Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Desmoplastic melanoma: a review of its pathology and clinical behaviour, and of management recommendations in published guidelines.

Desmoplastic melanomas are uncommon. Their behaviour differs from that of other melanoma subtypes; therefore, management guidelines for non-desmoplastic melanomas may not be applicable. This review sought to examine all available evidence relating to the behaviour and management of desmoplastic melanomas, based on review of all relevant English-language publications, and to critically assess the recommendations for their management in current published melanoma management guidelines. Compared with other melanoma subtypes, patients with 'pure' desmoplastic melanomas (where ≥90% of the invasive melanoma is of desmoplastic melanoma subtype) have much lower rates of sentinel node positivity and distant metastasis. Local recurrence rates are higher for desmoplastic melanomas, but resection margins wider than those recommended for non-desmoplastic melanomas have not been shown to be of benefit. Adjuvant radiotherapy reduces the risk of local recurrence when a satisfactory histological clearance (≥8 mm) cannot be achieved. Of 29 published melanoma management guidelines identified, only 11 specified management for desmoplastic melanomas, while seven simply stated that the feature should be reported. Desmoplastic melanoma is a unique melanoma subtype with biology that differs from that of other melanoma subtypes. It requires specific management strategies but few current guidelines address these.

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients.

BACKGROUND: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma. PATIENTS AND METHODS: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS). RESULTS: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma. CONCLUSION: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

Representativeness of initial skin biopsies showing pure desmoplastic melanoma: implications for management.

Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is ≥90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but to the best of our knowledge this has not been previously assessed or quantified. The aim of this study was to assess the concordance of the proportion of desmoplastic melanoma in an initial partial biopsy of PDM with the proportion in the entire tumour following complete excision, in patients with cutaneous melanoma. A secondary aim was to determine how frequently this potentially resulted in a patient not receiving a SLNB. Seventy-eight cases of cutaneous melanoma were identified from the Melanoma Institute Australia (MIA) database and 23 cases from the Memorial Sloan Kettering Cancer Centre (MSKCC), where an initial biopsy contained PDM and a subsequent wide excision had residual invasive melanoma. Clinicopathological features were analysed in all patients, including whether a SLNB was performed, the results of SLNB, and any subsequent recurrence. Ninety percent (91/101) of cases were still classified as PDM in the complete wide excision specimen while 10% (10/101) of cases were reclassified as MDM, which was a significant change in classification of final desmoplastic melanoma subtype (p<0.001). The proportion of desmoplastic melanoma was also significantly different between the initial and excisional biopsies (p=0.004). Forty-eight (48/101) patients had a SLNB, of which two (4.5%) were positive for metastatic melanoma; both cases were PDM in the excision specimen. Of the 10 cases demonstrating MDM in the excision specimen, the initial biopsy was a punch biopsy in six cases, shave biopsy in two cases and subcutaneous tissue was sampled in two patients (one punch biopsy, one incisional biopsy). Four of these 10 patients underwent SLNB which was negative in all cases. Twenty-two patients developed recurrence in the follow-up period (median 30 months, range 1-192 months), three with MDM in their excision specimen. One patient did not have a SLNB and developed regional lymph node recurrence. In this study there was a 10% risk that the percentage of desmoplastic melanoma in an initial biopsy of PDM was not representative of the entire lesion, resulting in reclassification as MDM in the excision specimen. If a SLNB is not performed in such cases, a positive SLNB may be missed (one patient in our study) which could impact treatment options for the patient. We recommend caution in not offering a SLNB in the setting of an initial biopsy of PDM if the biopsy is small compared with the overall lesion. If a SLNB is not procured at the time of wide excision in such cases, the SLNs should still be mapped by lymphoscintigraphy to facilitate careful follow up and to enable earlier detection and treatment of nodal disease.

The management of cervical lymph nodes in patients with cutaneous melanoma.

BACKGROUND: The aim of this study was to review the management of cervical lymph nodes in patients with cutaneous melanoma and to analyze factors influencing prognosis. METHODS: This was a retrospective cohort study of patients who had cervical node surgery at the Sydney Melanoma Unit from 1990 to 2004. RESULTS: Of 716 patients who met the study criteria, 339 had a sentinel node biopsy (SNB) and 396 had a neck dissection. Locoregional recurrence occurred in 27.6 % of those undergoing therapeutic neck dissection and 60 % eventually developed distant metastases. Radiotherapy was given as adjuvant treatment in 110 of the patients who had a therapeutic neck dissection (41 %), but this was not associated with improved regional control (p = .322). Multivariate analysis showed that nodal positivity (p < .001) and primary tumor ulceration (p = < .027) were the most important predictors of locoregional recurrence and that primary tumor Breslow thickness (p = .009) and node positivity (p = .046) were the most important factors predicting survival. SNB-positive patients who underwent immediate completion lymphadenectomy had a 5-year survival advantage over those who had a therapeutic neck dissection for macroscopic disease (54 % vs 47 %, p = .028). CONCLUSIONS: Nodal status was the most important factor predicting disease-free and overall survival in patients with melanoma of the head and neck. Adjuvant radiotherapy was not associated with better locoregional control in the non-randomized cohorts of patients in this study.

Expression of mutant p53 in melanoma.

