Immunomodulation by imiquimod in patients with high-risk primary melanoma.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.

Axillary recurrence after sentinel lymph node biopsy for breast cancer.

Sentinel lymph node biopsy (SLNB) is routinely performed as an axillary staging procedure for breast cancer. Although the reported false-negative rate approaches 10 per cent, this does not always lead to axillary recurrence. We previously reported an axillary recurrence rate of 1 per cent at a median follow-up of 2 years. Our objective is to determine the rate of axillary recurrence with longer follow-up. A retrospective review of patients with invasive breast cancer and a negative SLNB treated between 2001 and 2005 was performed. Cases where neoadjuvant therapy was used or where isolated tumor cells (ITCs) were found were included, whereas those with fewer than 18 months of follow-up were excluded. One (0.7%) out of 139 patients had an axillary recurrence after a median follow-up of 52 months. No patient who underwent neoadjuvant chemotherapy or with ITCs had axillary recurrence. Twelve (8.6%) patients have died, with death attributed to breast cancer in three. Our study demonstrates that axillary recurrence after SLNB remains a rare event after a median follow-up of 52 months, despite including potentially higher risk scenarios such as where neoadjuvant chemotherapy is used and ITCs are found. Therefore, axillary lymph node dissection can safely be avoided in patients where SLNB is negative.

Focused microwave thermotherapy for preoperative treatment of invasive breast cancer: a review of clinical studies.

BACKGROUND: Preoperative focused microwave thermotherapy (FMT) is a promising method for targeted treatment of breast cancer cells. Results of four multi-institutional clinical studies of preoperative FMT for treating invasive carcinomas in the intact breast are reviewed. METHODS: Externally applied wide-field adaptive phased-array FMT has been investigated both as a preoperative heat-alone ablation treatment and as a combination treatment with preoperative anthracycline-based chemotherapy for breast tumors ranging in ultrasound-measured size from 0.8 to 7.8 cm. RESULTS: In phase I, eight of ten (80%) patients receiving a single low dose of FMT prior to receiving mastectomy had a partial tumor response quantified by either ultrasound measurements of tumor volume reduction or by pathologic cell kill. In phase II, the FMT thermal dose was increased to establish a threshold dose to induce 100% pathologic tumor cell kill for invasive carcinomas prior to breast-conserving surgery (BCS). In a randomized study for patients with early-stage invasive breast cancer, of those patients receiving preoperative FMT at ablative temperatures, 0 of 34 (0%) patients had positive tumor margins, whereas positive margins occurred in 4 of 41 (9.8%) of patients receiving BCS alone (P = 0.13). In a randomized study for patients with large tumors, based on ultrasound measurements the median tumor volume reduction was 88.4% (n = 14) for patients receiving FMT and neoadjuvant chemotherapy, compared with 58.8% (n = 10) reduction in the neoadjuvant chemotherapy-alone arm (P = 0.048). CONCLUSIONS: Wide-field adaptive phased-array FMT can be safely administered in a preoperative setting, and data from randomized studies suggest both a reduction in positive tumor margins as a heat-alone treatment for early-stage breast cancer and a reduction in tumor volume when used in combination with anthracycline-based chemotherapy for patients with large breast cancer tumors. Larger randomized studies are required to verify these conclusions.

Outcomes following sentinel lymph node biopsy for breast cancer.

Evaluation of axillary lymph nodes for metastatic involvement is the most significant factor in gauging prognosis in breast cancer patients. Complete axillary dissection can be associated with significant morbidity. Therefore, sentinel node biopsy was developed to sample nodes and avoid dissection in patients without clinical evidence of nodal involvement. While most surgeons currently perform the procedure, the technique remains unstandardized. Sentinel node identification rates, false-negative rates and procedural complication rates are the main outcomes measured and can depend significantly on variations in technique. Future studies on sentinel lymph node biopsy will probably focus on clarifying accuracy of the procedure in different clinical settings, delineating standard technical practice guidelines and further achieving improved outcomes.

Evaluation of three scoring systems predicting non sentinel node metastasis in breast cancer patients with a positive sentinel node biopsy.

