Inguinal and Ilio-inguinal Lymphadenectomy in Management of Palpable Melanoma Lymph Node Metastasis: A Long-Term Prospective Evaluation of Morbidity and Quality of Life.

PURPOSE: Prospective data are lacking on long-term morbidity of inguinal lymphadenectomy including the influence of extent of surgery, use of radiotherapy, and patient factors. The aim of this study is to evaluate the effects of these factors on patient outcome, quality of life (QOL), regional symptoms, and limb volumes after inguinal or ilio-inguinal lymphadenectomy for melanoma. METHODS: Analysis of the subgroup of patients with inguinal lymph node field relapse of melanoma, treated by inguinal or ilio-inguinal lymphadenectomy in the ANZMTG/TROG randomized trial of adjuvant radiotherapy versus observation. RESULTS: Sixty-nine patients, 46 having undergone inguinal and 23 ilio-inguinal lymphadenectomy, with median follow-up of 73 months were analyzed. Mean limb volume increased rapidly after surgery (7% by 3 months) and continued to increase for at least another 18 months. Patients with body mass index (BMI) ≥ 25 kg/m2 had greater limb volume increase than normal-weight patients (13.3% versus 6.9%, P = 0.030). QOL improved over the first 18 months, but despite initial improvement, regional symptoms persisted long term. Type of surgery (inguinal or ilio-inguinal lymphadenectomy) had no demonstrably significant effect on limb volume (9.9% versus 13.4%, P = 0.35), QOL (P = 0.68), or regional symptoms (P = 0.65). There was no difference in overall survival between inguinal and ilio-inguinal lymphadenectomy [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.40-1.40, P = 0.43]. CONCLUSIONS: Inguinal lymphadenectomy for melanoma is a potentially morbid procedure with significant increases in limb volume. Patients report reasonable QOL but may have ongoing regional symptoms. Overweight/obesity is associated with poorer QOL, increased limb volume, and regional symptoms.

Setting up a health education website: practical advice for health professionals.

Recently, both popular and professional publications about health care have begun to express enthusiasm for the Internet as a source of medical information and possibly of psychological support for those with serious illnesses. However, there are pitfalls for practitioners and researchers who seek to capitalise on these patient education possibilities. We describe here the process and mixed outcomes of the efforts of a multidisciplinary team to set up and evaluate a website for rural women with breast cancer. We provide recommendations for other health professionals contemplating similar ventures, and also identify some future steps to develop and research this potentially valuable form of patient education and support.

Association between melanoma and dermal mast cell prevalence in sun-unexposed skin.

BACKGROUND: Both exposure to intermittent intense sunlight during childhood and ultraviolet (UV) radiation-induced immunomodulation have been directly associated with melanoma development. In mice, the prevalence of dermal mast cells determines susceptibility to UVB-induced systemic suppression of contact hypersensitivity responses and thus may affect immunological responses to melanoma antigens. OBJECTIVES: To determine the relevance of murine studies of dermal mast cell prevalence to human melanoma pathogenesis. METHODS: The prevalence of mast cells was examined in sun-unexposed buttock skin of 45 melanoma patients and 68 control volunteers who had no history of skin cancer development. Buttock skin was studied because mast cell prevalence is stable with ageing and the confounding effects of environmental UV exposure are minimized. RESULTS: Using tissue immunostaining, the buttock skin from melanoma patients had a significantly higher dermal mast cell prevalence (mean +/- SEM 38 +/- 2 mast cells mm(-2)) than controls (32 +/- 2 mast cells mm(-2)) (P = 0.02). Analysis by binary logistic regression showed that the association between mast cell prevalence and melanoma outcome was not significantly altered by skin phototype. CONCLUSIONS: The immunomodulatory effects of mast cell products in UV-irradiated skin may contribute significantly to the initiation and development of human cutaneous malignant melanoma.

Removal of two sentinel nodes accurately stages the axilla in breast cancer.

