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Background Management of stage IV melanoma patients remains a challenge. In spite of promising new therapies, many patients develop resistance and progression. The aim of this pilot study was to determine if circulating tumor cells (CTCs) are associated with shortened (180-day) progression-free survival (PFS) after a baseline CTC assessment in stage IV melanoma patients. Study Design A baseline CTC assessment was performed in 93 stage IV melanoma patients using a commercially available immunomagnetic system. The presence of 1 or more CTC was considered a positive result. A Cox multivariable regression model was used to evaluate the association between presence of CTCs at baseline and PFS, after adjusting for covariables. Kaplan-Meier curves and a log-rank test were used to summarize and compare unadjusted PFS for patients stratified by CTC positivity. Results Median follow-up was 17 months; mean age was 55 years. Thirteen of 93 (14%) patients had no evidence of disease (NED) at baseline CTC assessment. One or more CTC was detected in 39 of 93 (42%) of patients at baseline; CTCs were not associated with primary melanoma features or NED status. Twenty-eight of 93 (30%) patients progressed within 180 days of baseline draw, with 20 of 39 (51%) of the CTC-positive patients relapsing compared with 8 of 54 (15%) of the CTC-negative patients. In adjusted Cox models, a significant association was found suggesting worse PFS within 180 days for CTC-positive patients at baseline (vs CTC-negative) (hazard ratio 4.69, 95% CI 1.59 to 13.77, p = 0.005). Conclusions One or more CTCs at baseline were associated with progression within 180 days in stage IV melanoma patients. This information warrants further study of CTCs as a means of identifying patients at high-risk for disease progression.

Background There is no consensus about the use of the various diagnostic tests and surgical procedures available to confirm or rule out breast cancer in patients presenting with nipple discharge. This study was designed to identify patient and nipple-discharge characteristics associated with the diagnosis of breast cancer and to determine the utility of mammography, sonography, ductography, and cytology in surgical decision making in patients presenting with pathologic nipple discharge. Study design We reviewed the medical records of all patients who presented with nipple discharge at our institution between August 1993 and September 2000. Patient and nipple-discharge characteristics and findings on imaging studies and cytologic examination were analyzed. Results A total of 146 patients presented at our institution with nipple discharge during the study period. Of these, 52 had clinically benign discharge and were managed without surgical intervention; 94 patients had pathologic discharge and underwent a biopsy procedure for histologic diagnosis, treatment, or both. Logistic regression analysis identified mammographic (relative risk [RR] = 10.47, 95% confidence interval [CI] 2.36 to 46.39, p=0.0002) and sonographic (RR = 5.54, 95% CI 1.27 to 25.40, p=0.028) abnormalities as independent factors associated with a malignant diagnosis. Nineteen cancers, 62 papillomas, and 13 other benign lesions were identified among the patients with pathologic discharge. In 3 patients with cancer (15.8%) and 30 patients with a papilloma (48.4%), ductography was the only means of identifying lesions to be resected. Patients who underwent ductography-guided operation (n = 42, 50%) or any surgical procedure including a localization study (n = 66, 78.6%) were significantly more likely than patients who underwent central duct excision alone to have a specific underlying lesion identified (p = 0.045 and p=0.033, respectively). Conclusions Abnormalities on mammography and sonography in patients with nipple discharge should alert physicians to the possibility of a breast cancer diagnosis. In patients with pathologic discharge with normal findings on physical examination and other imaging studies, ductography might be the only means of localizing and resecting breast lesions associated with nipple discharge.

Historically, radical surgery was the only potentially curative treatment for cancer. Recently, neoadjuvant chemotherapy, also termed preoperative, induction, or primary chemotherapy, has assumed an increasingly important role in the management of several solid-organ malignancies, including cancers of the breast, bone, head and neck, bladder, esophagus, and lung. In breast cancer, the use of postoperative, or adjuvant, chemotherapy is inextricably linked to the improved outcomes seen over the past several decades. Neoadjuvant chemotherapy has become the standard of care for patients with locally advanced breast cancer and has rapidly come to the forefront among potential treatments for patients with earlier-stage operable disease.

