Follow-Up Recommendations after Diagnosis of Primary Cutaneous Melanoma: A Population-Based Study in New South Wales, Australia.

BACKGROUND: Follow-up practices after diagnosis and treatment of primary cutaneous melanoma vary considerably. We aimed to determine factors associated with recommendations for follow-up setting, frequency, skin surveillance, and concordance with clinical guidelines. METHODS: The population-based Melanoma Patterns of Care study documented clinicians' recommendations for follow-up for 2148 patients diagnosed with primary cutaneous melanoma over a 12-month period (2006/2007) in New South Wales, Australia. Multivariate log binomial regression models adjusted for patient and lesion characteristics were used to examine factors associated with follow-up practices. RESULTS: Of 2158 melanomas, Breslow thickness was < 1 mm for 57% and ≥ 1 mm for 30%, while in situ melanomas accounted for 13%. Follow-up was recommended for 2063 patients (96%). On multivariate analysis, factors associated with a recommendation for follow-up at a specialist center were Breslow thickness ≥ 1 mm [prevalence ratio (PR) 1.05, 95% confidence interval (CI) 1.01-1.09] and initial treatment at a specialist center (PR 1.12, 95% CI 1.08-1.16). Longer follow-up intervals of > 3 months were more likely to be recommended for females, less likely for people living in rural compared with urban areas, and less likely for thicker (≥ 1 mm) melanomas compared with in situ melanomas. Skin self-examination was encouraged in 84% of consultations and was less likely to be recommended for patients ≥ 70 years (PR 0.88, 95% CI 0.84-0.93) and for those with thicker (≥ 1 mm) melanomas (PR 0.92, 95% CI 0.86-0.99). Only 1% of patients were referred for psychological care. CONCLUSIONS: Follow-up recommendations were generally consistent with Australian national guidelines for management of melanoma, however some variations could be targeted to improve patient outcomes.

The Contemporary Role of Major Amputation in the Management of Advanced Limb Melanoma.

BACKGROUND: Major amputations are rarely performed for melanoma, with limb-preserving techniques used whenever possible. This article reviews the indications for major amputation in patients with melanoma and reports outcomes with the aim of better classifying progressive and potentially curable disease patterns. METHODS: At a single institution in Australia, 55 major amputations were performed for melanoma in 51 patients treated between 1984 and 2012. Clinicopathologic characteristics, treatments before amputation, and outcomes were analyzed. RESULTS: The 55 cases included 17 upper limb (9 forequarter) and 38 lower limb (3 hindquarter) amputations. The most common reasons for amputation were progressive in-transit metastases (ITM, 67 %), troublesome limb metastases from distant sites (14 %), pain or ulceration after regional chemotherapy (14 %) and otherwise inoperable regional recurrence (6 %). Regional chemotherapy was used before amputation for 58 % of the patients, and for those with ITM, it was associated with an increased interval between ITM diagnosis and amputation. The overall 5-year survival rate (5YS) from the time of amputation was 22.8 %. For stage 3 patients with either ITM or regional recurrence, who had all known disease resected at the time of amputation, the 5YS was 38.4 %. CONCLUSION: Major amputation may be indicated for advanced limb melanoma when limb-preserving strategies have been exhausted. Although they have advanced locoregional disease, some patients undergoing potentially curative amputation can achieve long-term survival.

In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy.

PURPOSE: To analyze a large, single-institution database to further understanding of melanoma in-transit metastases (ITM) with regard to incidence, prognosis, and the role of lymphadenectomy. METHODS: A total of 11,614 patients with single primary cutaneous melanomas were treated at Melanoma Institute Australia between January 1994 and December 2009. Of these, 505 developed ITM. Clinicopathologic characteristics, sentinel node (SN) status, patterns of disease progression, and outcomes were analyzed. RESULTS: In the 505 patients with ITM, the median primary tumor thickness was 2.95 mm, and 39.4 % were ulcerated. The ITM rates for patients with primary melanomas <1 or ≥1 mm in size and in those who underwent sentinel node biopsy were 0.4, 7.8, and 7.2 %, respectively. The ITM rates for SN-positive and SN-negative patients were 21.6 and 4.7 %, respectively. The median time from primary diagnosis to the development of ITM was 17.9 months. After ITM diagnosis, the median survival time was 19.9 months, 5-year survival was 32.8 %, and 10-year survival was 27.5 %. After ITM diagnosis, primary tumor site (head/neck, trunk) and ulceration were predictors of poorer survival. Five-year survival from the time of ITM ranged from 47.9 % for nonulcerated limb primary lesions to only 13.6 % for ulcerated trunk primary lesions. Elective lymph node dissection in clinically node-negative patients with ITM did not significantly alter overall survival. CONCLUSIONS: This large study demonstrates that the diagnosis of melanoma ITM carries serious adverse prognostic implications and will assist in improving the accuracy of staging and prognostic estimates as well as treatment in these patients.

