Acute sensorimotor paraneoplastic neuropathy in a patient with small cell prostate cancer.

The authors describe a patient with a background of metastatic small cell prostate cancer who presented with a rapidly evolving sensorimotor neuropathy with bulbar features closely resembling Guillain-Barré syndrome, with a good initial response to intravenous immunoglobulins and platinum-based chemotherapy. This represented a likely paraneoplastic manifestation of the patient's urological malignancy.

Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells.

Kinase Suppressor of RAS 1 (KSR1) is a scaffolding protein for the RAS-RAF-MEK-ERK pathway, which is one of the most frequently altered pathways in human cancers. Previous results have shown that KSR1 has a critical role in mutant RAS-mediated transformation. Here, we examined the role of KSR1 in mutant BRAF transformation. We used CRISPR/Cas9 to knock out KSR1 in a BRAFV600E-transformed melanoma cell line. KSR1 loss produced a complex phenotype characterised by impaired proliferation, cell cycle defects, decreased transformation, decreased invasive migration, increased cellular senescence, and increased apoptosis. To decipher this phenotype, we used a combination of proteomic ERK substrate profiling, global protein expression profiling, and biochemical validation assays. The results suggest that KSR1 directs ERK to phosphorylate substrates that have a critical role in ensuring cell survival. The results further indicate that KSR1 loss induces the activation of p38 Mitogen-Activated Protein Kinase (MAPK) and subsequent cell cycle aberrations and senescence. In summary, KSR1 function plays a key role in oncogenic BRAF transformation.

Interactome dynamics of RAF1-BRAF kinase monomers and dimers.

RAF kinases play major roles in cancer. BRAFV600E mutants drive ~6% of human cancers. Potent kinase inhibitors exist but show variable effects in different cancer types, sometimes even inducing paradoxical RAF kinase activation. Both paradoxical activation and drug resistance are frequently due to enhanced dimerization between RAF1 and BRAF, which maintains or restores the activity of the downstream MEK-ERK pathway. Here, using quantitative proteomics we mapped the interactomes of RAF1 monomers, RAF1-BRAF and RAF1-BRAFV600E dimers identifying and quantifying >1,000 proteins. In addition, we examined the effects of vemurafenib and sorafenib, two different types of clinically used RAF inhibitors. Using regression analysis to compare different conditions we found a large overlapping core interactome but also distinct condition specific differences. Given that RAF proteins have kinase independent functions such dynamic interactome changes could contribute to their functional diversification. Analysing this dataset may provide a deeper understanding of RAF signalling and mechanisms of resistance to RAF inhibitors.

Merkel cell carcinoma: a forty-year experience at the Peter MacCallum Cancer Centre.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin malignancy, with Australia having the highest reported incidence in the world. There is currently a lack of consensus regarding optimal management of this disease. METHODS: This was a retrospective audit conducted by reviewing existing medical records of MCC patients presenting to the Peter MacCallum Cancer Centre (PMCC) between 1980 and 2018. The primary endpoint was locoregional recurrence. The secondary endpoints were distant recurrence, disease-free survival (DFS) and overall survival (OS). RESULTS: A total of 533 patients were identified. Locoregional recurrence occurring at one, two and 5 years was 24, 31 and 32%, respectively. The estimated 5-year OS and DFS were 46% (95% Confidence Interval [CI] 41-51%) and 34% (95% CI 30-39%) respectively. Older age at diagnosis (hazard ratio [HR] per year = 1.07, 95% CI 1.06-1.07, p < 0.001), and larger primary tumour diameter (HR =1.16, 95% CI 1.03-1.31, p = 0.019) were associated with worse OS on multivariable analysis. Positive or negative histopathological margin status was not associated with OS or DFS differences in patients treated with post-operative radiotherapy. CONCLUSIONS: In our study, about a third of patients developed locoregional recurrence, distal recurrence or both, and there appears to be no change over the last four decades. If treated with adjuvant radiotherapy, there is no difference in OS or DFS with positive surgical margins. Findings should influence future guidelines.

Long-term control of melanoma adrenal metastasis treated with radiotherapy.