Ariyan and colleagues recently reported their experience with sentinel lymph node (SLN) biopsies from 263 patients with primary cutaneous melanoma. The SLNs were evaluated by intraoperative frozen section (F/S). Paraffin-embedded sections of the SLNs, stained with hematoxylin and eosin and immunohistochemically for S100 and HMB45, were assessed subsequently. Twentyeight patients (10.6%) had melanoma in a SLN, 23 (82%) of whom had tumor identified intraoperatively on F/S. The authors concluded that their series “attests to the reliability of frozen sections in identifying SLN harboring metastases.” Although we do not dispute that F/S examination of SLNs, when performed by a practiced and committed group such as that of Dr Aryian and his colleagues, can have an occasional role in some specialist melanoma treatment centers, we are concerned that use of this technique in other professional contexts can reduce the accuracy and reliability of the SLN biopsy procedure. Although the authors went to some length to suggest that their low yield of positive nodes (10.6%) compared with most large series (15% to 34%) reflected the high percentage of patients with thin primary tumors and fewer thick melanomas in their series, we cannot draw the same conclusion from the limited data presented. Indeed, the rate of positive SLNs for most groups of tumor thicknesses is lower than in the other series referenced in their article, and considerably lower than in a published (but uncited) report from the M D Anderson Cancer Center (Table 1). Unfortunately, the very limited clinicopathologic details provided prevent statistical comparison with other series. The inexplicably low rate of SLN positivity in the study raises the disturbing possibility that use of F/S might have led to a substantial number of false-negative SLNs resulting from loss of diagnostic tissue during the technical manipulations required for the F/S procedure, and/or that subsequent permanent section analysis may have been rendered more difficult by earlier freezing of some or all of the tissue. Our extensive combined experience with intraoperative F/S evaluation of SLNs, obtained during development of the modern SLN approach, was associated with a failure to identify melanoma micrometastases in 4% to 8% of ultimately positive patients. In view of this, and the practical considerations detailed below, we have long discontinued performing routine F/S examination on SLNs from melanoma patients. There is a major possibility that limited amounts of relatively localized diagnostic material in an SLN may be lost as a consequence of examining the node by F/S. First, substantial tissue is inevitably lost when “facing up” the frozen tissue block. Facing up is removal of tissue to obtain a section that contains all areas of the tissue. Melanoma micrometastases are most likely to lodge in the subcapsular region of an SLN and in adjacent and abutting lymphoid tissues around the central plane through the hilum and longest dimension of the node. It is absolutely critical that this portion of the SLN is included in the F/S and examined carefully. To obtain a full-face F/S that includes the subcapsular sinus region of the entire SLN, it is unavoidable that substantial nodal tissue is lost during facing up. Because it is difficult to make the cut surface of the SLN sit flat during freezing of the tissue, some discarded tissue inevitably derives from the critical subcapsular region. When a fresh SLN is bisected, the nodal capsule retracts and central tissue bulges from the cut surface. Metastases that are localized only in the central part of the node, as is occasionally observed, may also be discarded as a result of the facing-up procedure. Second, because tissue and cellular preservation is generally inferior in frozen

Isolated limb infusion (ILI) is a minimally invasive approach for treating in-transit extremity melanoma, with only two US single-center studies reported. Establishing response and toxicity to ILI as compared with hyperthermic isolated limb perfusion is important for optimizing future regional chemotherapeutic strategies in melanoma.Patient characteristics and procedural variables were collected retrospectively from 162 ILIs performed at 8 institutions (2001 to 2008) and compared using chi-square and Student's t-test. ILIs were performed for 30 minutes in patients with in-transit melanoma. Melphalan dose was corrected for ideal body weight (IBW) in 42% (n = 68) of procedures. Response was determined at 3 months by Response Evaluation Criteria in Solid Tumors; toxicity was assessed using the Wieberdink Limb Toxicity Scale.In 128 evaluable patients, complete response rate was 31%, partial response rate was 33%, and there was no response in 36% of patients. For all patients (n = 162), 36% had Wieberdink toxicity gradeor=3 with one toxicity-related amputation. On multivariate analysis, smaller limb volumes were associated with better overall response (p = 0.021). Use of papaverine in the circuit to achieve cutaneous vasodilation was associated with better response (p0.001) but higher risk of gradeor=3 toxicity (p = 0.001). Correction of melphalan dose for ideal body weight did not alter complete response (p = 0.345), but did lead to marked reduction in toxicity (p0.001).In the first multi-institutional analysis of ILI, a complete response rate of 31% was achieved with acceptable toxicity demonstrating this procedure to be a reasonable alternative to hyperthermic isolated limb perfusion in the management of advanced extremity melanoma.

