Anthony Lucci

Surgical Complications Associated With Sentinel Lymph Node Biopsy: Results From a Prospective International Cooperative Group Trial

BackgroundAmerican College of Surgeons Oncology Group Z0010 is a prospective multicenter trial designed to evaluate the prognostic significance of micrometastases in the sentinel lymph nodes and bone marrow aspirates of women with early-stage breast cancer. Surgical complications associated with the sentinel lymph node biopsy surgical procedure are reported.MethodsEligible patients included women with clinical T1/2N0M0 breast cancer. Surgical outcomes were available at 30 days and 6 months after surgery for 5327 patients. Patients who had a failed sentinel node mapping (n = 71, 1.4%) or a completion lymph node dissection (n = 814, 15%) were excluded. Univariate and multivariate analyses were performed to identify predictors for the measured surgical complications.ResultsIn patients who received isosulfan blue dye alone (n = 783) or a combination of blue dye and radiocolloid (n = 4192), anaphylaxis was reported in .1% of subjects (5 of 4975). Other complications included axillary wound infection in 1.0%, axillary seroma in 7.1%, and axillary hematoma in 1.4% of subjects. Only increasing age and an increasing number of sentinel lymph nodes removed were significantly associated with an increasing incidence of axillary seroma. At 6 months, 8.6% of patients reported axillary paresthesias, 3.8% had a decreased upper extremity range of motion, and 6.9% demonstrated proximal upper extremity lymphedema (change from baseline arm circumference of >2 cm). Significant predictors for surgical complications at 6 months were a decreasing age for axillary paresthesias and increasing body mass index and increasing age for upper extremity lymphedema.ConclusionsThis study provides a prospective assessment of the sentinel lymph node biopsy procedure, as performed by a wide range of surgeons, demonstrating a low complication rate.

Circulating tumour cells in non-metastatic breast cancer: a prospective study

BACKGROUND The identification of circulating tumour cells correlate with poor prognosis in metastatic breast cancer, but there are few data describing the importance of circulating tumour cells in patients with non-metastatic disease. Our aim was to establish if circulating tumour cells predicted worse outcome in patients with non-metastatic breast cancer. METHODS We prospectively collected data on circulating tumour cells at the time of definitive surgery from chemonaive patients with stage 1-3 breast cancer from February, 2005, to December, 2010. We deemed eligible all patients with operable breast cancer presenting at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients were ineligible if they had bilateral breast cancer or any other malignancy within 5 years of the diagnosis of the present cancer. We measured circulating tumour cells with the CellSearch System (Veridex, Raritan, NJ). We correlated findings of circulating tumour cells with standard tumour characteristics, including tumour size and grade; oestrogen and progesterone receptor and human epidural growth factor receptor 2 (HER2) status; and axillary lymph node status with χ(2) or Fisher exact tests. We assessed outcomes at a median follow-up of 35 months. Log-rank test and Cox regression analysis was applied to establish the association of circulating tumour cells with progression-free and overall survival. FINDINGS No patients reported adverse events or complications from blood collections. We identified one or more circulating tumour cells in 73 (24%) of 302 patients. Detection of one or more circulating tumour cells predicted both decreased progression-free survival (log-rank p=0·005; hazard ratio [HR] 4·62, 95% CI 1·79-11·9) and overall survival (log-rank p=0·01; HR 4·04, 1·28-12·8). INTERPRETATION The presence of one or more circulating tumour cells predicted early recurrence and decreased overall survival in chemonaive patients with non-metastatic breast cancer. These results suggest that assessment of circulating tumour cells might provide important prognostic information in these patients. FUNDING Society of Surgical Oncology, Morgan Welch Inflammatory Breast Cancer Program, The University of Texas MD Anderson Cancer Center, and the State of Texas Rare and Aggressive Breast Cancer Research Program.

