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Alistair J Cochran

Publications and source records attributed to Alistair J Cochran.

At least 19 recordsLinked to original sources
PubMed2006

Sentinel-node biopsy or nodal observation in melanoma.

BACKGROUND: We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma. METHODS: Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. RESULTS: Among 1269 patients with an intermediate-thickness primary melanoma, the mean (+/-SE) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6% in the biopsy group and 73.1+/-2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59 to 0.93; P=0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1+/-1.3% and 86.6+/-1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3+/-4.6% among patients with tumor-positive sentinel nodes and 90.2+/-1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3+/-4.6% vs. 52.4+/-5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P=0.004). CONCLUSIONS: The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496 [ClinicalTrials.gov].).

Disease Progression↗
PubMed2006

Immune responses in the draining lymph nodes against cancer: implications for immunotherapy.

Regional lymph nodes are the first site for melanoma metastases. The sentinel node (SN), on the direct lymphatic drainage pathway, which usually harbors first metastases, demonstrates significant suppression in its ability to respond to antigenic stimulation. This down-regulation of SN immunity is likely the basis of its susceptibility to tumor metastases, suggesting a potential role of the immune system in the control of malignant tumors. Despite immune dysfunction in the SN, phase II trials of systemic post-operative immunotherapy with a polyvalent melanoma vaccine developed at the John Wayne Cancer Institute showed improved 5-year overall survival in patients with melanoma metastatic to regional nodes. However, most immunotherapy clinical trials have failed to demonstrate a significant clinical response, and analyses of immune responses to tumor-associated antigens that correlate clinical responses have not been established. Therefore, refinements in assay methodologies and improvements in vaccine designs are critical to the success of cancer immunotherapy. Antigen presentation by dendritic cells (DCs) is the most potent means to initiate a T cell immunity. Dendritic cell-based immunotherapies have been vigorously attempted in the past decade. To improve the immunogenicity of cancer vaccines, we recently generated heterokaryons of DCs and tumor cells by electrofusion. The fusion hybrids retained their full antigen-presenting capacity and all natural tumor antigens. In pre-clinical animal experiments, a single injection of the DC-tumor fusion hybrids was sufficient to mediate the regression of tumors established in the lung, skin and brain. Most interestingly, successful therapy required the delivery of fusion hybrids directly into lymphoid organs such as lymph nodes. A clinical trial is now being carried out to test the immunogenicity and therapeutic effects of fusion hybrids for the treatment of metastatic melanoma.

Animals↗
PubMed2006

Pathologic reporting and special diagnostic techniques for melanoma.

Pathologists play a central role in the management of cutaneous melanoma in determining that a tumor is a melanoma, whether or not it is primary or metastatic, and whether or not the margins of excision are tumor free and in evaluating prognostic indicators from examination of the primary tumor and, where appropriate, lymph nodes, including the sentinel nodes.

Humans↗
PubMed2006

Tumour-induced immune modulation of sentinel lymph nodes.

Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.

Animals↗
PubMed2006

Hidradenocarcinoma: a histological and immunohistochemical study.

The diagnosis of hidradenocarcinoma is difficult due to a combination of factors including inconsistent nomenclature/ classification, rarity of the neoplasm, and variable morphology of cells composing the neoplasm. Immunohistochemistry has not been previously performed on a series of hidradenocarcinomas. We evaluated six cases of hidradenocarcinoma histologically and immunohistochemically using antibodies to gross cystic disease fluid protein-15 (GCDFP-15), carcino-embryonic antigen (CEA), epithelial membrane antigen (EMA), S-100 protein, keratin AE1/3, cytokeratin 5/6, p53, bcl-1, bcl-2, and Ki67. Histology suggested concurrent eccrine and apocrine differentiation of the cases. Ki67 and p53 staining was strongly positive in five of six tumors. The neoplasms stained with antibodies to CEA, S-100 protein, GCDFP-15, EMA, bcl-1, and bcl-2 in no consistent pattern. All tumors studied stained positively for keratin AE1/3 and cytokeratin 5/6. In making the diagnosis of hidradenocarcinoma, it may be unnecessary to separate hidradenocarcinoma into eccrine and apocrine categories, and although Ki67 and p53 may be helpful, histological parameters remain paramount.

