Faculty Bibliography

The organochlorines, dichloro-diphenyl-trichloroethane and polychlorinated biphenyl (PCB) are pervasive environmental contaminants. Results from previous studies have been conflicting regarding the relationship between the internal dose of these organochlorine residues and breast cancer risk. To determine whether these compounds are present in breast cyst fluids and whether cyst fluid and plasma concentrations are correlated, we analyzed organochlorines in paired cyst fluid and plasma samples from 24 subjects using gas chromatography and electron capture detection. All but one of the women had a history of multiple cysts, suggesting that they were at elevated risk for future breast cancer. DDE (a metabolite of dichloro-diphenyl-trichloroethane) was present in 22 of the cyst samples and PCB was detected in 19 of the cyst samples. Organochlorine levels were more concentrated in the plasma than in breast cyst fluids. Levels of DDE in plasma were significantly correlated with those in cyst fluid (r = 0.73; P < 0.001); in contrast to PCB levels in cyst and plasma (r = 0.37; P = 0.12). Congener specific analysis of the PCBs showed that some individual congeners were preferentially excluded from or concentrated in the cyst fluid. To our knowledge, this study is the first to demonstrate that PCB and DDE are present in cyst fluids and thus in contact with the ductal epithelium of the breast. These results support the use of plasma DDE as a proxy for DDE in the target tissue in research on the role of environmental factors in breast cancer.

The risk of development of breast lesions in patients on chronic immunosuppression is unknown. In order to assess this risk, a retrospective review was performed of the records of 87 women between the ages of 12 and 47 years who received thoracic organ transplant from 1987 to 1996 at our institution. Inclusion criteria consisted of patients who were premenopausal, had no previous history of breast disease, and survived for at least 1 year posttransplantation. All patients were on a triple immunosuppressive regimen consisting of cyclosporine, steroids, and azathioprine. Mean follow-up was 4 +/- 1.2 years with a range of 1-6 years. During this period, 21 patients (24%) with a mean age of 38 +/- 10 years had screening or diagnostic mammography. The remainder of patients with a mean age of 24 +/- 9 years were followed clinically. Overall, 10 patients (11%) developed a total of 17 palpable, solid lesions at 33 to 72 months posttransplantation. Fifteen of these lesions were surgically excised. Five of the patients had multiple lesions. Pathological examination of the specimens revealed fibroadenoma in nine, fibrocystic disease in four, low grade phylloides tumor in one, and T-cell lymphoma in one case. None of the patients have developed primary breast cancer during follow-up. In conclusion, short-term immunosuppression does not increase the risk of the development of benign breast lesions in young women after thoracic organ transplantation, but rather the distribution of benign lesions is similar in an age-matched population. There were several cases of multiple fibroadenomas in the transplant population, but mammography revealed no malignant disease in this age group and does not need to be utilized in this population beyond what is considered standard for immunocompetent patients. The long-term effect ofimmunosuppressive therapy on the developmentof breast cancer in this group remains to be defined.

Immediate breast reconstruction for patients with early-stage disease is well established. This study evaluates a consecutive series of 22 patients with locally advanced disease (stage IIB or III) who underwent mastectomy and immediate breast reconstruction. All patients received several cycles of neoadjuvant chemotherapy (average, 3.5 cycles) followed by completion of chemotherapy beginning approximately 3 weeks following surgery. The perioperative morbidity was 14% and no patient suffered a delay in the resumption of chemotherapy. Patients have been particularly grateful about being offered reconstruction in this setting. Our preliminary results with this technique have been encouraging and further study is warranted.

Alterations in renal prostaglandin production have recently been postulated to modulate the decrease in renal blood flow associated with cyclosporine nephrotoxicity. In particular, increases in renal production of the potent vasoconstrictor thromboxane A2 have been implicated in the pathogenesis of this disorder. The present study was undertaken to explore the relationship between alterations in urinary thromboxane B2 excretion (UTxB2V) and CsA nephrotoxicity in two rat models. Male Sprague-Dawley (SD) rats were treated for 14 days with CsA 50 mg/kg/day (n = 8) or olive oil (C) (n = 9) by gavage. Creatinine clearance (Ccr), urine flow (V), and urinary excretion rates of sodium, N-acetyl-beta-D-glucosaminidase (NAG), glucose, and TxB2 were determined before and after treatment. A similar study was conducted using Fischer rats (CsA: n = 10, C: n = 13). In Fischer rats, CsA caused a 35% decrease in Ccr (P = 0.01), a 33% decrease in sodium excretion (P = 0.02), and a greater than 2-fold increase in NAG excretion (P = 0.03), while V, glucose excretion, and UTxB2V did not change. Although similar changes in sodium and NAG excretion were seen after CsA administration in SD rats, Ccr was not affected. Additional findings in SD rats included a 3-fold increase in V (P less than 0.01), a 24-fold increase in glucose excretion (P = 0.03), and a 5-fold increase in UTxB2V (P = 0.04). Thus, Fischer rats developed CsA nephrotoxicity in the absence of increased UTxB2V. In contrast, SD rats failed to develop nephrotoxicity despite a marked increase in UTxB2V. We conclude that changes in renal TxA2 production are unrelated to the development of CsA nephrotoxicity

The renal dysfunction associated with liver disease appears to be caused by decreased renal perfusion. Altered renal vascular reactivity (RVR) may contribute to the development of decreased renal blood flow. This study was undertaken to assess the effect of bile duct ligation (BDL) on RVR to norepinephrine and angiotensin II in the rat and to evaluate the role of prostaglandins in the modulation of altered RVR. Male Sprague-Dawley rats underwent either sham operation (SO) or BDL. Four days later, isolated kidney perfusions were established. Dose-response curves to norepinephrine (SO, n = 9; BDL, n = 10) and angiotensin II (SO, n = 7; BDL, n = 9) were obtained. The perfusate was modified to contain indomethacin, 10(-6) mol/L, and dose-response curves to norepinephrine (SO, n = 10; BDL, n = 8) and angiotensin II (SO, n = 4; BDL, n = 8) were obtained as well. Baseline resistances did not differ between any of the groups. RVR to norepinephrine did not appear to be altered by BDL; however, increased RVR to norepinephrine was unmasked by inhibition of prostaglandin synthesis. BDL did not affect the RVR to angiotensin II with or without indomethacin. BDL is associated with an increase in renal vascular sensitivity to norepinephrine, which is balanced by a compensatory increase in renal prostaglandin activity in response to norepinephrine stimulation. These findings are consistent with theories that decreased renal perfusion associated with liver disease may be mediated by catecholamines