Faculty Bibliography

HYPOTHESIS: The changes reported with pulse oximetry after the injection of isosulfan blue for sentinel lymph node identification in patients with breast cancer are consistent and predictable. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS AND METHODS: The complete anesthesia records of 92 patients who underwent sentinel lymph node biopsy with intraparenchymal injection of isosulfan blue were reviewed. The study extended from January 1999 to February 2000. The operations were all performed after the patient received general anesthesia. We injected 5 mL of isosulfan blue into the breast tissue surrounding the tumor. The data reviewed included preinjection pulse oximeter saturation readings and postinjection values continuing until the readings returned to baseline levels in the postanesthesia care unit. MAIN OUTCOME MEASURES: Changes in oxygen saturation readings with the pulse oximeter before and after injection of isosulfan blue. RESULTS: Isosulfan blue injection interfered with pulse oximeter measurements for a substantial time-as much as 195 minutes. The mean time to the maximum change in the pulse oximeter reading was 35 minutes. The median decrease in oxygen saturation was 5%. The maximum decrease in the pulse oximeter reading was 11%. CONCLUSIONS: Although the changes in pulse oximeter readings can be substantial, their course appears to be predictable, and therefore in most otherwise healthy patients with normal pulmonary function, invasive monitoring is not necessary

Disparities in breast cancer survival have been observed between African American and white women. There are also known differences in mean baseline white blood cell (WBC) count among racial and ethnic groups. If the WBC count falls below conventionally defined treatment thresholds for patients undergoing adjuvant chemotherapy, reduced doses or treatment delays may occur, which could lead to race-based differences in treatment duration. We used the tumor registry at Columbia-Presbyterian Medical Center to identify 1178 women with newly diagnosed stage I and II breast cancer from whom we collected base-line information for 73 African American women and 126 age- and tumor stage-matched white women. Of these women, 43 African American and 93 white women underwent adjuvant chemotherapy. African American women had statistically significantly lower WBC counts than white women at diagnosis (6.2 x 10(9)/L for African American women versus 7.4 x 10(9)/L for white women, difference = 1.2, 95% confidence interval [CI] = 0.2 to 1.2; P =.02) and after treatment (5.3 x 10(9)/L for African American women versus 6.4 x 10(9)/L for white women, difference = 1.1, 95% CI = 0.2 to 2.5; P =.03). Overall, African American women required a statistically significantly longer duration of treatment than white women (19 weeks versus 15 weeks, respectively, difference = 4 weeks, 95% CI = 0.5 to 7.2 weeks; P =.03). The lower baseline WBC counts and longer duration of treatment for early-stage breast cancer in African American women compared with those in white women result in lower dose intensity of treatment for African American women, possibly contributing to observed racial differences in breast cancer survival

BACKGROUND: The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC). METHODS: Thirty-six patients with MBC were treated with estramustine 900 mg/m(2) per day divided into 3 doses given on Days 1-3 and docetaxel 70 mg/m(2) given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC. RESULTS: Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14-48%). The median progression free survival was 4 months (range, 1-41 months), and the median overall survival was 17 months (range, 2-45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life. CONCLUSIONS: The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) are serious complications of chemotherapy and radiotherapy for cancer. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may be associated with an increased incidence of these complications. The frequency of t-MDS/AML after ASCT for breast cancer is uncertain. We reviewed our database of 379 consecutive breast cancer ASCT patients treated with alkylator-based chemotherapy, followed for a median of 1.52 years (range 0-8.97), with a median survival of 6.16 years. Three patients have developed tMDS/AML. The probability of developing this complication at 5 years is 0.032 in our series. We have used pathologic, cytogenetic and molecular methods to evaluate which portions of therapy may have predisposed to the development of this complication. Cytogenetic abnormalities were not found in the stem cell harvests of these patients by metaphase analysis or by fluorescence in situ hybridization (FISH). One patient demonstrated a clonal X chromosome inactivation pattern in her stem cell harvest, indicating pre-transplant chemotherapy may have been responsible for the development of her leukemia. As two of our patients developed this complication at greater than 4 years post-transplant, the number of cases may increase with longer follow-up. While the incidence appears to be low, further prospective and retrospective analysis will be necessary to determine which portions of therapy predispose to the development of t-MDS/AML in patients undergoing ASCT for treatment of breast cancer.

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease

This article reviews existing approaches for joint analysis of longitudinal measurements, possibly measured with error or incompletely observed, and event-time data, possibly censored. The models take the form of selection or pattern-mixture models; estimation proceeds via the EM algorithm or Bayesian sampling techniques. The models are compared, their estimation and inferential procedures described, and advantages and disadvantages noted. Examples are discussed from several disease areas, including cancer and AIDS.

