Malcolm M. Bilimoria

Axillary Recurrence After Sentinel Node Biopsy

BackgroundSentinel node biopsy (SNB) has evolved as the standard of care in the surgical staging of breast cancer. This technique is accurate for surgical staging of axillary nodal disease. We hypothesized that axillary recurrence after SNB is rare and that SNB may provide regional control in patients with microscopic nodal involvement.MethodsWith institutional review board approval, SNB was performed with peritumoral injection of 99mTc-labeled sulfur colloid. From 1996 to 2003, 1167 patients were entered into a prospective cancer database after surgical therapy; 916 patients consented to long-term follow-up. Fifty-two patients (5.7%) did not map successfully and were excluded, leading to a study population of 864 patients. The median follow-up was 27.4 months (range, 1–98 months).ResultsThe median number of sentinel nodes harvested was 2, and 633 (73%) patients had negative sentinel nodes. Thirty (4.7%) of those sentinel node–negative patients underwent completion axillary dissection, whereas 592 (94%) patients were followed up with observation. A total of 231 (27%) had positive sentinel nodes: 158 (68%) of these patients underwent completion axillary dissection, and 73 (32%) were managed with observation alone. Two (.32%) patients who were sentinel node negative had an axillary recurrence; one of these patients had undergone completion axillary dissection. No patient in the observed sentinel node–positive group had an axillary recurrence (odds ratio, .37; P = .725).ConclusionsOn the basis of a median follow-up of 27.4 months, axillary recurrence after SNB is extraordinarily rare regardless of nodal involvement, thus indicating that this technique provides an accurate measure of axillary disease and may impart regional control for patients with node-positive disease.

Effect of Hospital Volume on Margin Status after Pancreaticoduodenectomy for Cancer

BACKGROUND The volume-outcome relationship has been repeatedly demonstrated for pancreatectomy, but identifying underlying reasons for this association has been challenging. Some have suggested that differences in surgical technique may affect longterm survival, but it is unknown whether margin-positive resection rates vary by hospital volume. Our objective was to evaluate the effect of hospital pancreatectomy volume on margin status. STUDY DESIGN Patients who underwent pancreaticoduodenectomy for localized pancreatic adenocarcinoma were identified from the National Cancer Data Base (1998 to 2004). Regression modeling adjusting for patient, tumor, and hospital factors was used to assess predictors of margin involvement and to evaluate the effect of margin status on survival. Volume quintiles were based on average annual hospital pancreatectomy volume. RESULTS Of 12,101 patients, 24.4% had positive resection margins (14.6% microscopic/R1; 9.8% macroscopic/R2). From 1998 to 2004, there was not a significant change in margin-positive resection rates (p=0.43). On multivariable analysis, patients were more likely to have a margin-positive resection if they had a higher T classification or nodal involvement, were uninsured or living in lower-income areas, or underwent resection at lowest-volume hospitals compared with highest-volume hospitals (25.9% versus 22.6%, p < 0.0001; odds ratio, 1.21; 95% confidence interval, 1.01 to 1.43). On multivariable analysis, margin involvement was associated with a higher risk of longterm mortality compared with margin-negative resections (p < 0.0001). CONCLUSIONS Involved resection margins are a poor prognostic factor after a pancreaticoduodenectomy. Patients undergoing pancreaticoduodenectomy at low-volume centers are more likely to have margin-positive resections. Standardization of pathologic evaluation for pancreatectomy specimens is needed.

Estrogen Replacement Therapy and Breast Cancer: Analysis of Age of Onset and Tumor Characteristics

Background: The use of exogenous estrogen has been scrutinized as a risk factor for breast cancer formation. This prospective study addresses the relationship between the use of estrogen replacement therapy and the age of onset of breast cancer. In addition, an analysis of differences in pathological features of breast cancer between estrogen users and non-estrogen-users was evaluated.Methods: A total of 425 women (age, ≥ 50 years) were evaluated during a 4-year period (1994–1997). Data, including the age at diagnosis, method of detection, family history, use of estrogen therapy, and tumor ploidy, S-phase fraction, histological category, estrogen receptor positivity, and grade, were prospectively collected. Data from a control group of 657 women without a diagnosis of breast cancer were obtained from the Evanston Northwestern division of the Women’s Health Initiative. Significant associations between the use of estrogen and pathological parameters were determined using the χ2 test and t-test (P < .05).Results: At the time of breast cancer diagnosis, 140 patients were currently receiving estrogen and 202 patients had no history of estrogen use. Eighty-three patients were excluded from analysis (76 patients had a history of previous but not current use of estrogen therapy, four women used only progesterone, and three patients provided incomplete information). There was no difference between patients with breast cancer using estrogen at the time of diagnosis and those with no history of estrogen use with respect to tumor size, age of menopause, family history, mammographic sensitivity, axillary lymph node status, and histological features. Women using estrogen at the time of diagnosis were younger at the time of breast cancer diagnosis, by an average of 5.1 years (61.3 years vs. 66.4 years, P < .001). Women without a history of breast cancer who were receiving estrogen therapy were an average of 2.4 years younger (63.3 years vs. 65.7 years, P < .001) than women without a history of breast cancer who were not receiving estrogen therapy. Patients with breast cancer receiving estrogen also tended to have more grade II tumors (45.9% vs. 36.5%, P = .045) and fewer grade III tumors (25.6% vs. 37.0%, P =.015), compared with women not receiving estrogen therapy at the time of their diagnoses. Estrogen receptor positivity was noted to be more frequent for estrogen users presenting with lobular carcinoma (85% vs. 76%, P =.042) and less frequent for estrogen users presenting with ductal carcinoma (72% vs. 85%, P = .003).Conclusions: A significantly earlier age of diagnosis for women receiving estrogen therapy suggests that exogenous estrogen may accelerate the pathogenesis of postmenopausal breast cancer. Estrogen therapy may also play a role in altering the grade and estrogen receptor positivity for certain histological types of breast cancer.

The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival

BACKGROUND The goal of this study was to compare the characteristics of breast cancers and survival rates in HRT users versus nonusers. METHODS Data were analyzed for 1055 patients > or = 50 years of age who had definitive therapy for breast cancer from 1994 through 2002. RESULTS There were 471 (45%) HRT users. The median age at diagnosis was 61.0 years for HRT users and 68.0 years for HRT nonusers (P < .001). HRT users more often had tumors that were <1 cm (P = .007), node negative (P = .033), and grade I (P = .016). HRT users had a decreased risk of death versus nonusers (hazard ratio = .438, 95% confidence limit = .263 to .729, P = .002). CONCLUSIONS HRT users developed breast cancer at a younger age than nonusers; HRT use was associated with the development of biologically more favorable cancers than those that developed in nonusers; and overall and disease-free survival rates were higher in HRT users than nonusers.

Cloning and characterization of a 77-kDa oestrogen receptor isolated from a human breast cancer cell line

We have cloned and characterized a 77-kDa oestrogen receptor (ER) from an oestrogen-independent subclone of the MCF-7 human breast cancer cell line. This receptor contains an in-frame, tandem duplication of exons 6 and 7, located in the steroid-binding domain of the ER. This mutation has abrogated ligand binding, but not DNA binding, in this mutant ER. We previously described the partial structure of a unique oestrogen receptor (ER) that is expressed in an oestrogen-independent MCF-7:2A subclone of the breast cancer cell line MCF-7 (Pink JJ, Wu SQ, Wolf DM, Bilimoria MM, Jordan VC 1996a, Nucleic Acids Res 24 962-969). Sequence analyses determined the molecular weight of this 80-kDa ER to be 77 kDa, and hereafter this protein will be designated as ER77. Examination of the entire coding sequence of the ER77 mRNA indicates that it contains a tandem duplication of exons 6 and 7. Using a coupled transcription/translation system, a 77-kDa ER, which corresponds to the protein observed in the MCF-7:2A cells, was expressed. The ER77 protein does not bind the ligands [3H] oestradiol or [3H]tamoxifen aziridine. In DNA binding gel shift assays, the in vitro synthesized ER77 binds to a consensus vitellogenin A2 oestrogen-response element. In transient transfection experiments, the mutant ER, alone or in combination with the wild-type ER, does not induce expression of an oestrogen-responsive luciferase reporter construct. In fact, expression of the ER77 in the ER-positive T47D:A18 cell line inhibits E2-induced luciferase expression. Overexpression of wild-type ER in T47D:A18 cells leads to elevated constitutive expression of the luciferase reporter, which was inhibited by co-transfection with ER77. These data suggest that the ER77 can interfere with normal ER activity and does not act as a constitutive activator of oestrogen-independent growth in MCF-7:2A cells. Consequently, the constitutive growth observed in MCF-7:2A cells is probably the result of other ER-mediated pathways.