Diverse presentations of acral melanoma.

BACKGROUND: Acral melanoma (AM) is an uncommon melanoma subtype occurring on the palms, soles and nail apparatus. It often lacks the typical features of primary melanoma resulting in delayed diagnosis. OBJECTIVE: This article aims to raise awareness of AM and promote a high index of clinical suspicion to enable early diagnosis and improve outcomes for patients with AM. DISCUSSION: The diagnosis of AM is often delayed because its presentation mimics other benign conditions such as fungal infections and ulcers. When lesions that were thought to be benign fail to respond to appropriate therapies, biopsy is critically important to exclude AM or other malignant pathology. Clinician awareness of the diversity of AM presentations, maintaining AM as part of their differential diagnosis and facilitating early biopsy are essential for early diagnosis and improving outcomes in patients with AM.

Surgical management of a giant fibroadenoma during lactation.

Fibroadenomas are the most common breast lesion in women of reproductive age. During pregnancy and lactation, fibroadenomas can undergo rapid growth in response to hormonal stimulus. These changes may prompt further investigation and/or intervention due to the risk of an underlying phyllodes tumour. We present a case of a female patient who underwent surgical excision of a giant fibroepithelial lesion at 4 months post partum while continuing to breastfeed. The lesion was successfully excised while maintaining lactation. A postoperative milk fistula resolved with non-operative management. There is limited literature on the surgical management of breast lesions in lactating women. This case illuminates the surgical management of breast lesions in an often well informed group of patients who may choose to have surgery while lactating in spite of the increased risk of complications. This case also highlights the need for a holistic approach to maintain the overall health of mother and child.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

The role of regional chemotherapy for advanced limb melanoma in the era of potentially effective systemic therapies.

To review the current role of regional chemotherapy in the management of advanced limb melanoma. Articles reporting the results of isolated limb infusion (ILI) were identified by performing a comprehensive literature search using the PubMed database. Keywords included isolated limb infusion, in-transit melanoma and melphalan. No publication date restrictions were applied. ILI data were compared with those from current systemic therapy clinical trials and the previously reviewed isolated limb perfusion (ILP) literature. Regional chemotherapy is today required in fewer patients because effective systemic therapies now provide an alternative treatment for those who develop extensive local melanoma recurrence or in-transit metastases (ITMs). However, regional chemotherapy may be a valuable treatment option when the side-effects of systemic therapies are of concern, or after systemic treatment failure. ILP achieves overall response rates (ORRs) of 64-100% and complete response rates (CRRs) of 25-89%. ILI achieves ORRs of 41-91% and CRRs of 6-39%. ILP and ILI can have a low risk of serious morbidity. Early results from treatment with ILP or ILI in conjunction with systemic immune therapies suggest that these modalities can be safely combined, which may be useful in patients with refractory limb disease. Regional chemotherapy remains important in the armamentarium of clinicians managing patients with unresectable limb melanoma and may be preferable in those who are frail, elderly or who are at high risk from complications of systemic therapies. The efficacy of combining regional chemotherapy with systemic immune therapy is currently being assessed.

Requirement of fission yeast Cid14 in polyadenylation of rRNAs.

Polyadenylation in eukaryotes is conventionally associated with increased nuclear export, translation, and stability of mRNAs. In contrast, recent studies suggest that the Trf4 and Trf5 proteins, members of a widespread family of noncanonical poly(A) polymerases, share an essential function in Saccharomyces cerevisiae that involves polyadenylation of nuclear RNAs as part of a pathway of exosome-mediated RNA turnover. Substrates for this pathway include aberrantly modified tRNAs and precursors of snoRNAs and rRNAs. Here we show that Cid14 is a Trf4/5 functional homolog in the distantly related fission yeast Schizosaccharomyces pombe. Unlike trf4 trf5 double mutants, cells lacking Cid14 are viable, though they suffer an increased frequency of chromosome missegregation. The Cid14 protein is constitutively nucleolar and is required for normal nucleolar structure. A minor population of polyadenylated rRNAs was identified. These RNAs accumulated in an exosome mutant, and their presence was largely dependent on Cid14, in line with a role for Cid14 in rRNA degradation. Surprisingly, both fully processed 25S rRNA and rRNA processing intermediates appear to be channeled into this pathway. Our data suggest that additional substrates may include the mRNAs of genes involved in meiotic regulation. Polyadenylation-assisted nuclear RNA turnover is therefore likely to be a common eukaryotic mechanism affecting diverse biological processes.