Adenoma, Sweat Gland↗
PubMed2005

American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer.

PURPOSE: To develop a guideline for the use of sentinel node biopsy (SNB) in early stage breast cancer. METHODS: An American Society of Clinical Oncology (ASCO) Expert Panel conducted a systematic review of the literature available through February 2004 on the use of SNB in early-stage breast cancer. The panel developed a guideline for clinicians and patients regarding the appropriate use of a sentinel lymph node identification and sampling procedure from hereon referred to as SNB. The guideline was reviewed by selected experts in the field and the ASCO Health Services Committee and was approved by the ASCO Board of Directors. RESULTS: The literature review identified one published prospective randomized controlled trial in which SNB was compared with axillary lymph node dissection (ALND), four limited meta-analyses, and 69 published single-institution and multicenter trials in which the test performance of SNB was evaluated with respect to the results of ALND (completion axillary dissection). There are currently no data on the effect of SLN biopsy on long-term survival of patients with breast cancer. However, a review of the available evidence demonstrates that, when performed by experienced clinicians, SNB appears to be a safe and acceptably accurate method for identifying early-stage breast cancer without involvement of the axillary lymph nodes. CONCLUSION: SNB is an appropriate initial alternative to routine staging ALND for patients with early-stage breast cancer with clinically negative axillary nodes. Completion ALND remains standard treatment for patients with axillary metastases identified on SNB. Appropriately identified patients with negative results of SNB, when done under the direction of an experienced surgeon, need not have completion ALND. Isolated cancer cells detected by pathologic examination of the SLN with use of specialized techniques are currently of unknown clinical significance. Although such specialized techniques are often used, they are not a required part of SLN evaluation for breast cancer at this time. Data suggest that SNB is associated with less morbidity than ALND, but the comparative effects of these two approaches on tumor recurrence or patient survival are unknown.

Breast Neoplasms↗
PubMed2005

Quantitative analysis of melanoma-induced cytokine-mediated immunosuppression in melanoma sentinel nodes.

PURPOSE: Melanoma sentinel nodes (SN) show evidence of immunosuppression prior to tumor metastasis. Interleukin (IL)-10 and IFN-gamma can induce dendritic cells (DC) that express immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). The goals of this study are to evaluate the role of melanoma in SN immunosuppression and to assess reversibility of SN immunosuppression by a cytokine therapy. EXPERIMENTAL DESIGN: Fifty-seven clinical stage I/II melanoma patients underwent wide local excision and sentinel lymphadenectomy (WLE/SL), with removal of non-SN. In 21 patients, nodal RNA was analyzed by quantitative real-time PCR for expression levels of IL-2, IL-10, IL-12, IFN-gamma, and IDO genes. Among the remaining 36 patients, 15 received peritumoral injection of recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) 2 to 5 days prior to WLE/SL. Lymph nodes (LN) from these 36 patients were assessed for T-cell area, DC area, and DC density. RESULTS: Of 21 patients whose nodal RNA was analyzed, 13 had residual melanoma at the primary site or a tumor-positive SN. In these patients, expression levels of IL-10 (P = 0.05), IFN-gamma (P < 0.05), and IDO (P = 0.06) were dramatically higher in SNs than non-SNs. This difference was not evident in the 8 patients without residual melanoma or SN metastasis. Of the 36 patients whose LNs were examined for histologic features, the 15 patients who received rhGM-CSF had significantly higher SN values of T-cell area, DC area, and DC density than those who did not receive rhGM-CSF. CONCLUSIONS: Our data provide molecular evidence of cytokine-mediated SN immunosuppression that is associated with presence of melanoma. Furthermore, SN immunosuppression can potentially be reversed by a cytokine therapy.

Adult↗
PubMed2005

Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial.

OBJECTIVE: The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. SUMMARY BACKGROUND DATA: Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. METHODS: After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (> or =1 mm with Clark level > or =III, or any thickness with Clark level > or =IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. RESULTS: Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. CONCLUSIONS: LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.

Adolescent↗
PubMed2004

Pathologic analysis of sentinel lymph nodes in melanoma patients: current and future trends.

