TBX2 controls a proproliferative gene expression program in melanoma.

Senescence shapes embryonic development, plays a key role in aging, and is a critical barrier to cancer initiation, yet how senescence is regulated remains incompletely understood. TBX2 is an antisenescence T-box family transcription repressor implicated in embryonic development and cancer. However, the repertoire of TBX2 target genes, its cooperating partners, and how TBX2 promotes proliferation and senescence bypass are poorly understood. Here, using melanoma as a model, we show that TBX2 lies downstream from PI3K signaling and that TBX2 binds and is required for expression of E2F1, a key antisenescence cell cycle regulator. Remarkably, TBX2 binding in vivo is associated with CACGTG E-boxes, present in genes down-regulated by TBX2 depletion, more frequently than the consensus T-element DNA binding motif that is restricted to Tbx2 repressed genes. TBX2 is revealed to interact with a wide range of transcription factors and cofactors, including key components of the BCOR/PRC1.1 complex that are recruited by TBX2 to the E2F1 locus. Our results provide key insights into how PI3K signaling modulates TBX2 function in cancer to drive proliferation.

Sentinel node biopsy status is strongly predictive of survival in cutaneous melanoma: Extended follow-up of Oxford patients from 1998 to 2014.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is widely used as a key investigatory tool for cutaneous melanoma, with results incorporated into the latest AJCC staging guidelines. We present the results of our extended follow-up of sentinel lymph node biopsy for melanoma over a sixteen-year period. METHODS: Data were collected prospectively from June 1998 to December 2014 from a single tertiary skin cancer referral centre. Chi-squared analysis was used to analyse patient demographics and primary tumour pathology. Survival analysis was conducted using Cox regression models and Kaplan-Meier survival curves. RESULTS: Over a sixteen-year period 1527 patients underwent SLNB in 1609 basins, with 2876 nodes harvested. 347 patients (23%) had a positive biopsy. The most common primary tumour sites for males was the back (32%); women had a significantly higher number of melanomas occurring on the lower and upper limbs (45% and 26% respectively) [all p < 0.0001, Chi-squared]. Mean follow-up time was 4.9 years. Patients with a positive SLNB at diagnosis were significantly more likely to die from melanoma (subhazard ratio 5.59, p = 0.000, 95% CI 3.59-8.69). Breslow thickness and ulceration were also significant predictors of melanoma-specific mortality. For patients with a primary Breslow >4.0 mm ten-year disease free survival was 52% for SLNB negative and 26% for SLNB positive patients. For Breslow thicknesses of 2.01-4 mm these values were 66% and 32% respectively. CONCLUSIONS: Sentinel lymph node biopsy status is strongly predictive of survival across all thicknesses of primary cutaneous melanoma.

New treatment approaches in melanoma: current research and clinical prospects.

Ipilimumab and vemurafenib have changed the clinical landscape in melanoma. Both drugs offer effective treatment for metastatic melanoma, but with limitations. Ipilimumab benefits only a minority of those treated, with no means to identify them prospectively. The efficacy of vemurafenib is tied to the presence of an activating mutation in BRAF, and so is more predictable. However, acquired resistance develops within months. As we understand these, and similar, agents better, the means to select patients for treatment, to increase the duration of response and to identify the best stage at which to intervene will lead to improved outcomes for patients. Several trials are already under way or being developed to build upon these exciting discoveries.

Sentinel lymph node biopsy in melanoma: The Oxford ten year clinical experience.

Sentinel lymph node biopsy (SLNB) has become an established investigation for assessing microscopic nodal metastasis in melanoma. The American Joint Committee on Cancer (AJCC) incorporates the sentinel node status in its staging criteria for melanoma. We present our clinical evaluation of performing SLNB in a single UK centre between 1998 and 2008. There were 697 patients with a mean age 53 years (range 13-92). We were able to surgically harvest at least one sentinel node in 694 patients of which 532 (76%) were negative. Of the 162 positive patients, 129 underwent further completion lymphadenectomy with 29 showing further pathologically positive nodes. At median follow up of 46 months, mortality from melanoma for SLN positive and negative patients was 32% and 4%, respectively. Disease recurrence was noted in 10% of the SLN negative group. Survival curves showed significant difference (p<0.001) in outcomes for patients grouped by Breslow thickness. Postoperative complications were noted in 6% of patients. No life-threatening complications were noted. Our results are comparable to other national and international studies. We await the outcomes of ongoing trials to assess the therapeutic value of SLNB for melanoma.