Managing in-transit melanoma metastases in the new era of effective systemic therapies for melanoma.

Introduction: Melanoma in-transit metastases (ITMs) occur between the primary tumor site and the regional node field. Most patients with ITMs have a poor prognosis. The treatment of ITMs can be simple if surgical excision is possible, but challenging when ITMs are advanced, multiple or recurrent and impacting quality of life.Areas covered: The management of ITM is still evolving. Patients who are disease-free after surgical excision of ITMs are today candidates for adjuvant systemic treatment to reduce recurrence risk. Some who have multiple or advanced ITMs may achieve long-term survival or disease control with systemic therapies alone. Those who do not remain candidates for the numerous locoregional therapies used to treat ITMs, including electrocautery, intralesional injection, topical therapy, electrochemotherapy, isolated limb infusion, isolated limb perfusion, radiation therapy and, rarely, amputation. Relevant publications identified in Pubmed and MEDLINE databases are reviewed.Expert opinion: Patients with multiple ITMs can benefit from use of systemic therapies as primary treatment, in the adjuvant setting and in neoadjuvant trials. Multiple alternative treatment modalities exist for patients unsuitable for systemic therapies or in whom systemic therapies have failed. Trials assessing combined systemic and locoregional therapies for ITMs are in progress.

Futility of imaging to stage melanoma patients with a positive sentinel lymph node.

The use of staging imaging in melanoma patients with a positive sentinel lymph node (SLN) has been reported to be of limited value. Improved accuracy resulting from the development of time-of-flight positron emission tomography (PET) and ongoing image quality improvement of computed tomography (CT) may challenge this statement. Our retrospective study assessed the clinical value of routine staging CT and PET/CT imaging in a recent cohort of asymptomatic SLN-positive patients. Between January 2011 and April 2014, 143 patients with a positive SLN were routinely staged using CT of various parts of the body or whole-body PET/CT. Scores were assigned for level of certainty for regional or distant metastases and incidental second primary malignancies. Diagnostic test performance was assessed, as well as the number and nature of ensuing additional diagnostic actions. CT was performed in 102 of 143 (71%) patients and PET/CT in 41 (29%) patients. The use of PET/CT increased over the study period. Metastases were found in two of the 143 patients (true-positive yield 1.4%). Sensitivity, specificity and positive predictive value were 11, 73 and 4% for CT and 17, 57 and 6%, respectively, for PET/CT. None of the 143 patients had a change in AJCC stage. Two other primary malignancies were found. Twenty-one (15%) patients were subjected to 37 additional investigations, referrals or procedures. Routine staging imaging with CT or PET/CT in SLN-positive patients is not useful. The yield is low and the results are often false positive, leading to unnecessary additional tests, most of which are costly and some potentially morbid.

Utility of neoadjuvant chemotherapy in the treatment of operable breast cancer.

Neoadjuvant chemotherapy (NAC) is a legitimate alternative to first-line surgical therapy for the treatment of breast cancer patients, as level one evidence shows the effect on overall survival is equivalent to that of adjuvant chemotherapy. In the treatment of women with operable breast cancer, NAC provides a number of potential advantages including: improving the chance of achieving breast-conserving surgery, improving cosmesis after breast-conserving surgery, downstaging the breast and axilla, allowing time to fully consider surgical options, time for genetic testing and facilitating breast reconstruction in otherwise high-risk patients. However, in Australia, NAC is poorly utilized with less than 3% of women with operable breast cancer receiving NAC. This review discusses the potential harms and benefits of NAC, discusses areas of controversy in the use of NAC and describes how we have used NAC in our own practice. We conclude that if it is obviously necessary for the newly presenting breast cancer patient to have chemotherapy as part of the treatment, it is worth considering NAC. In many patients, the potential benefits of NAC outweigh the harms. However, maximizing these benefits is closely aligned with appropriate patient selection and timely multidisciplinary team communication.

Head and neck multidisciplinary team meetings: Effect on patient management.

BACKGROUND: The purpose of this study was for us to present our findings on the prospectively audited impact of head and neck multidisciplinary team meetings on patient management. METHODS: We collected clinical data, the pre-multidisciplinary team meeting treatment plan, the post-multidisciplinary team meeting treatment plans, and follow-up data from all patients discussed at a weekly multidisciplinary team meeting and we recorded the changes in management. RESULTS: One hundred seventy-two patients were discussed in 39 meetings. In 52 patients (30%), changes in management were documented of which 20 (67%) were major. Changes were statistically more likely when the referring physician was a medical or radiation oncologist, when the initial treatment plan did not include surgery, and when the histology was neither mucosal squamous cell cancer nor a skin malignancy. Compliance to the multidisciplinary team meeting treatment recommendation was 84% for all patients and 70% for patients with changes in their treatment recommendation. CONCLUSION: Head and neck multidisciplinary team meetings changed management in almost a third of the cases.

