Simon Donahoe

CD271 Expression on Patient Melanoma Cells Is Unstable and Unlinked to Tumorigenicity.

The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271(-) and CD271(+) melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271(-) or CD271(+) cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271(-) and CD271(+) melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271(-) or CD271(+) cells showed large pairwise differences in copy number (28%-48%). Differences were also apparent in the copy number profiles of CD271(-) and CD271(+) cells purified directly from each of the four melanomas (1.4%-23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965-77. ©2016 AACR.

Why there are two rows of deep inferior epigastric artery perforators despite variability in the number of deep inferior epigastric artery trunks: An anatomical and embryological argument

The deep inferior epigastric artery (DIEA) distributes musculocutaneous perforators in a uniform pattern that comprises “medial row” versus “lateral row” perforators, with these two rows having anatomical and functional differences. This pattern of two perforator rows is distributed from the DIEA regardless of the number of major DIEA trunks, with there variably being one to four major trunks. As such, a single DIEA trunk will still distribute two perforator rows, as will four major DIEA trunks. What remains to be answered is how such an anatomical fact may come to be? The answer probably lies in the anatomy and embryology of the rectus abdominis muscle itself. With two muscle heads to each hemiabdominal rectus abdominis muscle present from early in its development, it is highly likely that each head of rectus abdominis muscle draws its own blood supply from its source DIEA pedicle, one “perforator row” for each head, regardless of DIEA branching pattern from which these rows are drawn, thus providing an embryological and anatomical basis for the observation of two uniform perforator rows. Clin. Anat. 24:786–788, 2011.

Don't sit on chronic inflammation

A 77-year-old male presented with a long-standing, slow growing, painful, fungating lesion in the natal cleft (Fig. 1a). The patient stated that he had first presented at the age of 18 on routine examination for National Service with a weeping sore in that area. At the time, he was offered treatment, but refused surgery. Five years later, the patient had a pilonidal cystectomy for a ‘ruptured cyst’. Over the proceeding 50+ years, the patient has experienced discomfort and discharge from the area and more recently a growth. On examination, a number of small pits were detected running the length of the natal cleft (Fig. 1b). Histological biopsy confirmed well-differentiated squamous cell carcinoma (SCC). PET scanning revealed an 11-cm long lobulated area in the natal cleft involving the medial aspect of the left gluteus maximus, with no involvement of the coccyx. No nodal or metastatic disease was evident (Fig. 2). Following Multidisciplinary discussion, the patient underwent surgery. With the patient in the prone jack knife position, a wide en bloc excision of the tumour and skin was performed down to the sacrum and the circular muscle fibres of the rectum. A fasciocutaneous flap was raised from the right buttock, based on perforating vessels from the superior and inferior gluteal arteries, and advanced across the midline. The flap was advanced and rotated medially into the operative defect (Fig. 3). Post-operative histopathology confirmed a large (150 ¥ 60 ¥ 55 mm) SCC arising in a pilonidal sinus. The tumour was largely well differentiated with areas of poorly differentiated tissue, with no lymphovascular invasion. The patient subsequently received radiotherapy. Owing to the paucity of evidence concerning chemotherapy, it was felt by the Multidisciplinary members that this would be of questionable benefit. Malignant degeneration of pilonidal disease is rare, most being SCC, with basal cell carcinoma and sweat gland adenocarcinoma also being reported. Currently, there are around 60 cases published worldwide. (a)

A unique deep inferior epigastric artery perforator and implications for a muscle and fascia sparing vertical rectus abdominis myocutaneous flap: A case report†‡§

Despite the sacrifice of rectus abdominis muscle, the vertical rectus abdominis musculocutaneous (VRAM) flap is still a preferred option for perineal reconstruction. This journal has previously reported on the utility of preoperative computed tomographic angiography (CTA) in this setting to identify cases that are both suitable and unsuitable for rectus abdominis flaps after previous surgery. We report a case which highlights a unique example of the benefits of such imaging, with the largest deep inferior epigastric artery (DIEA) perforator described to date identified on imaging, and used to potentiate a donor‐site sparing procedure. The use of this dominant perforator was able to limit donor site harvest to only a small cuff of anterior rectus sheath and a small segment of rectus abdominis, potentiating a muscle‐sparing and fascia‐sparing VRAM flap for perineal reconstruction. As such, preoperative CTA was found to be a useful tool in identifying a unique anatomical variant in the largest DIEA perforator described to date, and was used to potentiate a muscle‐sparing and fascia‐sparing VRAM flap for perineal reconstruction.

Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma

Background As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Melanoma in the very elderly, management in patients 85 years of age and over

OBJECTIVES Melanoma treatment in the elderly can entail complex decision making. This study characterizes the presentation, management, and outcome of melanoma in the very elderly. METHOD Retrospective review of all patients in their 85th year or older presenting to a tertiary referral cancer centre between 2000 and 2012 with American Joint Committee on Cancer stages 0-II cutaneous melanoma. RESULTS 127 patients, 26 with in-situ disease and 101 with stages I-II disease, were included. For invasive primary disease, the median age was 87years (IRQ=86-89). Most patients had melanomas with poor prognoses at diagnosis: 49.5% were ulcerated, 68.3% mitotically active (mitotic rate≥1), and the median tumor thickness was 3.7mm (IQR=1.7-5.8). Nodular melanomas were the most frequent subtype (31.7%, 32/101). Only 66.3% received an excision margin≥10mm. Suboptimal excision margins were associated with increased risk of local recurrence (HR=6.87, 95% CI=5.53-8.20, p=0.0045) but not poorer disease specific survival (DSS, p=0.37) or overall survival (OS, p=0.19). Sentinel node biopsy (SNB) did not influence survival (DSS, p=0.39, OS, p=0.78). Median OS was 33months. Overall, one-third (34.7%) of patients died from causes other than melanoma during the follow up period. In patients aged ≥90 only 1 patient (4.3%) died from melanoma, while 10 patients (43.5%) died of other causes. CONCLUSIONS Older patients have thick, mitotically active and frequently ulcerated melanomas. An excision margin≥10mm should be considered to reduce risk of local recurrence. SNB did not impact on survival. With increasing age, patients will more commonly die of causes other than melanoma regardless of the extent of surgical care.

Excision margins and sentinel lymph node status as prognostic factors in thick melanoma of the head and neck: A retrospective analysis.

Recommended margins for thick cutaneous melanoma (Breslow thickness >4 mm; T4) have decreased over recent decades. Optimal margins and the role of sentinel node biopsy (SNB) in thick head and neck melanoma remain controversial.

A giant fungating metastatic basal cell carcinoma of the back and novel reconstruction using two large keystone design island perforator flaps

became 94.4% in our study (82.0% Heal). In most of the cases without specified clinical diagnoses, description of the lesions and durations were reported. The surgeons performed the excision or incision biopsies due to features of malignancy, including ulceration, telangiectasia and crusting. PPV for the punch or incision biopsy were relatively low (Table 2), reflecting the fact that they were performed whenever the clinical diagnosis was in doubt. The false positive and false negative results indicate the importance of skin cancer training programmes and audits that allow doctors to systematically review their practice and improve the accuracy of diagnosis. The accuracy of clinical diagnosis determines the prioritisation of treatment and use of resources. Establishing a benchmark for the PPV and sensitivity of clinical diagnosis of BCC is important. This facilitates ongoing audit to monitor and maintain the healthcare provided to our patients.