Mutant p53 has been noted in a variety of human malignancies including carcinomas of lung, breast, and colon, which have also been reported to have frequent karyotype anomalies involving the locus of the p53 gene (17p13). Whereas chromosomal abnormalities of chromosomes 1, 6, and 7 have been noted previously in melanoma, frequent aberrations in chromosome 17 have not been reported previously. Due to the common mutation of this locus in so many types of neoplasms, a range of melanomas from different stages of tumor progression were examined immunohistochemically for expression of mutant p53, in order to assess its prevalence and consider the role of this oncogene in the biological progression of melanoma. Forty-five of 53 (85%) specimens from a range of primary and metastatic melanomas were found to have detectable evidence of p53 gene mutation, by virtue of the immunohistochemical detection of mutant p53 protein. Significantly increased prevalence of mutant p53 was found in metastatic melanoma, compared with primary tumors (P less than 0.05). These findings represent one of the highest incidences of this oncogenic mutation yet recorded in a human malignancy and support the concept that p53 may have a functional role in development of the metastatic tumor phenotype.

Quality assurance in melanoma surgery: The evolving experience at a large tertiary referral centre.

BACKGROUND: The quality of melanoma surgery needs to be assessed by oncological outcome and complication rates. There is no published consensus on complication rates for common melanoma surgeries, namely wide excision (WE), sentinel node biopsy (SNB) and regional lymph node dissection (RLND). Consequently there are no agreed standards by which surgeons can audit their practices. METHODS: Surgical standards were proposed in 2008 following review of the literature and from expert opinion. Melanoma Institute Australia (MIA) self-reported audit data from 2011 and 2012 were compared with these standards. To quality check the self-reported audit, RLND data were extracted from the MIA database. RESULTS: Six surgeons performed a mean of 568 surgeries each quarter; with a mean of 106 major procedures. Following WE with primary closure or flap repair, wound infection or dehiscence occurred in <1% of cases. When skin grafting was required non-take of >20% of the grafted area was observed in 5.9% of cases. Following SNB wound infection and significant seroma occurred in 1.8% of cases. RLND node counts were below the 90% standard in 4 of 409 procedures. In comparison, data extraction identified 405 RLNDs, with node counts below the 90% standard in eight procedures. Two of these patients had previously undergone surgery removing nodes from the field and two had gross coalescing disease with extensive extra-nodal spread. CONCLUSION: The quality standards proposed in 2008 have been validated long-term by high volume caseloads. The data presented provide standards by which melanoma surgeons can audit their surgical performance.

Radioimmunodetection of human melanoma.

Radioimmunodetection has been shown to be an invaluable method in the diagnosis of primary and metastatic malignant disease. Fourteen patients, consisting of four men and 10 women with clinical suspicion of metastatic malignant melanoma or ocular melanoma were prospectively evaluated with the technique. Ten (71%) had positive and four (29%) had negative scintigrams. There was one false-positive scintigram. The overall sensitivity and specificity were 100% and 80%, respectively. SPET was necessary for the radioimmunodetection of patients with ocular melanoma. Combined immunoscintigraphy and immunolymphoscintigraphy enhanced the diagnosis of small, cutaneous melanoma and metastatic lymph node disease.

Nasolacrimal abnormalities in oblique facial clefts.

A patient with a Tessier No. 4 cleft and an associated bifid nasolacrimal system is presented and considered within the Tessier classification of craniofacial clefting. Previous accounts of nasolacrimal abnormalities associated with facial clefts are reviewed together with the accepted developmental embryology. It is proposed that the bifid nasolacrimal duct system described constitutes a new addition to the literature.

Pneumosinus dilatans as the aetiology of progressive bilateral blindness.

Pneumosinus Dilatans is a rare condition of the craniofacial skeleton which was diagnosed in an adolescent male who presented with progressive bilateral blindness and many features of osteodysplasty (Melnick-Needles Syndrome). The clinical course and unusual pathology of this case which included the compression of both optic nerves within long tubes of bone are described, together with the surgical intervention performed to arrest the patient's loss of vision.

Long term central venous access catheters: review of 134 catheters inserted in 100 patients.

The first 100 patients at Westmead Centre who received long term central venous access catheters were reviewed. The indication for insertion in 77% of the patients was administration of chemotherapy, 15% had insertion for parenteral nutrition and 8% for blood product administration or anti-microbial therapy. Catheter manipulations were carried out under strict aseptic conditions by a limited group of nursing staff. Of the catheters, 73.1% functioned satisfactorily and were removed electively or were functioning at death or time of review. The main reason for removal was suspected infection, but this was proven in only 4.5% although strongly suspected in another 5.2%. The infection rate was 13 episodes per 13 987 catheter days. The duration of function of catheters was analysed by the life table method, demonstrating a 50% catheter survival rate of 300 days.

A study of adhesion molecules as markers of progression in malignant melanoma.

Adhesion molecules are substances which are involved in the interactions between cells, and between cells and the extracellular matrix in both benign and malignant tissues. Two members of this group--intercellular adhesion molecule-1 (ICAM-1) and MUC18--have previously been found to be expressed on melanoma; however, studies seeking a correlation between expression and metastatic behaviour have yielded conflicting results. In this study we investigated the expression of these two antigens and that of a number of other adhesion molecules [VCAM-1, ELAM, and the neural cell adhesion molecule (NCAM)] on a range of benign and malignant melanocytic lesions. Both ICAM-1 and MUC18 were found on a high percentage of all melanocytic lesions including benign naevi. VCAM-1 was found to be expressed on 79 per cent of benign naevi, 62 per cent of primary melanomas less than 1.5 mm in depth, and 6 per cent of thick primaries. The antigen was present on 14 per cent of lymph node metastases and on no extranodal deposits. This suggests that loss of melanoma cell adhesion mediated by VCAM-1 may be important in the development of metastatic melanoma.

Preclinical detection of metastatic melanoma.

We present a patient with melanoma in whom the performance of combined immunoscintigraphy and immunolymphoscintigraphy indicated the presence of metastatic disease 16 months before clinical manifestation. This approach may be useful in the early detection of metastatic disease and the patient presented is a lesson that cutaneous foci of uptake should not be dismissed as false-positive in the absence of clinical correlation.