Sentinel lymph node dissection (SLND) has become the standard of care for the staging of clinically-node negative melanomas and breast cancers. A large literature documents the efficacy of SLND in the staging of melanoma and breast cancer. The SLND has lower associated patient morbidity in comparison to elective node dissections that remove the closest regional-draining node group. SLND has improved accuracy over traditional regional node dissection for the staging of melanoma. Currently, several multicenter trials are evaluating the prognostic significance of melanoma micrometastases in SLN detected by immunohistochemical and molecular methods. Pending trial outcome analysis, SLND has no proven effect on mortality. However, given the current oncologic emphasis on detection and removal of nodal tumor metastases, the technique has an important role in minimizing the invasiveness of tumor staging for melanoma and breast cancer. As long as lymph node metastases are used for staging solid malignancies, surgical pathologists are likely to encounter SLN excisional biopsies as a part of their routine practice.

Antigens, Neoplasm↗
PubMed2004

Optimized assessment of sentinel lymph nodes for metastatic melanoma: implications for regional surgery and overall treatment planning.

Correct identification of the sentinel node (SN) and accurate evaluation of this node's tumor status constitute the most precise technique for staging clinically localized cutaneous melanoma. However, even if tumor is present in the SN (as in approximately 20% of patients), the remaining nodes in the basin are often tumor-free. We have found that the Breslow thickness of the primary, the relative area of tumor in the SN (with respect to the area of the SN), and the density of dendritic leukocytes in the SN paracortex not only can predict the likelihood of nonsentinel node metastases but also are correlated with likelihood of tumor recurrence and melanoma-specific survival. The most robust of these predictors is relative tumor area, and this may be used as the basis of practical predictive algorithms.

Algorithms↗
PubMed2004

Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node.

Lymphatic mapping and sentinel node biopsy are well-established techniques for staging and managing patients with melanoma, breast cancer and other malignancies that spread initially to the regional lymph nodes. Identification of tumor in the sentinel node is the most precise staging technique currently available. The sentinel node is the site of metastatic melanoma in approximately 20% of melanoma patients and if tumor is present in the sentinel node it is customary to perform a complete dissection of the lymph nodes of the affected nodal basin. This may be overtreatment for some patients as tumor is identified in the nonsentinel nodes of only one-third of sentinel node-positive melanoma patients treated by completion lymphadenectomy. If it were possible accurately to identify the minority of patients with tumor in the nonsentinel nodes, the patients most likely to benefit from lymphadenectomy, the remaining patients could be spared a potentially morbid operation that is unlikely to confer clinical advantage. In 90 patients with a melanoma-positive sentinel node, who subsequently had a completion lymphadenectomy, we evaluated and compared the capacity of characteristics of the primary melanoma and of the sentinel node to predict individuals likely to have tumor in nonsentinel nodes. We assessed the Breslow thickness of the primary, the amount of tumor in the sentinel node (relative tumor area) and, as an index of immune modulation of the sentinel node, the density of dendritic leukocytes in the nodal paracortex. The relative area of tumor in the sentinel node and Breslow thickness of the primary melanoma most accurately predicted the presence of tumor in the nonsentinel nodes (P=0.0001 in both cases-Wilcoxon rank sums). The presence of melanoma in the nonsentinel nodes was also predicted by the density of dendritic leukocytes in the paracortex (P=0.008-Wilcoxon rank sums). These three observations assessed alone and in combination predict the presence of tumor in the nonsentinel nodes with high accuracy. The same characteristics also significantly correlated with tumor recurrence (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0007) and death from melanoma (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0026).

Antigens, Neoplasm↗
PubMed2004

Update on lymphatic mapping and sentinel node biopsy in the management of patients with melanocytic tumours.