Agents that Reverse Multidrug Resistance, Tamoxifen, Verapamil, and Cyclosporin A, Block Glycosphingolipid Metabolism by Inhibiting Ceramide Glycosylation in Human Cancer Cells

We have previously shown that multidrug-resistant cancer cells display elevated levels of glucosylceramide (Lavie, Y., Cao, H., Bursten, S. L., Giuliano, A. E., and Cabot, M. C. (1996) J. Biol. Chem. 271, 19530-19536). In this study we used the multidrug-resistant human breast cancer cell line MCF-7-Adriamycin-resistant (AdrR), which exhibits marked accumulation of glucosylceramide compared with the parental MCF-7 wild type (drug-sensitive) cell line, to define the relationship between glycolipids and multidrug resistance (MDR). Herein it is shown that clinically relevant concentrations of tamoxifen, verapamil, and cyclosporin A, all circumventors of MDR, markedly decrease glucosylceramide levels in MCF-7-AdrR cells (IC50 values, 1.0, 0.8, and 2.3 μM, respectively). In intact cells, tamoxifen inhibited glycosphingolipid synthesis at the step of ceramide glycosylation. In cell-free assays for glucosylceramide synthase, tamoxifen (1:10 molar ratio with ceramide) inhibited glucosylceramide formation by nearly 50%. In cell cultures, inhibition of glucosylceramide synthesis by tamoxifen is correlated with its ability to sensitize MCF-7-AdrR cells to Adriamycin toxicity. Moreover, treatment of cells with 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthesis, likewise sensitized MCF-7-AdrR cells to Adriamycin. It is concluded that high cellular levels of glucosylceramide are correlated with MDR, and that glycolipids are a target for the action of MDR-reversing agents such as tamoxifen. The data entertain the notion that drug resistance phenomena are aligned with cell capacity to metabolize ceramide.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment

BACKGROUND Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Inflammatory Breast Cancer: The Disease, the Biology, the Treatment

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBCs unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy. CA Cancer J Clin 2010.

Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.

Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. Clin Cancer Res; 18(24); 6758–70. ©2012 AACR.

Validation of a breast cancer nomogram for predicting nonsentinel lymph node metastases after a positive sentinel node biopsy

BackgroundAlthough completion lymph node dissection (CLND) is the standard of care for breast cancer patients with sentinel lymph node (SLN) metastases, the SLN is the only node with tumor in 40% to 60% of cases. To assist with decision-making regarding CLND, investigators at Memorial Sloan-Kettering Cancer Center devised and validated a nomogram for predicting the likelihood of non-SLN metastases. To assess the generalizable use of this nomogram, validation analysis was performed by using an external database.MethodsEight clinicopathologic variables for 200 consecutive breast cancer patients at the University of Texas M. D. Anderson Cancer Center with SLN metastases and CLND were entered into the nomogram. The accuracy of the nomogram to predict non-SLN metastases was assessed by the receiver operating characteristic (ROC) curve and linear regression analysis. The accuracy of the nomogram with touch-imprint cytology (TIC) as a substitute variable for frozen section was also evaluated.ResultsThe linear correlation coefficient of the nomogram-predicted probabilities correlated with the observed incidence of non-SLN metastases for all patients (.97). The accuracy of the nomogram as measured by the area under the ROC curve was .71. When applied solely to patients who had TIC assessment of the SLN, the area under the ROC curve was .74.ConclusionsThis study validated the Memorial Sloan-Kettering Cancer Center breast cancer nomogram by using an external database. TIC seems to be an acceptable substitute for frozen section as a nomogram variable. The nomogram may help predict an individual’s risk of non-SLN metastases and assist in patient decision making regarding the benefit of CLND.

Factors influencing career choice among medical students interested in surgery

PURPOSE The number of applicants to general surgery programs has recently declined. We set out to determine factors that influence career choice among medical students. METHODS DESIGN survey; SETTING university medical center; PARTICIPANTS fourth-year medical students; INTERVENTION distribution and completion of the survey. PARTICIPANTS ranked 18 items coded on a Likert scale from 1 (not important) to 8 (very important). These factors were career opportunities, academic opportunities, experience on core rotation/subinternship, role model(s) in that specialty (mentors), length of training required, lifestyle during residency, work hours during residency, ability to obtain residency position, concern about loans/debt, call schedule, lifestyle after training, work hours after training, financial rewards after training, intellectual challenge, patient relationships/interaction, prestige, future patient demographics, and gender distribution in the specialty. Students were asked to provide gender, career choice, number of programs they applied to, and the number of programs at which they were interviewed. RESULTS A total of 111 of the 160 surveys distributed were returned (69%). A total of 48 of the students were men, 31 were women, and 32 did not identify their gender. Nineteen students were interested in pursuing a career in surgery or a surgical subspecialty. Factors predicting surgery as a career choice were career opportunities (p < 0.04) and prestige (p < 0.003). Lifestyle during residency (p < 0.0007), work hours during residency (p < 0.008), and quality of patient/physician relationships (p < 0.05) were all significantly negatively correlated with the choice of a surgical career. Students pursuing a surgical career applied to greater than 31 programs compared with 11 to 15 for the nonsurgical students (p < 0.0001). CONCLUSIONS Prestige and career opportunities are more important to students seeking surgical residencies. Concerns about lifestyle and work hours during residency and perceived quality of patient/physician relationships were deterrents to surgery as a career choice. These issues may need to be addressed to increase the number of applicants to surgical programs.