Male breast cancer accounts for1% of breast cancers. Sentinel lymph node (SLN) operation is commonly used in the evaluation of female breast cancer patients. The purpose of this study was to determine whether SLN operation is as feasible and accurate in male patients compared with female patients.Between 1999 and 2005, 30 men and 2,784 women underwent SLN operation. Clinical and pathologic data were reviewed and statistical analysis performed.Men presented at an older age (p = 0.005) and with larger tumors than women (p = 0.04). The SLN was identified in 100% of men and in 98.3% of women (p = NS). The mean number of SLNs harvested was 3.5 in men and 3.0 in women (p = NS). The incidence of positive SLNs was higher in men (37.0% versus 22.3%), although this did not reach statistical significance (p = 0.1). In patients with a positive SLN there were additional non-SLNs positive in 62.5% of men, compared with 20.7% in women (p = 0.01). The median size of the largest lymph node metastasis was 10 mm in men and 3 mm in women (p = 0.03).SLN operation in clinically node-negative men is feasible and accurate. Male breast cancer patients present at an older age and with larger tumors than female breast cancer patients. Male patients have higher nodal tumor burden reflected in a larger size of nodal metastasis and increased risk of harboring additional disease in axillary lymph nodes when the SLN is positive. Intraoperative SLN evaluation should be considered in the surgical management of male breast cancer.

Lymphoscintigraphy (LSG) can identify lymphatic drainage patterns before sentinel lymph node (SLN) biopsy is performed in patients with early-stage breast cancer, but the importance of extraaxillary SLNs seen on LSG is unknown. We assessed whether drainage patterns seen on LSG were associated with histologic findings in axillary SLNs recovered at SLN biopsy.From a prospectively maintained database, we identified 1,201 clinically node-negative patients with invasive breast cancer who underwent preoperative LSG and axillary SLN biopsy. Patient and tumor characteristics, LSG results, and final SLN pathology results were examined.LSG showed drainage to internal mammary (IM) nodes in 1.6% of patients, axillary nodes in 68.1%, both IM and axillary nodes in 19.8%, and no drainage in 10.3%. Drainage to IM nodes was observed for tumors in all quadrants of the breast. Patients with IM drainage had a younger median age than patients without IM drainage (51.8 versus 58.3 years, respectively; p0.001). The intraoperative axillary SLN identification rate was higher when axillary drainage was observed on LSG than when it was not observed (98.7% versus 93.0%, respectively; p0.001), but the LSG drainage pattern was not associated with pathologic status of the SLN or number of metastatic SLNs. At a median followup of 32 months, 4 patients had regional nodal recurrence.Almost one-fourth of patients had lymphatic drainage to the extraaxillary lymph nodes, particularly the IM nodes, seen on LSG. Extraaxillary drainage seen on LSG did not preclude identification of axillary SLNs at operation. Longterm followup of patients with lymphoscintigraphic evidence of extraaxillary drainage is needed to determine whether regional and systemic recurrence patterns differ in these patients.

Does Hospital Proficiency Vary for Melanoma Sentinel Lymph Node Biopsies? An Evaluation of Hospital-Level Adjusted Node Positivity Rates and Outcomes Christine V Kinnier, MD, Jeanette W Chung, PhD, Jennifer L Paruch, MD, Jeffrey D Wayne, MD, Merrick I Ross, MD, David P Winchester, MD, FACS, Karl Y Bilimoria, MD, MS, FACS Northwestern University, Chicago, IL, Massachusetts General Hospital, Boston, MA

The Society of Surgical Oncology has developed a position statement54 that lists conditions warranting consideration of prophylactic mastectomy (Table 4). It must be stressed that there are no absolute indications for prophylactic mastectomy. The data are limited about the efficacy of prophylactic mastectomy in humans, but recent studies suggest that it results in up to 90% reduction in the risk for breast cancer. Total mastectomy is technically a more definitive procedure, although reported series have had a predominance of patients undergoing subcutaneous, nipple-sparing procedures. Prophylactic mastectomy may improve longevity in BRCA mutation carriers, but this must be balanced against the impact on quality of life. The benefits of prophylactic mastectomy relative to chemoprevention are unclear because there are no prospective randomized studies comparing these two strategies. Contralateral prophylactic mastectomy in patients with a unilateral cancer is unlikely to improve survival, but this approach may be considered for high-risk or difficult-to-observe patients, to facilitate breast reconstruction, and for the psychologic benefits. Patients considering prophylactic mastectomy should be well informed of risk-reduction alternatives and the limitations in the efficacy and cosmetic results of the procedure.