Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

Development of melanoma clinical quality indicators for the Australian melanoma clinical outcomes registry (MelCOR): A modified Delphi study.

BACKGROUND: Clinical quality registries aim to identify significant variations in care and provide anonymised feedback to institutions to improve patient outcomes. Thirty-six Australian organisations with an interest in melanoma, raised funds through three consecutive Melanoma Marches, organised by Melanoma Institute Australia, to create a national Melanoma Clinical Outcomes Registry (MelCOR). This study aimed to formally develop valid clinical quality indicators for the diagnosis and early management of cutaneous melanoma as an important step in creating the registry. METHODS: Potential clinical quality indicators were identified by examining the literature, including Australian and international melanoma guidelines, and by consulting with key melanoma and registry opinion leaders. A modified two-round Delphi survey method was used, with participants invited from relevant health professions routinely managing melanoma as well as relevant consumer organisations. RESULTS: Nineteen participants completed at least one round of the Delphi process. 12 of 13 proposed clinical quality indictors met the validity criteria. The clinical quality indicators included acceptable biopsy method, appropriate excision margins, standardised pathology reporting, indications for sentinel lymph node biopsy, and involvement of multidisciplinary care and referrals. CONCLUSION: This study provides a multi-stakeholder consensus for important clinical quality indicators that define optimal practice that will now be used in the Australian Melanoma Clinical Outcomes Registry (MelCOR).

Translationally controlled tumour protein TCTP is induced early in human colorectal tumours and contributes to the resistance of HCT116 colon cancer cells to 5-FU and oxaliplatin.

BACKGROUND: Translationally controlled tumour protein TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Here we study the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin. METHODS: Using immunohistochemistry, we assessed TCTP levels in surgical samples from adenomas and adenocarcinomas of the colon, compared to normal colon tissue. We also studied the regulation of TCTP in HCT116 colon cancer cells in response to 5-FU and oxaliplatin by western blotting. TCTP mRNA levels were assessed by RT-qPCR. We used mTOR kinase inhibitors to demonstrate mTOR-dependent translational regulation of TCTP under these conditions. Employing the Real-Time Cell Analysis (RTCA) System and the MTS assay, we investigated the effect of TCTP-knockdown on the sensitivity of HCT116 cells to the anti-cancer drugs 5-FU and oxaliplatin. RESULTS: 1. TCTP levels are significantly increased in colon adenomas and adenocarcinomas, compared to normal colon tissue. 2. TCTP protein levels are about 4-fold upregulated in HCT116 colon cancer cells, in response to 5-FU and oxaliplatin treatment, whereas TCTP mRNA levels are down regulated. 3. mTOR kinase inhibitors prevented the up-regulation of TCTP protein, indicating that TCTP is translationally regulated through the mTOR complex 1 signalling pathway under these conditions. 4. Using two cellular assay systems, we demonstrated that TCTP-knockdown sensitises HCT116 cells to the cytotoxicity caused by 5-FU and oxaliplatin. CONCLUSIONS: Our results demonstrate that TCTP levels increase significantly in the early stages of CRC development. In colon cancer cells, expression of this protein is largely upregulated during treatment with the DNA-damaging anti-cancer drugs 5-FU and oxaliplatin, as part of the cellular stress response. TCTP may thus contribute to the development of anti-cancer drug resistance. These findings indicate that TCTP might be suitable as a biomarker and that combinatorial treatment using 5-FU/oxaliplatin, together with mTOR kinase inhibitors, could be a route to preventing the development of resistance to these drugs.

Metastatic Ductal Eccrine Adenocarcinoma with Excellent Response to Immunotherapy.

Eccrine carcinoma, a subtype of which is ductal eccrine adenocarcinoma (DEA), is a rare cutaneous malignancy. For metastatic eccrine carcinoma, there are very limited data to guide treatment. Conventional chemotherapy is of limited benefit and there is only a small body of evidence for the use of immunotherapy in non-DEA eccrine carcinomas. We report the first case of metastatic DEA treated with a multimodality approach including surgery, radiotherapy, and immunotherapy, with an excellent prolonged response to pembrolizumab, and provide a review of the literature on pathological and management aspects for this rare tumour subtype. A 60-year-old male with a history of pT1N0M0 left scalp DEA, managed 2 years prior with excision and adjuvant radiotherapy, represented with a symptomatic right pontine metastasis. Imaging demonstrated intracranial, pulmonary, and hilar disease; biopsy of the cranial and lung lesions showed metastatic adenocarcinoma, morphologically similar to the previously resected scalp DEA. The patient was treated with stereotactic resections of his pontine metastases and adjuvant cranial radiotherapy, then commenced on immunotherapy with pembrolizumab. The patient has completed 21 months of pembrolizumab with a significant radiological response of the pulmonary and hilar disease and nil evidence of intracranial recurrence or further metastases. In this case report, we provide the first evidence of efficacy of immunotherapy in metastatic DEA, demonstrating an excellent and prolonged response of metastatic DEA to pembrolizumab. Further research is required to better establish the role of immunotherapy within the management protocol for this uncommon but aggressive tumour subtype.

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.

Expression of cancer stem cell markers is prognostic in metastatic gastroesophageal adenocarcinoma.