BACKGROUND: Completion axillary lymph node dissection (cALND), performed after a positive sentinel lymph node biopsy (SLNB) in breast cancer patients, often results in no additional positive nodes. Scoring systems have been published to aid in the prediction of nonsentinel node metastasis. Our purpose was to assess the validity of these scoring systems in our patient population. METHODS: For 39 consecutive patients who underwent cALND after a positive SLNB, scores were calculated using retrospective patient data for each of the three scoring systems used. Receiver operating characteristics (ROC) curves were drawn, and the areas under the curves were calculated to assess the discriminative power of each system. Univariate analysis was performed to assess the predictability of individual patient and tumor characteristics. RESULTS: Nonsentinel nodes were positive in 23 (59%) patients. The areas under the ROC curves were 0.63, 0.70, and 0.68, respectively. The proportion of sentinel nodes that were positive and the total number of sentinel nodes retrieved were the only individual predictors of nonsentinel node metastasis. CONCLUSIONS: Given the high incidence of retrieving no additional metastasis on cALND, individualized patient management according to risk is desirable. Scoring systems provide additional information regarding the likelihood of metastasis in nonsentinel nodes, but their predictability remains less than optimal. The use of scoring systems must be applied with caution until future studies provide a more accurate assessment of risk for patients with a positive SLNB.

Success of neoadjuvant chemotherapy in conversion of mastectomy to breast conservation surgery.

Neoadjuvant chemotherapy (NC) in patients with breast cancer results in high response rates and has been used with the purpose of reducing tumor size and achieving breast conservation (BC) in individuals who initially require mastectomy. Our objective is to determine the success of NC in achieving BC in women who initially were not candidates for BC. We conducted a cohort study of women with invasive breast cancer who required mastectomy but desired BC surgery. Outcomes measured were tumor response and rates of BC. Thirty-seven women had a mean age of 45 years. Mean tumor size was 51 mm, and 62 per cent were larger than 4 cm. Tumors were predominantly infiltrating ductal carcinoma (83.3%) and high grade (62.2%). Cyclophosphamide, doxorubicin, and 5-fluorouracil with or without taxotere were most commonly used (86%). Complete clinical and pathologic responses were seen in 32.4 per cent and 10.8 per cent of patients, respectively. BC was achieved in 56.7 per cent of cases. Only initial tumor size predicted tumor regression and success of BC (P = 0.014). Neither tumor histology nor biologic markers predicted tumor response. In conclusion, NC is an effective alternative in achieving tumor reduction and BC in selected patients who require mastectomy but desire BC surgery.

Axillary regional recurrence after sentinel lymph node biopsy for breast cancer.

The accuracy of sentinel lymph node biopsy (SLNB) staging in breast cancer has been demonstrated in studies comparing it with axillary dissection. There is a 5 per cent false-negative rate, but this does not always correlate with axillary recurrence. Our purpose was to determine the rate of axillary lymphatic recurrence in breast cancer patients who had a negative SLNB. We conducted a cohort study of breast cancer patients who underwent SLNB between 2001 and 2005. Only patients who had a negative SLNB were included. Patient demographics and tumor factors were reviewed. Outcomes measured were axillary and systemic recurrence and survival. Eighty-nine patients with a mean age of 54.4 +/- 9.9 years were included. Eighty-nine per cent of cases had infiltrating ductal carcinoma histology. Mean tumor size was 19 +/- 14 mm. Breast conservation surgery was done in 65 cases and mastectomy in 24. A mean of 2.3 +/- 2.4 SLN were found. After a median follow-up of 2.15 years, 1 (1%) patient developed a lymphatic recurrence in the axilla. SLNB provides accurate staging of breast cancer. Patients with negative SLNB do not require axillary dissection.

Percutaneous excisional biopsy of palpable breast masses under ultrasound visualization.

A palpable breast mass is a common reason for surgical consultation. Our goal was to determine whether ultrasound-guided vacuum-assisted core biopsy (US-VACB) is safe and effective in completely removing presumed benign palpable breast masses. We conducted a cohort study of 201 consecutive patients with presumed benign palpable masses who underwent removal with US-VACB. The main outcome measured was the successful removal of palpable masses. Palpable masses were successfully removed with US-VACB in 99% of cases; 2% were cancer and 7.5% were atypical ductal hyperplasia or phyllodes tumor. Two clinical recurrences representing a seroma were seen on follow-up. US-VACB is safe and effective in the initial diagnosis and management of presumed benign palpable breast masses. It provides the benefits of percutaneous biopsy and the palpable abnormality no longer remains.

Intraoperative injection of technetium-99m sulfur colloid is effective in the detection of sentinel lymph nodes in breast cancer.

BACKGROUND: Our objective was to determine if intraoperative injection of technetium-99m-labeled sulfur colloid is as effective as preoperative injection in the detection of sentinel lymph nodes (SLNs). METHODS: Two hundred consecutive patients with breast cancer underwent SLN biopsy examination. Radiocolloid was injected in the preoperative area (group A) or immediately after induction of anesthesia in the operating room (group B). RESULTS: The SLN detection rate was similar for groups A (96%) and B (100%; P = .2). Radioactive SLNs were detected in 95% of patients in group A and in 97% of patients in group B (P = .1). The mean number of SLNs harvested was 1.6 and 2.1 for groups A and B, respectively. There was no significant difference in positive SLNs between groups (P = .11). CONCLUSIONS: Intraoperative injection of sulfur colloid is highly effective in the detection of SLNs, avoiding patient discomfort and surgical schedule delays.

Outcomes of clinical and surgical assessment of women with pathological nipple discharge.

There is no consensus about the diagnostic approach to pathologic nipple discharge (PND). We hypothesize that lactiferous duct excision (microdochectomy) or image-guided biopsy are safe and effective means of diagnosis of PND. Eighty-two patients with PND underwent history and physical exam followed by breast sonography and mammogram. Image-guided biopsy was done if imaging studies were positive, whereas microdochectomy was done if normal. Discharge was unilateral (96%), bloody (79%), and spontaneous (62%). The sensitivity, specificity, positive and negative predictive values for the detection of neoplasia were 0.07, 1.0, 1.0, and 0.4 for mammography and 0.26, 0.97, 0.91, and 0.48 for sonography, respectively. Tissue diagnosis revealed papillary lesion (57%), mammary duct ectasia (33%), breast cancer (5%), and inflammatory/infectious (5%) causes. Hemorrhagic discharge associated with pregnancy or infections was managed successfully without surgery. After a median follow-up of 18 months, no PND recurrence was seen, but one patient developed cancer in a different location after diagnosis of atypical ductal hyperplasia. In conclusion, imaging studies provide confirmatory information and a biopsy target when positive. Negative imaging does not reliably exclude neoplasia or malignancy. Microdochectomy provides a sensible and effective approach in the workup of patients with PND.

Outcomes of surgical and sonographic assessment of breast masses in women younger than 30.

Assessment of breast masses in young women is challenging due to normal glandular variance. Our purpose is to define the outcomes of specialized physical exam, selective breast sonography (BUS), and biopsy in women younger than 30. Five hundred forty-two patients younger than 30 referred with a palpable breast mass were studied. Patients' mean age was 24.8. Surgeon's physical exam confirmed a dominant mass in 44 per cent of cases. Thirty-seven per cent had normal clinical exams. Median tumor size was 2.2 cm. On multivariate analysis, a mass on surgeon's clinical exam (P < 0.0001), and BUS (P = 0.0001) predicted the presence of a true mass. Fifty-three per cent of self-detected abnormalities were true masses compared to 18 per cent when detected by the primary care provider (PCP) (P < 0.001). Most common diagnoses were fibroadenoma (72%), breast cysts (4%), or fibrocystic changes (3%). Malignancy occurred in 1 per cent. In summary, breast mass is a common reason for surgical consultation. Normal glandular nodularity is often mistaken for a mass. However, a judicious approach of physical exam by a surgeon using selective BUS and image guided core biopsy provides an efficient and safe approach for diagnosis. Breast malignancy is a rare but serious cause of breast mass in young women.

Diagnosis of palpable breast masses: ultrasound-guided large core biopsy in a multidisciplinary setting.

