Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade-resistant Melanoma for Anti-PD-L1 Rechallenge.

Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma.

Experimental Design: A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab.

Mind Over Matter: Confronting Challenges in Post-Mortem Brain Biobanking for Glioblastoma Multiforme.

Over the past 10 years, there has been limited progress for the treatment of brain cancer and outcomes for patients are not much improved. For brain cancer researchers, a major obstacle to biomarker driven research is limited access to brain cancer tissue for research purposes. The Mark Hughes Foundation Brain Biobank is one of the first post-mortem adult brain banks in Australia to operate with protocols specifically developed for brain cancer.

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.

Confocal microscopy, dermoscopy, and histopathology features of atypical intraepidermal melanocytic proliferations associated with evolution to melanoma in situ.

Background: Atypical intraepidermal melanocytic proliferations (AIMP) is a descriptive term sometimes applied to biopsies that do not fulfill diagnostic criteria of melanoma. They are common on sun-damaged skin, but their definition and management are controversial.

Objective: To describe dermoscopic (DS), reflectance confocal microscopic (RCM) and histopathological features of AIMP and identify features associated with subsequent melanoma in situ (MIS).

Pilot early phase II study of decitabine and carboplatin in patients with advanced melanoma.

Introduction: Resistance to targeted and immune checkpoint blockade treatment remains a major problem in patients with advanced metastatic melanoma. To overcome this problem, there needs to be a decrease in burden of disease as well as re-establishing of immune sensitivity. The aim of this early phase 2 clinical trial is to investigate a novel way of sequencing and combining decitabine and carboplatin to decrease methylation and increase DNA repair resulting in a decrease in the disease burden and to re-establish sensitivity to the immune response.

The prognostic value of tumor mitotic rate in children and adolescents with cutaneous melanoma: A retrospective cohort study.

Background: Mitotic rate is a strong predictor of outcome in adult patients with primary cutaneous melanoma, but for children and adolescent patients this is unknown.

Objective: We sought to assess the prognostic value of primary tumor mitotic rate in children and adolescents with primary melanoma.

Methods: This was a cohort study of 156 patients who were <20 years of age and who had clinically localized cutaneous melanoma.

Monitoring Patient Response to Pembrolizumab With Peripheral Blood Exhaustion Marker Profiles.

Exhausted T cells are effector T cells that are silenced due to continuous T cell receptor (TCR) stimulation from persistent antigens. Characteristics of exhaustion include the increased expression of multiple inhibitory receptors such as programme death-1[PD-1], lymphocyte activation gene 3 [LAG-3], T cell Ig and mucin domain [TIM-3], the loss of effector cytokine secretion and altered transcriptional profile. The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and interferes with anti-tumor T cell immunity.

Fatal Exsanguination Following Rupture of an Iliac Artery Aneurysm in an Infant With Menkes Disease.

Menkes disease (MD) usually presents in infancy with respiratory and neurological complications. Severe isolated vasculo-connective tissue involvement in infancy is rare, and hence the precise and timely diagnosis is difficult. We report a case of an 8-week-old male infant who succumbed to acute, severe exsanguination, and hemorrhagic shock secondary to a large retroperitoneal hematoma due to rupture of a right iliac artery aneurysm.

Nucleotide excision repair protein ERCC1 and tumour-infiltrating lymphocytes are potential biomarkers of neoadjuvant platinum resistance in high grade serous ovarian cancer.

Objective: ERCC1 is a nucleotide excision repair protein that may have a role in drug resistance in high grade serous ovarian cancer (HGSOC). We hypothesized that ERCC1 expression and tumour infiltrating lymphocytes (TILS) are induced by chemotherapy in HGSOC, which may be prognostically useful.

Methods: 115 HGSOC patients were used for this study.

Programmed Death-Ligand 1 Expression in a Large Cohort of Pediatric Patients With Solid Tumor and Association With Clinicopathologic Features in Neuroblastoma.

Purpose: Programmed death-ligand 1 (PD-L1) expression represents a potential predictive biomarker of immune checkpoint blockade response. However, literature about the prevalence of PD-L1 expression in the pediatric cancer setting is discordant.

Methods: PD-L1 expression was analyzed using immunohistochemistry in 500 pediatric tumors (including neuroblastoma, sarcomas, and brain cancers).

Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma.

Disruption of PD-L1/cytotoxic T-cell PD-1 signaling by immune checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response. Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed.

Whole-genome landscapes of major melanoma subtypes.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation.

5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms.

Background: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms.

Methods: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors.

PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials.

In this study, we examined PD-L1 expression by immunohistochemistry in 99 patients with tonsillar cancer and known human papillomavirus (HPV) status to assess its clinical significance. We showed that the pattern of PD-L1 expression is strongly related to HPV status. The PD-L1 positivity rate was 83.

Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair.

UVB exposure leads to DNA damage, which when unrepaired induces C>T transitions. These mutations are found throughout the melanoma genome, particularly in non-transcribed regions. The global genome repair (GGR) branch of nucleotide excision repair (NER) is responsible for repairing UV-induced DNA damage across non-transcribed and silent regions of the genome.

Breslow Thickness Measurements of Melanomas Around American Joint Committee on Cancer Staging Cut-Off Points: Imprecision and Terminal Digit Bias Have Important Implications for Staging and Patient Management.

Background: Breslow thickness is the most important prognostic factor in patients with clinically localized primary cutaneous melanomas, and its accuracy has important implications for staging and management. A review of the Melanoma Institute Australia database and population-based data for the state of New South Wales, Australia, found an unexpectedly large number of melanomas reported as being exactly 1.0 mm thick.

The regenerating naevus.

The re-emergence of a melanocytic proliferation at the site of a previously excised pigmented lesion may not only cause great concern clinically but may also be amongst the most difficult of all melanocytic lesions for pathologists to assess. These lesions can adopt an appearance which may be impossible to confidently distinguish from a regressing or traumatised melanoma on histological grounds alone. For this reason, careful attention must be paid to the clinical context which has given rise to the lesion or a misdiagnosis may occur.

PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma.

Purpose: Understanding why some melanomas test negative for PD-L1 by IHC may have implications for the application of anti-PD-1 therapies in melanoma management. This study sought to determine somatic mutation and gene expression patterns associated with tumor cell PD-L1 expression, or lack thereof, in stage III metastatic melanoma to better define therapeutically relevant patient subgroups.

Experimental Design: IHC for PD-L1 was assessed in 52 American Joint Committee on Cancer stage III melanoma lymph node specimens and compared with specimen-matched comprehensive clinicopathologic, genomic, and transcriptomic data.

Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation.

A number of common driver mutations have been identified in melanoma, but other genetic or epigenetic aberrations are also likely to play a role in the pathogenesis of melanoma and present potential therapeutic targets. Translocations of the anaplastic lymphoma kinase (ALK), for example, have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK expression. In this study, we sought to determine whether ALK was also expressed in nonspitzoid primary and metastatic cutaneous melanomas.

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

Aims: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC.