Ki-67 expression in melanoma. A potential method of risk assessment for the patient with a positive sentinel node.

Melanoma patients with a positive sentinel node biopsy generally proceed to regional lymph node dissection, though ultimately only around 20% have evidence of tumour in their "non-sentinel" nodes. A means to identify patients at high risk of non-sentinel node involvement could potentially spare a large number of patients a procedure with significant morbidity. The proliferation marker Ki-67 has been associated with tumour progression in primary melanoma but has not been extensively studied in metastases. The study aims to investigate Ki-67 in primary melanoma and lymph node metastases and investigate any relationship with disease progression. Tissue Arrays of primary melanoma (n=79) and lymph node metastases (n=92) were constructed from paraffin embedded tissue and Ki-67 expression examined by immunohistochemistry. Staining positivity and intensity were assessed and correlated with standard staging criteria and clinical outcome. High Ki-67 expression was associated with both Breslow thickness (chi(2)=8.54, p=0.035) and presence of ulceration (Fisher's Exact test p=0.003) in primary melanoma. In lymph node metastases high Ki-67 expression correlated with Nodal (N) Stage (chi(2)=8.193, p=0.0 17). High Ki-67 expression is associated with melanoma progression and multiple lymph node involvement. This might potentially form the basis of a risk analysis for patients with positive sentinel nodes.

The use of a cocktail of single chain Fv antibody fragments to improve the in vitro and in vivo targeting of melanoma.

Radioscintigraphy using single chain antibody fragments (scFvs) offers a potential means of early detection of melanoma metastases. However, previous studies have shown suboptimal levels of tumour localization and non-specific background accumulation which may be due to antigen heterogeneity. We aimed to improve tumour localization by using a cocktail of different scFvs targeting different epitopes on melanoma cells. We have previously developed three scFvs against distinct and highly tumour-specific melanoma cell-surface antigens by chain shuffling and antibody phage selection on melanoma cells. Three scFvs, RAFT3, B3 and B4 were labeled with 125Iodine and tested both individually and as a cocktail in a nude mouse xenograft model for human melanoma. Results demonstrated improved tumour localization in vivo when compared to the individual scFvs. Tumour uptake of the cocktail at 1 hour was 24.220% ID/g (injected dose/gram) compared with 2.854%, 2.263% and 1.355% for B4, RAFT3 and B3, respectively, when injected individually. In addition, the cocktail exhibited significantly superior tumour to normal tissue ratios for muscle and spleen (p<0.05). A combination or 'cocktail' of scFv clones may have an advantage over individual scFvs for melanoma targeting in patients because of heterogeneity in the expression of different epitopes of antigens on melanoma cells.

Preoperative planning for DIEP breast reconstruction: early experience of the use of computerised tomography angiography with VoNavix 3D software for perforator navigation.

The deep inferior epigastric perforator (DIEP) flap is normally the first choice in breast reconstruction; however, due to the considerable vascular anatomical variation and the learning curve for the procedure, muscle-sparing transverse rectus abdominis musculocutaneous (TRAM) flaps are still frequently performed to reduce the rate of complications. Accurate preoperative investigation of the perforators would allow better operative preparation and possibly shorten the learning curve. In an effort to increase accuracy of preoperative planning and to aid preoperative decision-making in free abdominal flap breast reconstruction, we have acquired the use of VoNavix, software that creates three dimensional images from computerised tomography angiography (CTA) data. The use of the VoNavix software for analysis of CTA provides superior imaging that can be viewed in theatre. It, together with CTA, enables decisions to be made preoperatively, including: which side to raise the flap; whether to aim for a medial or lateral row perforator; whether to take a segment of muscle and whether to expect an easy or difficult dissection. We have now performed over 60 free abdominal flap breast reconstructions aided with CTA, and 10 of these cases also used VoNavix technology. This paper presents our initial experience with the use of this software, illustrated with three patient examples. The advantages and disadvantages are discussed.

Stratification of patients by melanoma cell adhesion molecule (MCAM) expression on the basis of risk: implications for sentinel lymph node biopsy.