BACKGROUND: Assessment of lymph node status in breast cancer is still necessary for staging. Sentinel lymph node biopsy (SNB) may provide accurate staging with less morbidity than axillary clearance. The aim of this study was to assess the effect of the number of sentinel nodes removed on the false-negative rate. METHODS: Data were collected prospectively from 395 women undergoing SNB for breast cancer, between June 1995 and December 2001. All nodes that were hot and/or blue were removed and analysed. RESULTS: During this interval 136 patients who had SNB were lymph node positive. The median number of sentinel nodes removed was two (range one to five). The overall false-negative rate of SNB in these women was 7.1 per cent. If only one sentinel node had been removed, the false-negative rate would have been 16.5 per cent. The removal of more than two nodes had no effect on axillary staging in all but two women. CONCLUSION: In early breast cancer, when there were multiple sentinel nodes, removal of two sentinel nodes significantly reduced the false-negative rate compared with removal of one node. Removing more than two sentinel nodes did not significantly reduce the false-negative rate further.

CD1a-positive infiltrating-dendritic cell density and 5-year survival from human breast cancer.

Infiltrating CD1a(+) dendritic cells (DCs) have been associated with increased survival in a number of human cancers. This study investigated DC infiltration within breast cancers and the association with survival. Classical established prognostic factors, of tumour size, lymph node status, histological grade, lympho-vascular invasion, the KI-67 (MIB-1) fraction and the Nottingham Prognostic Index (NPI) were also compared. A total of 48 breast cancer patients were followed from the time of surgery and CD1a density analysis for 5 years or until death. Our data set validated previous studies, which show a relationship between survival and the NPI (P<0.001), tumour size (P<0.01) and lymph node status (P<0.05). Although more patients were alive at the 5-year time point in the group with higher CD1a DC density than the lower CD1a DC group, this failed to reach statistical significance at the P=0.05 level. Analysis at 10 years postsurgery is required to investigate the association further.

Dendritic cell density and activation status in human breast cancer -- CD1a, CMRF-44, CMRF-56 and CD-83 expression.

Low CD1a-positive putative dendritic cell numbers in human breast cancer has recently been described and may explain the apparent 'poor immunogenicity' previously reported in breast cancer. Little attention has been given to dendritic cell activation within the tumour microenvironment, which is another reason why the in-situ immune response may be severely deficient. We have therefore examined CD1a expression as a marker for dendritic cells, together with CMRF-44 and -56 as markers of dendritic cell activation status, in 40 human breast cancers. The results demonstrate few or no CD1a-positive putative dendritic cells and minimal or no expression of the dendritic cell activation markers. Both dendritic cell number and dendritic cell activation appear substantially deficient in human breast cancers, regardless of tumour histological grade.

Quality assurance in a multidisciplinary symptomatic breast assessment clinic.

BACKGROUND: Although quality assurance guidelines for surgeons have been issued and adopted for use in population-based breast screening programs in Australia, similar guidelines are unavailable for women referred with symptomatic breast problems. METHODS: Six hundred and ninety-six women who attended the Royal Adelaide Hospital Women's Health Centre between February and November 1998 for investigation and management of a new breast-related complaint were prospectively evaluated. Investigation strategies and outcomes of the initial consultation were determined and the results compared with the performance quality standards for symptomatic breast disease according to the British Association of Surgical Oncology (BASO) Breast Surgeons' Group. RESULTS: A breast lump was the presenting symptom in 45%, while breast pain was present in 26%. Ninety per cent of women referred with breast symptoms were given a definitive benign or malignant diagnosis at the initial clinic visit. Although the median time delay between the date of general practitioner referral and breast clinic appointments for all patients was < or =7 days, the time delay for 'urgent' cases was not met according to BASO performance indicators. All other Royal Adelaide Hospital Breast Clinic audit data were within the range suggested by BASO performance indicators for new consultations in a symptomatic breast assessment clinic. CONCLUSIONS: A multidisciplinary breast clinic in a public hospital setting is able to provide clinical services to symptomatic women, with the majority of patients obtaining a confident diagnosis at the first presentation. Performance indicators for symptomatic breast disease are useful in identifying inadequacies at the clerical or clinical level which, following the implementation of subsequent changes, may lead to improvement in patient outcomes.

Clinical and histological factors associated with sentinel node identification in breast cancer.