AIMS: To communicate best practices for sentinel lymph node evaluation and assessment of prognosis for patients with melanoma. METHODS: Description and justification of approaches derive from experience with management of more than 2000 melanoma patients evaluated by lymphatic mapping and sentinel node biopsy (LMSNB). RESULTS: Pathologists, by detecting blue dye or carbon particles or alterations in nodal cell populations should attempt to confirm that a node submitted as sentinel is truly sentinel. Pathologists must adequately sample the node by examining multiple tissue sections and determine the presence or absence of metastatic melanoma using sections stained by H&E and immunocytochemistry. Approximately 20% of patients have melanoma in the sentinel node (SN) and accurate evaluation of SN tumour status is the most precise technique for staging clinically localised cutaneous melanoma. The remaining non-sentinel nodes (NSN) in the basin are tumour-free in 67% of patients with melanoma in the SN. Breslow thickness of the primary, the area of tumour in the SN (relative to total nodal area) and density of dendritic leukocytes in the SN paracortex (factors that are combinable in prognostic algorithms) predict metastases in the NSN and the likelihood of recurrence and melanoma-specific death. CONCLUSIONS: Careful pathological analysis is essential to determine the presence or absence of metastatic melanoma in sentinel nodes, findings that indicate whether completion lymphadenectomy is required. Quantitative analysis of the primary melanoma and the amount of tumour in the sentinel node, with evaluation of the dendritic cells in that node, provide invaluable information that predicts non-sentinel node tumour status with increased accuracy and the likelihood of future recurrence and death from melanoma. While these activities require considerable effort from pathologists, their clinical impact justifies the increased workload.

Humans↗
PubMed2004

Is MAGE-1 expression in metastatic malignant melanomas really helpful?

Melanoma antigen-encoding gene (MAGE-1) has been introduced as a sensitive immunohistochemical marker to aid in the diagnosis of malignant melanomas, in particular, those that are HMB-45 negative. Our goal was to determine the consistency of positive staining in melanomas on the basis of the usefulness of MAGE-1 in comparison with tyrosinase and MART-1. We studied 56 malignant melanomas using immunohistochemical markers to MAGE-1, tyrosinase, MART-1, HMB-45, and S-100. Six of 17 HMB-45-negative cases were strongly positive for MAGE-1 (35%), while 9 of 39 HMB-45-positive cases were positive for MAGE-1 (23%), overall, 27% positivity (n = 56). Tyrosinase and MART-1 were both strongly positive in 42 of 56 cases (75%). Fifty-two of 56 cases were strongly positive for S-100 (93%). We found MAGE-1 to be less sensitive than described in other studies, and overall, not very helpful, especially as a predictor of aggressive behavior. Although MAGE-1 expression has been considered as a target for immunomodulation therapy, our findings do not indicate consistent expression of this epitope in a majority of melanomas. S-100 protein, tyrosinase, and MART-1 immunomarkers were more frequently positive in our melanoma cases and appear to constitute a useful panel of markers to aid in the diagnosis of metastatic malignant melanomas, especially in patients with an unknown primary.

Adjuvants, Immunologic↗
PubMed2004

Dermatoscopic and histopathological diagnosis of primary and metastatic melanoma: report of a workshop at the Third Research Meeting on Melanoma, Milan, Italy, May 2003.

The clinical and histopathological session of the Third Research Meeting on Melanoma, Milan, Italy, held in May 2003, highlighted several key topics, including clinical, dermatoscopic and computer-aided diagnosis and the use of immunohistochemical, immunological and biochemical approaches to diagnosis and monitoring. This report is a brief summary of the main themes covered.

Biomarkers, Tumor↗
PubMed2003

The place of lymphatic mapping and sentinel node biopsy in oncology.

The techniques of sentinel lymphatic mapping (LM) and sentinel lymph node biopsy (SLNB) have become almost routine for the staging of clinically node-negative patients with high-risk cutaneous melanoma. The techniques are also widely applied to staging of the axilla in breast cancer. Investigations of the use of LM and SLNB for other solid malignancies have also shown promise. LM/SLNB requires a multidisciplinary effort involving experienced surgeons, nuclear medicine physicians, and surgical pathologists. The techniques require a learning curve for all involved personnel, requiring experience with at least 30 cases followed by complete nodal dissection after SLNB to achieve full competency. Surgical pathologists play a pivotal role in determining optimum sentinel node analysis. The techniques have lower morbidity and greater accuracy than traditional complete regional node dissection. Pathologists are receiving increasing numbers of SLN specimens and are expected to evaluate the results of the application of the LM/SLNB techniques to a range of solid tumors. We have reviewed LM/SLNB in regard to melanoma and breast cancer and other types of malignancies. The techniques have much to offer, but despite their seeming simplicity, need considerable technical skill and clinical judgment if they are to be effectively applied. They also provide unique opportunities for basic and translational research.

Breast Neoplasms↗