BACKGROUND: The usual indication for sentinel lymph node biopsy (SLNB) in melanoma is a primary tumour >1mm thickness but under these criteria less than 20% of SLNBs are positive. Of those patients with a negative sentinel node (SN) over 10% will have disease recurrence within 3 years. A more accurate delineation of candidate patients for SLNB and risk profile for negative SN patients is therefore desirable. Melanoma cell adhesion molecule (MCAM) is a predominant cell adhesion molecule of melanomas and its expression has been implicated in tumour progression and metastasis. AIMS: To compare MCAM expression in primary and metastatic melanoma and to investigate if MCAM expression in patients meeting the criteria for SLNB correlated with patient outcome. METHODS: Tissue arrays of primary (n=78) and metastatic (n=92) melanomas were constructed from archived paraffin embedded tissue and MCAM expression detected by immunohistochemistry. Staining positivity and intensity were assessed by visual scoring and correlated with clinical outcome. RESULTS: In patients meeting the current criteria for SLNB, Cox multivariate analysis showed both MCAM expression positivity and intensity were independently predictive of survival (P=0.007) and development of lymph node disease (P=0.01) in primary melanoma over and above established markers of prognosis, such as Breslow thickness. MCAM-negative patients had a 5-year survival of 92% compared with 40% for MCAM positive. CONCLUSIONS: Measurement of MCAM expression represents a potential method to stratify SLNB patients on the basis of risk. This would have considerable benefits in terms of both cost and patient morbidity.

The UK Government two-week rule and its impact on melanoma prognosis: an evidence-based study.

INTRODUCTION: In order to tackle increasing waiting lists the UK Government's 'two-week rule' was introduced for a number of cancers, including melanoma, in 2000. Whilst there is evidence that secondary prevention (i. e. early diagnosis) improves patient outcome, particularly in melanoma where early surgical excision is the only intervention to improve survival, there is as yet no evidence base for a 2-week limit. Any survival benefit from this Government target will not be demonstrable until long-term follow-up is available, realistically 10-year mortality figures in 2010. PATIENTS AND METHODS: To investigate an evidence base for the two-week rule in melanoma, we performed a retrospective study on patients with suspected skin cancers referred to a rapid access Pigmented Lesion Clinic (PLC) over a 4-year period with long-term survival data, and compared them to a historical control group. RESULTS: A total of 4399 patients attended the PLC from January 1993 to December 1996 and all were seen within 2 weeks. Ninety-six melanomas were diagnosed during this period with 96% treated within 2 weeks of GP referral, the majority (74%) excised on the day of PLC attendance. Melanoma patients (n = 78) diagnosed in the 2 years prior to the inception of the PLC waited 3-34 days for consultation and 4-74 days for treatment. Melanoma patients diagnosed in the PLC had significantly thinner tumours (Mann Whitney test, P < 0.001) and improved overall survival (chi(2) 18.1924; P < 0.001) compared with melanoma patients diagnosed before the inception of the clinic. CONCLUSIONS: This is, to our knowledge, the first example that consultation within a 2-week time-frame of GP referral impacts patient survival and the first evidence base behind Government guidelines for this particular cancer.

Tibial stress fracture as a complication of free-fibula vascularised graft for mandibular reconstruction.

The free vascularised fibula graft is used for a variety of reconstructive procedures and is frequently associated with donor site morbidity. Non-traumatic stress fracture to the tibia following a vascularised free-fibula graft is an uncommon but important complication. The diagnosis may be missed if radiological "stress views" of a possible fracture site are not performed, which may result in its underreporting. The authors report a case in which the aetiology, diagnosis and management recommendations are presented for discussion.

Use of an early-detection strategy to improve disease control in melanoma patients.

In order to assess whether early detection might lead to improvement in disease control for patients with melanoma, a rapid access pigmented lesion clinic (PLC) was set up at Mount Vernon Hospital, UK in 1993. Previously we have shown that thinner melanomas were detected via the PLC compared with those presenting prior to its establishment and with those referred via existing routes of referral. The aim of this study was to investigate whether both rates of disease recurrence and disease-free interval were improved via a rapid access PLC. A retrospective case notes audit was performed on three patient groups: those diagnosed with melanoma 1991-1992, those diagnosed via the PLC (1993-1996) and those diagnosed with melanoma through existing routes of referral after establishment of the PLC (1993-1996). There was a significantly improved disease-free interval for patients with regional recurrences diagnosed via the pigmented lesion clinic (PLC) when compared with pre-PLC, non-PLC groups (chi2=13.8487, p=0.0002; chi2=17.0164, p<0.0001, respectively), and when compared with all melanoma patients diagnosed after the establishment of the PLC, irrespective of route of referral (chi2=5.2773, p=0.0216). Local recurrences developed later in patients in the PLC group compared with the pre-PLC group (chi2=6.4883, p=0.0109), and the non-PLC group (chi2=18.49, p<0.0001). In addition there was a reduction in the proportion of regional and local recurrences in the PLC group when compared with the pre-PLC group (chi2=13.92, P<0.001; chi2=2.85, P=0.09 respectively) and non-PLC group (chi2=17.15, P<0.001; chi2=7.73, P=0.005, respectively). These results support the use of rapid access PLCs as a means of improving disease control for melanoma patients.