An analysis of tamoxifen-stimulated human carcinomas for mutations in the AF-2 region of the estrogen receptor

The estrogen receptor (ER) contains two transcriptional activation domains: AF-1 and AF-2. AF-2 is dependent on a highly species-conserved region of the ER. It has been shown that site-directed point mutations of conserved hydrophobic amino acids within this region reduce estrogen-dependent transcriptional activation. In addition, when these mutated ERs are transfected into HeLa cells, both tamoxifen and ICI 164,384 become strong agonists. The implication is that mutations in this region could account for the tamoxifen-stimulated tumors seen clinically. We performed single stranded conformational polymorphism (SSCP) analysis spanning the entire ER along with DNA sequencing of the AF-2 region of the ER isolated from two different tamoxifen-stimulated breast cancers, MCF-7/TAM and MCF-7/MT2, and a tamoxifen-stimulated endometrial cancer, EnCa 101. In addition, a tamoxifen-stimulated endometrial carcinoma cell line, the Ishikawa cell line, was also studied. There were no mutations found by SSCP analysis and sequencing of all four AF-2 regions also revealed no mutations. Mutations within the AF-2 region of the human ER do not appear to account for the growth of human breast and endometrial carcinomas that are used as reproducible laboratory models of tamoxifen-stimulated growth observed clinically.

Coil embolization of a lumbar artery to control vascular injury during intradiscal surgery.

Study Design. Case study. Objective. To emphasize the role that interventional radiology can perform in stemming bleeding to vascular structures injured during spine surgery without altering patient position. Summary and Background Data. Injury to the lumbar artery or aorta may occur during lumbar disc surgery. Occasionally the site of bleeding may not be readily identifiable or accessible through the surgical incision. Interventional radiology techniques may be employed to help locate and stop these difficult to locate vascular structures without changing a patient position. Methods. A 48-year-old woman undergoing L4-L5 lumbar hemilaminectomy and discectomy secondary to a herniated disc sustained an injury to a right L3 lumbar artery. Several liters of blood were lost in an attempt to surgically locate and repair the injury to the lumbar artery. A literature search identified the potential severity and treatment options. Results. An interventional radiologist was called for and he was able to angiographically locate the source of bleeding and stem its source using coil embolization of the lumbar artery. Conclusion. Whenever there is bleeding from an inaccessible site, consultation with an interventional radiologist to perform an intraoperative coil embolization of the injured vessel should be done especially if a resort to an anterior abdominal approach would permit uncontrolled bleeding.

Is it time to develop an optimal endocrine therapy for premenopausal patients with axillary node positive and negative breast cancer

One hundred years ago ovarian ablation was shown to be an effective treatment for advanced breast cancer in premenopausal women. Since that time many different treatment modalities have been advocated to improve patient survival. The value of adjuvant ovarian ablation, however, has recently been established in the overview of breast cancer clinical trials. In fact, comparison of the efficacy of combination chemotherapy with earlier trials of oophorectomy demonstrate the superiority of oophorectomy. The effectiveness of chemotherapy may largely be the result of partial ovarian ablation produced in premenopausal patients. Based on this position, we propose a clinical trial that would establish the optimal therapy for premenopausal breast cancer. In addition, the beneficial effects of long-term tamoxifen as it pertains to serum lipids and bone density are highlighted. The use of tamoxifen maintenance in oophorectomized women might provide an optimal therapy for the control of breast cancer recurrence.