National practice patterns of sentinel lymph node dissection for breast carcinoma

BACKGROUND The sentinel node is the first regional lymph node to receive tumor cells that metastasize through the lymphatic channel from a primary tumor. The tumor status of the sentinel node should reflect the tumor status of the entire regional node basin. Sentinel lymph node dissection (SLND) has recently been investigated for use in patients with early breast carcinoma to avoid the sequelae of complete axillary lymph node dissection (ALND). Published studies of SLND in breast cancer patients identify marked variations in technique, and there are few guidelines for credentialing surgeons to perform SLND. STUDY DESIGN The purpose of this study was to assess the current practice of SLND for breast cancer in the United States. A 27-item questionnaire was mailed to 1,000 randomly selected Fellows of the American College of Surgeons. Responses were anonymous. Statistical analysis was performed using SAS software (SAS Institute, Cary, NC). RESULTS Response rate was 41% (n = 410), and 77% of those who responded performed SLND for breast cancer. The majority (60%) of surgeons responding routinely ordered preoperative lymphoscintigraphy. Of those who did lymphoscintigraphy, 28% removed internal mammary lymph nodes when lymphoscintigraphy showed drainage to these nodes. Ninety percent of surgeons used both blue dye and radiocolloid. Eighty percent of centers responding performed routine immunohistochemistry on sentinel lymph nodes, and 15% performed reverse transcription polymerase chain reaction. Ninety-six percent of surgeons performed SLND for primary tumors 5 cm or smaller, and 95% performed SLND for an excisional cavity 6 cm and smaller. Twenty-eight percent performed SLND for high-grade ductal carcinoma in situ, and 28% of respondents performed 10 or fewer SLND procedures with subsequent ALND before performing SLND alone. Surgeons learned SLND through courses (35%), oncology fellowships (26%), observation of other surgeons (31%), or were self-taught (26%). CONCLUSIONS The majority of surgeons in the United States use similar technique for SLND breast cancer. But, there was marked variation in the number of SLND cases validated by an ALND before performing SLND only.

A CXCR4 Antagonist CTCE-9908 Inhibits Primary Tumor Growth and Metastasis of Breast Cancer1

BACKGROUND CXCL12/CXCR4 signaling may be involved in tumor growth and angiogenesis, and homing of cancer cells to bone and other organs. Our purpose was to determine whether inhibition of CXCR4 with a peptide-based antagonist would reduce tumor growth and metastasis of breast cancer. METHODS We used two mouse models of breast cancer. In the first model, 1 x 10(6) MDA-MB-231 breast cancer cells transfected with luciferase were implanted into the inguinal mammary fat pad to produce primary tumors. In the second model, 1 x 10(5) MDA-231-BSC12 cells were injected into the left cardiac ventricle to produce bone metastases. CTCE-9908, a peptide analog of CXCL12 that competitively binds to CXCR4, was used to test the effect of inhibiting CXCR4. Five mice from each mouse model were treated with CTCE-9908 (25 mg/kg, injected subcutaneously 5 d/wk). All mice were assessed weekly using bioluminescent imaging to quantify relative volumes of tumor burden. RESULTS Bioluminescencent imaging showed that the mice treated with CTCE-9908 had significantly less primary tumor burden than the control mice. At 5 and 6 wk, the mice treated with CTCE-9908 had a 7-fold reduction and 5-fold reduction in primary tumor burden, respectively. Treatment with CTCE-9908 also significantly inhibited the rate of metastases compared with the control group. At 5 and 6 wk, the mice treated with CTCE-9908 demonstrated a 9-fold reduction and 20-fold reduction in metastatic tumor burden, respectively. CONCLUSION Treatment with the CXCR4 antagonist CTCE-9908 significantly reduced metastasis as well as primary tumor growth in mouse models of breast cancer.