history.ConclusionsA possible association between IVF therapy and breast cancer development was demonstrated, especially in women ≥40 years of age. These preliminary findings need to be replicated in other cohort studies.

Intracellular esterase activity in living cells may distinguish between metastatic and tumor-free lymph nodes

Background One of the major clinical problems in breast cancer detection is the relatively high incidence of occult lymph node metastases undetectable by standard procedures. Since the ascertainment of breast cancer stage determines the following treatment, such a “hypo-diagnosis” leads to inadequate therapy, and hence is detrimental for the outcome and survival of the patients. The purpose of our study was to investigate functional metabolic characteristics of living cells derived from metastatic and tumor-free lymph nodes of breast cancer (BC) patients. Methods Our methodology is based on the ability of living cells to hydrolyze fluorescein diacetate (FDA) by intracellular esterases and on the association of FDA hydrolysis rates with a specific cell status, both in physiological and pathological conditions. Results The present study demonstrates a significant difference in the ability to utilize FDA by lymph node cells derived from metastatic and tumor-free lymph nodes in general average, as well as in the metastatic and tumor-free lymph nodes of individual patients. Cells from metastatic lymph nodes had a higher capacity for FDA hydrolysis, and increased this activity after additional activation by autologous tumor tissue (tt). The association between increased FDA hydrolysis rate and activated T lymphocytes and antigen-presenting cells (APC) was shown. Conclusion The results of the present study may contribute to predicting the risk of involvement of seemingly “tumor-free” axillary lymph nodes in occult metastatic processes, and to reducing false-negative results of axillary examination.

Mondor's Disease of the Axilla: A Rare Complication of Sentinel Node Biopsy

Abstract:  Three cases of Mondors disease of the axilla following sentinel lymph node biopsy (SLNB) are described. In all cases we used the combination of blue dye and radiocolloid, and complete axillary dissection was not performed. The numbers of lymph nodes removed in each case were five, four, and two, respectively. All the events of Mondors disease resolved spontaneously or following a short therapy of anti‐inflammatory agents.

Cecal Diverticulitis: A Diagnostic Challenge

Background: Cecal diverticulitis is frequently indistinguishable from acute appendicitis preoperatively and is sometimes mistaken for carcinoma at laparotomy. The surgeon must be aware of the possibility of diverticulitis of the cecum in the operating room and choose the appropriate treatment. Purpose: Because there is no universal therapeutic approach to these patients, we decided to assess the presenting symptoms, clinical findings, preoperative diagnosis, operative findings determining the proper management of these patients. Methods: A retrospective chart review of 13 patients with pathologically confirmed cecal diverticulitis, who underwent surgery in our department from 1984 to 1998, was undertaken. Results: The mean age of patients was 43.5 years. Right lower quadrant pain and local tenderness were the only clinical findings in 92.3%, with preoperative diagnosis of acute appendicitis in 84.6% of patients. The operative finding in most cases was inflammatory mass of the cecum; in 6 cases it was indistinguishable from perforated cecal carcinoma. Six patients underwent right hemicolectomy, 5 had ileocecectomy, 1 patient was treated by tube cecostomy, and 1 had diverticulectomy. There were three minor postoperative complications: pneumonia, wound infection and lower limb superficial thrombophlebitis. Conclusions: Cecal diverticulitis needs a high index of suspicion for achieving a preoperative diagnosis. We suggest that the operative therapy should be ileocecectomy. The surgical specimen should be examined during surgery and only if carcinoma is found should the patient have a formal colectomy.

The characteristics of malignant breast tumors in hormone replacement therapy users versus nonusers.

BackgroundThe purpose of this study was to investigate the characteristics of breast cancer in hormone replacement therapy (HRT) users vs. nonusers.MethodsWe investigated the characteristics of all patients between the ages of 50 and 75 years with breast tumors. Then, an age-adjusted group of 55 nonusers was chosen to match and compare with HRT users.ResultsOf the 243 patients available for evaluation, 55 (22.6%) used HRT. Disease stages in HRT users vs. nonusers were as follows: ductal carcinoma in situ (DCIS), 20% and 17.1%; stage I, 45.5% and 41.7%; stage II, 30.9% and 26.2%; stage III, 3.6% and 13.4%; and stage IV, 0% and 1.6% (P=.27). In the age-adjusted cohort, stages in nonusers were as follows: DCIS, 7.3%; stage I, 47.3%; stage II, 25.5%; stage III, 20%; and stage IV, 0% (P=.03). Tumor grades in HRT users vs. nonusers were as follows: grade I, 30.4% and 15.7%; grade II, 52.2% and 52.2%; and grade III, 17.4% and 32.1% (P=.035). Grades in cohort nonusers were as follows: I, 13.2%; II, 52.8%; and III, 34% (P=.05). In the invasive tumors, the positive estrogen receptor (ER) rates were 81.6% and 85.7% (P=.89); positive progesterone receptor (PR) rates were 53.1% and 54% (P=.95); and Her 85.7% (P=.89); positive progesterone receptor (PR) rates were 53.1% and 54% (P=.95); and Her 2-neu positive rates were 18.4% and 17.6% (P=.95), respectively. No significant difference was found in intratumor DCIS, vascular invasion, and Ki-67 (P=.14, .9, and .79, respectively). The rate to lobular and favorable histological types was higher in the HRT user group: 26.6% vs. 15%.ConclusionsBreast tumors in HRT users vs. nonusers were of a significantly lower stage and grade and accounted for a higher number of favorable histological types, but all other parameters were similar in the two groups.

Tissue specific DNA methylation in normal human breast epithelium and in breast cancer.

Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.

A similar cell-specific pattern of HOXA methylation in normal and in cancer tissues.

HOX genes are developmental genes that determine anterior–posterior embryonic pattern and govern the process of differentiation. Inappropriate expression of HOX genes has been implicated in developmental abnormalities and hematopoietic malignancies. In addition, HOX genes silencing by DNA methylation has been reported in cancers and related to disease aggressiveness and outcome. On the other hand, accumulating evidence suggests that epigenetic changes at HOX genes are linked to normal development and differentiation. To better understand the relationship between HOXA methylation and cancer, we analyzed the methylation pattern of HOXA genes in human primary breast and colon carcinomas, normal tissues and normal white blood cells. Genome-wide methylation arrays of breast cancers and white blood cells demonstrated similar methylation patterns. Quantitative methylation analysis of seven representative HOXA genes revealed various levels of methylation in both normal tissues and cancers. Analysis of epithelial-enriched normal breast tissue and stroma indicated that the stroma was the major origin of HOXA methylation. Furthermore, in selected dense breast cancers, minimal increase in methylation of several HOXA genes did not correlate with the predominance of malignant epithelial cells in these tumors. Our results suggest that methylation of the HOXA cluster may be a normal developmental and cell type specific process rather than a cancer specific mechanism.

Indication for relumpectomy—a useful scoring system in cases of invasive breast cancer†

In two‐thirds of breast cancer patients undergoing reoperation no residual tumor will be found. A scoring system for selection of patients who might benefit from relumpectomy is proposed.

The Usefulness of MIBI Scanning to Detect Underlying Carcinoma in Women with Acute Mastitis.

Abstract: The efficacy of Tc‐99m sestamibi scintimammography in the detection of breast carcinoma has been proven in previous studies. In this study we evaluated the influence of active mammary inflammation on Tc‐99m sestamibi scintimammography and its ability to detect breast malignancy in the presence of this condition. Twenty‐one women with acute nonpuerperal mastitis underwent breast scintimammography using Tc‐99m sestamibi. Their mean age was 49.6 years. In 15 women the scan was positive, 2 suffered from inflammatory carcinoma of the breast, and all the other women had acute mastitis. Six patients had a negative scan, and in all of them, acute mastitis was diagnosed. Total accuracy, sensitivity and specificity in the detection of breast mastitis were 62%, 68%, and 88%, respectively. Scintimammography in patients with acute inflammation of the breast is frequently positive in the absence of malignant condition, therefore it should not be used during acute mastitis for the detection of breast cancer.

Gastrointestinal carcinomas occurring in breast cancer patients.

Abstract:  Breast cancer patients are reported to have a higher rate of second primary malignancies. We retrospectively reviewed the coexistence of breast and gastrointestinal (GI) tumors in the same patients and the characteristics of the tumors. The charts of all patients more than 35 years of age who were diagnosed with breast cancer and hospitalized for various reasons between 1985 and 2003 were reviewed and those who also had a diagnosis of GI malignancy were then selected. Age and tumor characteristics were evaluated. Out of all the patients, 2650 had a diagnosis of breast cancer, while 40 (1.5%) also had GI malignancies. Among a comparable group of 70,784 consecutive female patients without breast cancer, 1292 patients (1.8%) had a diagnosis of GI malignancy. The location of GI tumors in patients with both tumors was as follows: stomach, 6 (15%); right colon, 8 (20%); left colon, 7 (17.5%); sigma, 9 (22.5%); and rectum, 10 (25%). Seventeen of the patients (51.5%) had Dukes C and D tumors, 14 (42.5%) Dukes B, and 2 (6%) Dukes A or in situ. The stage of the others was not identified. The mean age at diagnosis of breast cancer was 68.5 years (range 48–88 years). In 23 (57.5%), GI cancer was diagnosed after breast cancer, in 7 (17.5%) it was diagnosed within 3 months of diagnosing breast cancer, and in 8 (20%) it was diagnosed prior to the diagnosis of breast cancer. Five patients suffered from an additional primary cancer: three endometrial, one lung, one esophageal, and one patient had two additional tumors in the endometrium and thyroid. We conclude that the rate of GI malignancies in breast cancer patients is slightly lower than in comparable patients without breast cancer. GI malignancies tend to be diagnosed later and are found more often in the distal colon.