BACKGROUND: Although sentinel lymph node biopsy is likely to be offered as a method of assessing nodal status in primary breast cancer, the inability to identify the sentinel node at the time of surgery will limit the number of patients who may benefit from the procedure. The purpose of the present study was to identify factors that are associated with intraoperative identification of the sentinel node(s). METHODS: Between September 1995 and May 1999, lymphatic mapping using a combination of preoperative lymphoscintigraphy and/or blue dye was performed on 169 consecutive patients with clinically lymph node-negative primary operable breast cancer. Clinical and histological factors were assessed using univariate and multivariate analysis to determine those that were associated with intraoperative identification of the sentinel node. RESULTS: The sentinel node was identified at the time of surgery in 142 cases (84%). Of the clinical factors assessed, preoperative identification of the sentinel node on lymphoscintigraphy (P < 0.0001), use of blue dye in combination with isotope (P = 0.001), symptomatic palpable tumours (P < 0.05) and the experience of the surgeon (P = 0.03) were significant in identifying the sentinel node at operation. No histological factor was associated with intraoperative identification of the sentinel node. Using multivariate analysis, positive identification of the sentinel node on lymphoscintigram, the experience of the surgeon and the use of both blue dye and isotope for sentinel node mapping were independent factors associated with intraoperative sentinel node identification. The lymphoscintigram result was the strongest independent factor according to its beta value, a measure of the weight of significance. CONCLUSION: Patients undergoing sentinel lymph node mapping and biopsy should be warned of the possibility of failure of sentinel node identification at operation. Our results suggest that the best predictor of intraoperative sentinel node identification is the visualization of the sentinel node on preoperative lymphoscintigraphy. The result of the lymhoscintigram may allow for additional preoperative counselling of the patient regarding the success or failure of sentinel node biopsy. Technical factors such as the experience and diligence of the surgeon, as well as the sentinel node mapping technique, are also important in determining the success of the procedure.

Clinicians and computers: friends or foes?

BACKGROUND: Computer-aided learning is accepted by students as a learning resource, but the views of the teaching community are largely unknown. PURPOSE: To document clinicians' experience with computers and to record their attitudes toward computer usage in clinical practice and student education. METHODS: Questionnaire mailed out to all clinicians, including interns and residents, fellows, and attending physicians in 3 major teaching hospitals in South Australia, with a total of 646 clinical staff. RESULTS: Replies were received from 246 staff. Eighty percent of clinicians had at least 2 years of experience with computers and used computers for at least 2 hr each week. Despite this, there was an obvious lack of conviction among clinicians that computer-aided learning was of use in student education and assessment. This may reflect their lack of experience with this medium as an educational tool. CONCLUSIONS: If computer-aided learning is to make any significant impact on medical student education, it must be carefully and objectively evaluated, and its benefit must be clearly demonstrated to clinical teachers.

Immunohistochemical localization of CD1a-positive putative dendritic cells in human breast tumours.

The presence of a high number of infiltrating CD1a+ cells in malignant neoplasms has been reported to be associated with an improved prognosis, reduced tumour recurrence and fewer metastases. This study identified a population of CD1a+ cells within the lymphoid cell infiltrate in human ductal breast carcinoma (n = 52), which was significantly different from normal breast tissue, in which only two out of nine cases expressed CD1a+ cells (P = 0.0192). In the majority of cases, the infiltrate was low compared with the number of macrophages and T cells present (results not shown). There was no correlation between the number of CD1a+ cells and tumour grade, with all tumour grades expressing similar numbers of infiltrating CD1a+ cells. There was clear evidence, however, that the CD1a+ cells were closely associated with tumour cells. It is likely that CD1a+ cells have a role in antigen capture and presentation in human tumours, and this study documents the density of CD1a+ cells in a large sample of all histological grades of human breast carcinomas.

Reliability of sentinel node status in predicting axillary lymph node involvement in breast cancer.

OBJECTIVES: To assess the reliability of determining sentinel node status in staging regional lymph nodes in breast cancer. DESIGN AND SETTING: Prospective validation study in a major public teaching hospital, comparing histological sentinel node status with that of remaining axillary nodes. PATIENTS: 117 women who underwent sentinel node biopsy and axillary dissection for primary breast cancer between 1995 and 1998. MAIN OUTCOME MEASURES: Intraoperative success rate in sentinel node identification; false negative rate; predictive value of negative sentinel node status; overall accuracy of sentinel node status. RESULTS: The sentinel node was identified at operation in 95 patients (81.2%). Tumour involvement of the sentinel node was demonstrated in 29 of 31 women (93.5%; 95% CI, 79%-99%). Sixty-four of the 66 women in whom the sentinel node was negative for tumour showed no further involvement of remaining axillary nodes (standard haematoxylin-eosin histological assessment), giving a predictive value of negative sentinel node status of 97% (95% CI, 89%-100%). The overall accuracy in 95 women in whom sentinel node status was compared with axillary node status was 97.9%. CONCLUSIONS: Histopathological examination of the sentinel node is an accurate method of assessing axillary lymph node status in primary breast cancer and is likely to be incorporated into future surgical management of women with primary breast cancer.