LINE-1 (L1) elements play an important creative role in genomic evolution by distributing both L1 and non-L1 DNA in a process called retrotransposition. A large percentage of the human genome consists of DNA that has been dispersed by the L1 transposition machinery. L1 elements are not randomly distributed in genomic DNA but are concentrated in regions with lower GC content. In an effort to understand the consequences of L1 insertions, we have begun an investigation of their genomic characteristics and the changes that occur to them over time. We compare human L1 insertions that were created either during recent human evolution or during the primate radiation. We report that L1 insertions are an important source for the creation of new microsatellites. We provide evidence that L1 first strand cDNA synthesis can occur from an internal priming event. We note that in contrast to older L1 insertions, recent L1s are distributed randomly in genomic DNA, and the shift in the L1 genomic distribution occurs relatively rapidly. Taken together, our data indicate that strong forces act on newly inserted L1 retrotransposons to alter their structure and distribution.

BACKGROUND: Identification of reliable predictors of axillary metastases (ALNM) may be useful in selecting appropriate management for patients with T1-size breast cancer. This study was undertaken to determine the degree of correlation between ALNM and several variables, including age, race, menopausal status, palpability, tumor size, positive margin on initial excision, histology, grade, lymphatic invasion (LI), estrogen receptor status (ER), progesterone receptor status, S-phase, and ploidy. METHODS: Data from 1416 patients with T1 breast cancers treated at Columbia-Presbyterian Medical Center between 1989 and 1998 was reviewed. Patients with multifocal tumors were excluded. RESULTS: Mean patient age was 57.5 years (SD = 12.0); 65% of the patients were postmenopausal. One hundred thirty-one patients with Tla (< or =0.5 cm), 435 with T1b (0.6-1.0 cm), and 850 patients with T1c (1.1-2.0 cm) lesions were studied. The overall rate of ALNM was 23%. AM was identified in 11% of T1a, 15% of T1b, and 29% of T1c patients. Statistically significant factors from univariate analysis were age, palpability, skin changes, tumor size, LI, histology, grade, ER status, and positive margin on initial excision. CONCLUSIONS: Axillary staging by either sentinel lymph node biopsy or level I/II axillary dissection is indicated for most T1 breast cancer patients. Omission of axillary staging can be considered for highly selected patients with T1a cancers.

PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

PURPOSE: We evaluated the pharmacokinetics and pharmacodynamics of high-dose paclitaxel (HDP) monotherapy (825 mg/m2 continuous infusion over 24 h) with peripheral blood progenitor cell (PBPC) and G-CSF support in 17 women with metastatic breast cancer. METHODS: Pharmacokinetic and pharmacodynamic data were collected in 17 women entered in a phase II trial of sequential HDP, and high-dose melphalan and cyclophosphamide/thiotepa/carboplatin. RESULTS: The maximal plasma concentration (Cmax), area under the plasma concentration time curve (AUC), apparent clearance (Clapp), duration of plasma concentration above 0.05 microM (t > 0.05 microM) for paclitaxel were (means SD): 9.11 +/- 7.45 microM, 145 +/- 88 microM x h, 8.06 +/- 2.90 l/h per m2 and 82.4 +/- 31.2 h, respectively. There was a significant correlation between the plasma paclitaxel concentration at 1 h (r2 = 0.87), 12 h (r2 = 0.85) and 23 h (r2 =0.92) and the AUC (P < 0.0001). Duration of neutropenia was brief (median 3 days, range 0-5 days) and neutrophil recovery occurred earlier (median 6 days, range 0-7 days) than could be attributed to infused PBPC. Median nadir count for platelets was 66 x 10(9)/l (range 13-160 x 10(9)/l). Pharmacodynamic analysis showed no correlation between pharmacokinetic parameters (Cmax, AUC, t > 0.05 microM) and time to neutropenic nadir, duration of neutropenia, platelet count nadir and grades of neuropathy or mucositis. In ten patients in whom detailed neurologic and nerve conduction studies were performed, linear regression analysis showed a significant correlation between pre- and post-HDP treatment total neuropathy scores (r2 = 0.46, P = 0.03). CONCLUSIONS: HDP (825 mg/m2 continuous infusion over 24 h) did not appear to be myeloablative. The degree of neurotoxicity subsequent to HDP was associated with the degree of baseline neuropathy but was not predictable from pharmacokinetic parameters.