Cytologic diagnosis of palpable breast masses is an accepted method for diagnosis. However, the high nondiagnostic rate causes repeat biopsy, unnecessary delays, and increased costs. Our purpose is to evaluate the use of ultrasound (US)-guided large-core needle biopsy as part of the minimally invasive multidisciplinary diagnosis of palpable breast masses. We studied 502 consecutive patients with 510 palpable solid breast masses seen and evaluated by a multidisciplinary team. Patients had US-guided core biopsy. Clinical-imaging-pathologic correlation (CIPC) was done in all cases. Core biopsy was deemed conclusive if CIPC was congruent and was used to guide definitive management. The median age of our patients was 39 years. Median tumor size was 2.2 cm. Of these cases, 463 (91%) had a conclusive diagnosis on CIPC. Core needle findings on 47 masses were nondefinitive to guide therapy (fibroepithelial lesion, atypical ductal hyperplasia, intraductal papilloma, CIPC). Three cancers were detected in this group on excisional biopsy. In conclusion, US-guided large-core needle biopsy is a sensitive method for diagnosis of palpable breast masses. Multidisciplinary correlation of clinical findings, imaging, and pathology is essential for success. This approach improves use of operating room resources and maximizes patient participation in the decision-making process.

Sentinel lymph node mapping of breast cancer: a case-control study of methylene blue tracer compared to isosulfan blue.

Isosulfan blue has been traditionally used as a tracer to map the lymphatic system during identification of the sentinel lymph node. However, allergic reactions may be life threatening. We compared the efficacy of methylene blue dye as a tracer for sentinel lymph node biopsy to isosulfan blue dye. In an analysis of 164 cases, there was no clinical or statistically significant difference in the success rate of sentinel node biopsy (P = 0.22), the number of blue sentinel nodes harvested (P = 0.46), the concordance with radioactive sentinel nodes (P = 0.92), or the incidence of metastases (P = 0.87) when methylene blue tracer was compared to isosulfan blue. No adverse reaction to either blue dye was observed. In conclusion, intraparenchymal injection of methylene blue dye is a reliable tracer for the lymphatic system and nodal identification during sentinel node mapping for breast cancer. It is safe, inexpensive, and readily available.

Outcomes of sonography-based management of breast cysts.

BACKGROUND: Ultrasound is commonly used during diagnosis of breast lesions. Our purpose was to study the role of sonography for risk stratification of malignancy in the diagnosis and management of palpable breast cysts. METHODS: This was a cohort study of 176 patients with palpable breast cysts. Sonographic findings were correlated with clinical and pathologic outcomes. RESULTS: Mean cyst size was 2.0 +/- 1.8 cm. Cysts were simple, complex and probably benign, and complex and suspicious for neoplasm in 82.25%, 10.25% and 7.5% of patients, respectively. Thick cyst wall (P = 0.0001), mural tumor (P <0.00001), eccentric mass (P = 0.034), and internal septae (P = 0.031) were predictive of neoplasm. Of cysts >3 cm, 33% were cancerous (P = 0.000027). After 378 days of follow-up, 26 % of cysts had recurred. Recurrence was more frequent in patients with bilateral or multiple cysts (P = 0.004). CONCLUSIONS: Sonography is useful in risk stratification of malignancy in breast cysts. There is a high risk of recurrence after cyst aspiration.

Use of preoperative breast ultrasonography for mapping of breast cancer extent improves resection margins during breast conservation surgery.

BACKGROUND: Positive margins after breast conservation surgery occur frequently and negatively influence local control rates. HYPOTHESIS: Preoperative breast ultrasonography reduces the incidence of positive margins during breast conservation surgery. DESIGN: Case-control analysis. PATIENTS AND INTERVENTION: One hundred twenty-two consecutive patients with invasive breast cancer were studied. Palpation or needle-wire-guided breast conservation surgery was used in the first 61 patients (group 1). Preoperative breast ultrasonography was added to the protocol in the last 61 patients (group 2). MAIN OUTCOME MEASURES: Incidence of positive margins, distance to closest margin. RESULTS: There was a 3.7-fold reduction in positive margins (P =.04, 95% confidence interval, 1.06-16.73) and improved resection margins (P =.04, 95% confidence interval, 0.14-3.88) when breast ultrasonography was used. Reexcision of margins was done in 11% (7 of 61 patients) in group 1 and 3% (2 of 61 patients) in group 2 (P =.17). CONCLUSION: Preoperative breast ultrasonography improves the margins of resection and decreases the incidence of positive margins during breast conservation surgery.