CD1a positive putative tumour infiltrating dendritic cells in human breast cancer.

CD1a molecules are expressed on dendritic cells (DC) during certain maturational phases coincident with the functions of antigen capture and processing. During these phases, CD1a is anchored to the cytoplasmic membrane through its cytoplasmic domain and the antigenic binding domain is projected from the cell surface. Membrane bound HLA Class I and II molecules are also expressed at relatively high levels on DC, but it is not known whether there is any interdependence between CD1 expression and that of the classical histocompatability molecules. Recent information concerning the structure, function and likely role of CD1 in presentation of hydrophobic lipid and carbohydrate antigens to the immune system is detailed. The potential relevance of the lipid presenting functions of CD1 molecules for the detection and recognition of tumour glycolipid antigens is hypothesised and discussed. CD1 a tumour infiltrating putative dendritic cells are discussed in terms of their density, separation, culture and possible function in breast cancers in the light of recent findings.

Intraoperative scintigraphic localization and laparoscopic excision of accessory splenic tissue.

The recent advent of laparoscopic splenectomy for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) has been embraced by surgeons and hematologists in many institutions. However, the occurrence of accessory splenic tissue in a proportion of such splenectomies, either concurrently or later, raises the question of how to deal with this problem when it arises. We report that the laparoscopic approach, facilitated by lateral positioning, can be successfully used for the treatment of an accessory spleen causing recurrent ITP. The use of intraoperative nuclear imaging can greatly aid the localization and provide confirmation of complete excision of the nuclear focus, especially for a very small accessory spleen.

Lymphoid cell infiltration during breast cancer growth: a syngeneic rat model.

The systematic study of potential alterations in lymphoid infiltrates during tumour growth is extremely limited in humans. Therefore, development of a model utilizing a spontaneously arising mammary adenocarcinoma in Dark Agouti rats was adopted for the study of the dynamics of lymphoid cell infiltration during tumour development. Syngeneic rats were inoculated with tumour cell suspensions and the tumours were resected from 5 to 15 days. Serial sections were immunohistochemically stained using a panel of monoclonal antibodies. Irrespective of tumour age, ED2 (macrophages) and W3/25 (CD4)-positive cells were the most prominent cell infiltrates in tumours. There were no significant differences in cell counts for any marker between 8-day and 15-day tumours. However, in 5-day tumours there were significantly fewer macrophages, OX19+ T cells, W3/25+ cells, OX8+ (CD8) cells and OX62+ dendritic cells. Interleukin-2 receptor alpha chain expression was low at all examined stages of tumour growth, indicating a lack of tumour infiltrating lymphocyte (TIL) activation and/or possible TIL anergy. B cell staining was absent in all tumours, negating the possibility of these cells mediating coregulatory signals for TIL activation in the micro-environment of established tumours. The results parallel previous immunohistochemical findings in humans, suggesting that a dysfunctional local immune response in breast cancer may be determined very early during tumour development.

The utility of the proliferative index in pretreatment biopsy specimens of esophageal squamous cell carcinoma.

The proliferative index detected immunohistochemically by monoclonal antibody MIB-1 from pre-treatment biopsy tissues of 33 patients with esophageal squamous cell carcinoma who underwent preoperative concurrent chemoradiotherapy was evaluated in relation to clinicopathologic features and chemoradiotherapeutic responses. The response to chemoradiotherapy was assessed both endoscopically and pathologically and classified as complete or partial response. Higher MIB-1 LI was significantly associated with lymph node metastases, suggesting that detection of MIB-1 LI from biopsy tissues may contribute to pre-treatment staging of tumors and prediction of persistence of lymph node involvement after chemoradiotherapy, which would permit the optimization of systemic treatment for individual patients. Statistically, significant correlation existed between higher MIB 1-LI and poor overall survival, implicating the prognostic significance of the MIB-1 LI in patients undergoing multimodality treatment. No significant relationship was found between the MIB-1 LI and either endoscopic or pathologic responses, although a trend for tumors with lower MIB-1 LI to have better responses was observed.