Gastroesophageal adenocarcinoma is a common and highly lethal malignancy. Cancer stem cells (CSCs) have a key role in the development and progression of metastatic disease. While expression of CSC markers CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1) in locoregional gastroesophageal cancer is known to be associated with poorer clinical outcomes, the significance of CSC marker expression in distal metastatic disease is unknown. We investigated the clinicopathological and prognostic associations of the CSC markers, CD44, CD133, and ALDH1, on metastatic deposits from gastroesophageal adenocarcinomas, and evaluated the association of CSC expression with urokinase-type plasminogen activator receptor (uPAR) expression. Of the 36 patients included in the study, 16 (44%) were positive for CD44, 13 (36%) were positive for CD133, and 26 (72%) were positive for ALDH1. CD44 expression was significantly associated with poorer overall survival (OS) in univariate [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.9, p=0.008] and multivariate analyses (HR 2.5, 95%CI 1.1-6.2, p=0.04). ALDH1 expression was significantly associated with poorer OS in univariate (HR 2.4, 95% CI 1.01-5.7, p=0.04) analysis but was not significant in multivariate analysis. Both CD44 and ALDH1 expression were significantly associated with uPAR expression. We found no association between CD133 expression and OS. CD44 expression on metastatic disease from gastroesophageal adenocarcinomas is an independent prognostic marker associated with poorer OS. These results expand current evidence to support the role of CSCs as biomarkers in metastatic gastroesophageal cancer.

Differences in the Pathological Diagnosis and Repeat Craniotomy Rates in Cerebral Tumors Undergoing Biopsy or Resection in an Urban Versus Regional Center.

Primary intracranial tumors occur with an incidence of between 2.5 and 6 per 100,000 individuals. They require specialist expertise for investigation and management including input from radiology, pathology, neurosurgery, and oncology. Therefore, most patients with intracranial neoplasia are investigated and managed in larger hospitals. The geographically dispersed population of Australia has facilitated the development of neurosurgical units in regional areas. However, major metropolitan hospitals are over-represented compared with regional centers in most research cohorts. We therefore sought to investigate the spectrum of intracranial neoplasms undergoing biopsy and surgery at a major regional center in Australia and to compare the demographic and pathological features to similar cohorts treated in major metropolitan hospitals.We searched the pathological databases of both a major regional pathology provider and a major metropolitan pathology practice, which provides surgical pathology services for both a large private and a large public neurosurgical hospital, to identify all cerebral tumors undergoing biopsy or resection over a 14-year period (calendar years 2001 and 2014).In all, 3717 cerebral tumors were identified. Among them, 51% were from an urban private hospital, 33% from an urban public hospital, and 16% from a regional public hospital. Overall, one-third of them were neuroepithelial in origin, a quarter metastatic disease, a fifth meningeal, and one-tenth were pituitary adenomas. The regional center treated a higher proportion of metastatic tumors and less meningeal tumors compared with the urban center. Additionally, patients were less likely to undergo a second operation in the regional center (P < 0.001). The differences give an important insight into the burden of neurosurgical disease in regional Australia, and how it differs from that encountered in large metropolitan centers.

Fat-soluble vitamin deficiency in children and adolescents with cystic fibrosis.

AIMS: Determine the prevalence of fat-soluble vitamin deficiency in children with cystic fibrosis (CF) aged ≤18 years in New South Wales (NSW), Australia, from 2007 to 2010. METHODS: A retrospective analysis of fat-soluble vitamin levels in children aged ≤18 years who lived in NSW and attended any of the three paediatric CF centres from 2007 to 2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. RESULTS: Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin level test in the study period. The prevalence of vitamins D and E deficiency fell from 22.11% in 2007 to 15.54% in 2010, and 20.22% to 13.89%, respectively. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Low vitamin K was present in 29% in 2007, and prevalence of prolonged prothrombin time increased from 19.21% to 22.62%. Fat-soluble vitamin deficiency is present in 10%-35% of children with pancreatic insufficiency, but only a very small proportion of children who are pancreatic-sufficient. CONCLUSIONS: This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.

Orbital and periorbital microcystic adnexal carcinoma.

PURPOSE: To review the clinical and histopathologic features of patients with microcystic adnexal carcinoma of the orbital and periorbital tissues. METHODS: This study was designed as a noncomparative interventional case series of three patients seen and treated at two oculoplastic surgical departments and a review of the literature. Clinical presentation, histopathologic findings, outcome of surgery, and clinical recurrence are presented. RESULTS: Three patients underwent surgery for lesions temporal to the lateral canthus. All had initial histopathology diagnosed as squamous cell carcinoma but were subsequently diagnosed as microcystic adnexal carcinoma after clinical recurrence. All patients had multiple recurrences and extensive perineural spread. Two patients required radiotherapy. CONCLUSIONS: Review of the literature shows that microcystic adnexal carcinoma affecting the orbital and periorbital tissues is difficult to differentiate clinically and microscopically from other conditions including squamous cell carcinoma. Eighty-one percent of cases that have histopathology checked in the initial assessment are still misdiagnosed. A high degree of suspicion is necessary if the lesion extends beyond an apparently adequate surgical margin, multiple recurrences occur, or superficial perineural spread is present. Mohs technique is the treatment of choice and may be improved if paraffin sections or immunohistocytochemistry are performed. Wide excision should be carried out once clear margins are obtained. Radiotherapy may be necessary in cases with multiple recurrences.