Focused microwave phased array thermotherapy for ablation of early-stage breast cancer: results of thermal dose escalation.

BACKGROUND: Tumor ablation as a means of treating breast cancer is being investigated. Microwave energy is promising because it can preferentially heat high-water-content breast carcinomas, compared to adipose and glandular tissues. METHODS: This is a prospective, multicenter, nonrandomized dose-escalation study of microwave treatment. Thermal dose was measured as (1) thermal equivalent minutes (cumulative equivalent minutes; CEM) of treatment relative to a temperature of 43 degrees C and (2) peak tumor temperature. Microwaves were guided by an antenna-temperature sensor placed percutaneously into the tumor. Outcomes measured were pathologic response (tumor necrosis) side effects. RESULTS: Twenty-five patients (mean age, 57 years) were enrolled. The mean tumor diameter was 1.8 cm. Tumoricidal temperatures (>43 degrees C) were reached in 23 patients (92%). Tumor size was unchanged after thermotherapy (P = not significant). Pathologic necrosis was achieved in 17 (68%) patients. Complete necrosis of the invasive component was achieved in two patients. One hundred forty CEM is predictive of a 50% tumor response, and 210 CEM is predictive of a 100% tumor response (P =.003). Univariate linear regression predicts that peak tumor temperatures of 47.4 degrees C and 49.7 degrees C cause a 50% tumor response and a 100% tumor response, respectively. CONCLUSIONS: Thermotherapy causes tumor necrosis and can be performed safely with minimal morbidity. The degree of tumor necrosis is a function of the thermal dose. Future studies will evaluate the impact of high doses of thermotherapy on margin status and complete tumor ablation.

Success of sentinel lymph node mapping after breast cancer ablation with focused microwave phased array thermotherapy.

BACKGROUND: Breast cancer tumor ablation as part of a multimodality approach in the treatment of breast cancer is the subject of recent interest. This study was conducted to determine if the ability to perform sentinel node biopsy was impaired after thermal-induced ablation of breast cancer. METHODS: We studied patients who had sentinel node biopsy after preoperative focused microwave phased array for breast cancer ablation. RESULTS: Twenty-one patients with T1-T2 breast cancer and clinically negative axilla underwent wide local excision and sentinel node biopsy guided by blue dye and sulfur colloid. Surgery was done an average of 17 days after microwave ablation. Fifteen of 22 patients (68%) had histologic evidence of tumor necrosis. Sentinel lymph node mapping was successful in 19 of 21 patients (91%). Axillary metastases were detected in 42% of cases. CONCLUSIONS: This study documents successful sentinel lymph node mapping for patients treated with antecedent local tumor ablation using focused microwave phased array ablation.

Lymphatic tumor burden negatively impacts the ability to detect the sentinel lymph node in breast cancer.

Sentinel lymph node (SLN) biopsy is the preferred method of nodal breast cancer staging. Techniques of SLN biopsy rely on transport of interstitial molecules through mammary lymphatics. Lymphatic flow may be disrupted by tumor emboli. Increased lymphatic tumor burden may be responsible for failure to identify the sentinel lymph node in patients with breast cancer. A prospective database of 110 patients who had SLN biopsy between January 2001 and December 2002 was analyzed. The number of metastatic axillary lymph nodes was used as a measure of lymphatic tumor burden. SLN was found in 94 per cent of cases. It was not found in seven patients; five of them had extensive axillary metastases (71%) compared to 23 per cent when SLN was found (P = 0.001). The average number of metastatic lymph nodes was larger when SLN was not found compared to when SLN was found (12.8 vs. 3.9, respectively, P = 0.002). Increasing numbers of metastatic nodes correlated with decreasing success in SLN biopsy (P = 0.075). The incidence of axillary metastases is higher in patients in whom the sentinel node is not found. High lymphatic tumor burden may have a causative role in SLN biopsy technical failure. Axillary dissection should be performed if SLN is not found, regardless of the tumor size or histology.