Identification and isolation of CD1a positive putative tumour infiltrating dendritic cells in human breast cancer.

Identification of dendritic cells (DC) in human tissues has been technically problematic due to the lack of truly specific immunohistochemical markers for DC's. Human dendritic cells express CD1a glycoprotein at certain points in their life cycle. CD1a positive cells are present in many human tumours and have been associated with improved survival. However, little information exists concerning the separation of DC from human tumours. The current study reports that human breast carcinomas have low densities of CD1a positive cells with dendritic morphology, and details are shown of a technique for successful separation of these cells from tumour tissues.

Laparoscopic versus open splenectomy for immune thrombocytopenic purpura.

BACKGROUND: We sought to determine whether laparoscopic techniques can reduce the operative morbidity of surgery in patients undergoing splenectomy for immune thrombocytopenic purpura (ITP). METHODS: All patients (60) undergoing splenectomy for ITP at the Royal Adelaide Hospital from January 1985 to November 1995 were reviewed. Results of patients undergoing open operation were obtained by means of retrospective case note review, whereas details of all patients undergoing laparoscopic splenectomy were collected prospectively and maintained on a computerized database. RESULTS: Forty-seven patients underwent splenectomy with an open technique and 13 with a laparoscopic technique. Patient groups were demographically similar. All laparoscopic procedures were completed with the laparoscopic technique. An accessory spleen was also removed at laparoscopic operation from two (15%) patients and at open operation from three patients (6%). Two more accessory spleens were missed at the original procedure, one at open operation and one at laparoscopic operation. These required later removal by using open and laparoscopic techniques, respectively. Blood and platelet transfusion requirements were reduced by the laparoscopic approach. Although mean operating times were similar (87 versus 88 minutes), laparoscopic splenectomy was associated with a greatly reduced postoperative hospital stay (10 versus 2 days, median; p < 0.0001) and no major morbidity. Long-term normalization of platelet counts was similar for the two techniques. The laparoscopic approach resulted in a reduction in hospital treatment costs from $4224 to $2238 per case (cost savings of $1986 per case). CONCLUSIONS: Laparoscopic splenectomy results in improved clinical outcomes and reduced costs for patients undergoing elective splenectomy for ITP.

Lack of IL-2 cytokine expression despite Il-2 messenger RNA transcription in tumor-infiltrating lymphocytes in primary human breast carcinoma: selective expression of early activation markers.

Tumor-infiltrating lymphocytes (TIL) are found in most human infiltrating ductal breast carcinomas. In studies of other tumors, TIL were capable of activation by IL-2, both in vitro and in vivo, to produce selective tumor cytolysis. Specific TIL-mediated tumor cytolysis in human breast tumors has recently been reported. The large numbers of TIL within human breast cancers imply that an immune response is occurring, since many of these cells express HLA class II as a late activation marker. However, the degree of early activation of the native TIL in breast tumors has not been fully investigated. Early activation markers CD69, CD43, and CD38 together with the IL-2R (CD25) and IL-2 cytokine were examined using mAbs and tissue section immunohistology. In situ hybridization was used to detect IL-2 mRNA (IL-2 mRNA) in parallel with immunohistochemical localization of IL-2. The results revealed the expression of CD69, CD43, and CD38, but markedly low CD25 (IL-2R) and IL-2 protein expression by the TIL. This strongly indicates that the TIL are an activated population of T cells that shows a deficiency in IL-2 protein and IL-2R expression despite adequate levels of IL-2 mRNA. The mechanism for apparent inhibition of IL-2 production and IL-2R expression in the presence of IL-2 mRNA is currently unclear; however, this may explain the relative anergic state of native TIL.

Laparoscopic splenectomy using the lateral position: an improved technique.

An alternative approach to laparoscopic splenectomy is described. This technique uses a lateral position and modified port placement. Initial experience with three patients has demonstrated advantages over previously described approaches, by providing a more direct view of the splenic hilum and by eliminating the need for retraction of adjacent organs.