PCR-based expression analysis and identification of microRNAs.

microRNAs (miRNAs) are small RNAs that regulate translation and hence control a variety of cellular processes in metazoans. The quantitation and identification of miRNAs has been hampered by their small size and low abundance. Here we describe two robust PCR-based assays of miRNA expression based on the original cloning strategy. The non-quantitative PCR method allows detection and identification of miRNAs and we utilise this method in the discovery of a new miRNA (miR-532) in retinoic acid differentiated P19 cells. The second and quantitative method (QM-RT-PCR) is simple and accurate, and uses commonly available technology. Of particular interest is the specificity of this PCR-based technology compared to hybridisation-based methods including arrays and northern blotting. Here we have shown that a single base pair mismatch in the priming sequence results in a two order of magnitude reduction in the amplification of let-7f. These streamlined methods will complement previously described methods and will facilitate analysis of miRNA expression in rare cell populations where the amount of RNA is limited.

Roles for cytoplasmic polyadenylation in cell cycle regulation.

Polyadenylation of eukaryotic mRNAs in the nucleus promotes their translation following export to the cytoplasm and is an important determinant of mRNA stability. An additional level of control of gene expression is provided by cytoplasmic polyadenylation, which activates translation of a number of mRNAs important in orchestrating cell cycle events in oocytes. Recent studies indicate that cytoplasmic polyadenylation may be a mechanism of translational activation that is more widespread in eukaryotic cells. Here we discuss the roles of a recently identified family of nucleotidyl transferases (encoded by the cid1 gene family) in cell cycle regulation. To date, this family has been characterised mainly in yeasts, but it is conserved throughout the eukaryotes. Biochemical studies have indicated that a subset of members of this family function as cytoplasmic poly(A) polymerases targeting specific mRNAs for translation. This form of translational control appears to be particularly important for cell cycle regulation following inhibition of DNA synthesis.

Fission yeast Pds5 is required for accurate chromosome segregation and for survival after DNA damage or metaphase arrest.

Sister chromatid cohesion, which is established during the S phase of the eukaryotic cell cycle and persists until the onset of anaphase, is essential for the maintenance of genomic integrity. Cohesion requires the multi-protein complex cohesin, as well as a number of accessory proteins including Pds5/BIMD/Spo76. In the budding yeast Saccharomyces cerevisiae Pds5 is an essential protein that localises to chromosomes in a cohesin-dependent manner. Here we describe the characterisation in the fission yeast Schizosaccharomyces pombe of pds5(+), a novel, non-essential orthologue of S. cerevisiae PDS5. The S. pombe Pds5 protein was localised to punctate nuclear foci in a manner that was dependent on the Rad21 cohesin component. This, together with additional genetic evidence, points towards an involvement of S. pombe Pds5 in sister chromatid cohesion. S. pombe pds5 mutants were hypersensitive to DNA damage and to mitotic metaphase delay, but this sensitivity was apparently not due to precocious loss of sister chromatid cohesion. These cells also suffered increased spontaneous chromosome loss and meiotic defects and their viability was dependent on the spindle checkpoint protein Bub1. Thus, while S. pombe Pds5 has an important cohesin-related role, this differs significantly from that of the equivalent budding yeast protein.

Cytoplasmic poly(A) polymerases mediate cellular responses to S phase arrest.

The S-M checkpoint delays mitosis until DNA replication is complete; cells defective in this checkpoint lose viability when DNA replication is inhibited. This inviability can be suppressed in fission yeast by overexpression of Cid1 or the related protein Cid13. Fission yeast contain six cid1/cid13-like genes, whereas budding yeast has just two, TRF4 and TRF5. Trf4 and Trf5 were recently reported to comprise an essential DNA polymerase activity required for the establishment of sister chromatid cohesion. In contrast, we find that Cid1 is not a DNA polymerase but instead uses RNA substrates and has poly(A) polymerase activity. Unlike the previously characterized yeast poly(A) polymerase, which is a nuclear enzyme, Cid1 and Cid13 are constitutively cytoplasmic. Cid1 has a degree of substrate specificity in vitro, consistent with the notion that it targets a subset of cytoplasmic mRNAs for polyadenylation in vivo, hence increasing their stability and/or efficiency of translation. Preferred Cid1 targets presumably include mRNAs encoding components of the S-M checkpoint, whereas Cid13 targets are likely to be involved in dNTP metabolism. Cytoplasmic polyadenylation is known to be an important regulatory mechanism during early development in animals. Our findings in yeast suggest that this level of gene regulation is of more general significance in eukaryotic cells.