Melanoma remains a large global burden with a significant proportion of patients succumbing to metastatic disease. The adrenal gland is a common area for metastasis with surgical treatment as the main modality. Radiotherapy is less utilised in this setting with uncertainty over deliverability and efficacy. Here, we present the details and outcomes of 20 patients treated with radiotherapy, with or without systemic therapy, for melanoma adrenal metastasis in a single institute. Twenty patients were identified from radiation treatment and medical records from between 2015 and 2019 at our institution. Three patients had bilateral radiotherapy treatments and therefore 23 adrenal lesions were analysed. Demographics, indications for treatment, radiotherapy methodology and outcomes were recorded. Outcomes were based on serial 18F FDG PET/computerized tomography scans reporting using the PERCIST criteria. The most common indication for radiotherapy was oligo-progressive disease (70%) followed by symptom palliation. Eight (35%) of the treatments were delivered by stereotactic ablative body radiotherapy. Twelve (60%) patients had concurrent immunotherapy. Twenty of twenty-three (87%) adrenal lesions had an initial response to treatment with 12 (60%) maintaining local control until death or end of follow-up. Median adrenal-specific progression-free survival was 13 months. Four patients (17%) required salvage adrenalectomy. Symptom palliation was achieved in the majority of patients for which it was indicated and there were no grade three toxicities. The median time from radiotherapy to change of immunotherapy treatment was 4 months. Radiotherapy for melanoma adrenal metastasis is effective and deliverable. With the majority of patients achieving a palliative and clinically relevant durable response, adrenalectomy can be reserved as a salvage option.

Axillary artery and brachial plexus injury secondary to blunt trauma.

Rupture of the axillary artery in the absence of a fracture of dislocation is a rare traumatic event. An associated injury to the brachial plexus may accompany an axillary artery injury but has rarely been reported in the literature. We present the case of an elderly female, who fell onto an outstretched arm and sustained an axillary artery rupture, combined with a brachial plexus injury. The patient in this case did well post-operatively. The challenge in these cases is early recognition and diagnosis of a vascular injury. A significant mechanism of injury needs to alert the clinician to the possibility of such injuries and if suspected, early investigation and surgical exploration should be initiated to prevent limb ischemia. Subsequently, if the neurological symptoms do not improve, consideration must be given to the possibility of a nerve injury and early recognition and management to prevent long-term functional deficits.

ADVANCE-1: An adapted collaborative benchmarking approach in centre-based lung cancer care.

The majority of research within lung cancer is focused on prevention, diagnosis and treatment rather than examining infrastructure or processes of lung cancer centres. Benchmarking is a systematic method for documenting and comparing processes, functions or performance of organisations against the best in the world. ADVANCE-1 is a European Respiratory Society funded pilot study with the main aim of creating a benchmarking tool that can easily document and reflect the structure and process within a lung cancer centre and its associated registry. By doing this we can then compare centres and generate best practice learning points from each centre in order to learn from each other. The ADVANCE-1 study group was constituted by two ERS fellowship-holders and senior lung cancer specialists from the two participating lung cancer services in Glasgow, Scotland, and Berlin, Germany. The study design and benchmarking tools were reviewed externally. Once the benchmarking tools were created, prospective testing was undertaken in the two participating centres in order to allow comparison to ascertain best practice in a so called 'collaborative benchmarking approach'. We were then able to create personalised learning points for each centre. The next phase of the project will be to expand the benchmarking across several European centres in the ADANCE-2 project.

Mutual detection of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in blood and saliva of Cameroonians with and without Kaposi's sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are prevalent in sub-Saharan Africa, together with HIV; the consequent burden of disease is grave. The cofactors driving transmission of the two viruses and pathogenesis of associated malignancies are not well understood. We measured KSHV and EBV DNA in whole blood and saliva as well as serum antibodies levels in 175 Cameroonians with Kaposi's sarcoma and 1,002 age- and sex-matched controls with and without HIV. KSHV seroprevalence was very high (81%) in controls, while EBV seroprevalence was 100% overall. KSHV DNA was detectable in the blood of 36-46% of cases and 6-12% of controls; EBV DNA was detected in most participants (72-89%). In saliva, more cases (50-58%) than controls (25-28%) shed KSHV, regardless of HIV infection. EBV shedding was common (75-100%); more HIV+ than HIV- controls shed EBV. Cases had higher KSHV and EBV VL in blood and saliva then controls, only among HIV+ participants. KSHV and EBV VL were also higher in HIV+ than in HIV- controls. Cases (but not controls) were more likely to have detectable KSHV in blood if they also had EBV, whereas shedding of each virus in saliva was independent. While EBV VL in saliva and blood were modestly correlated, no correlation existed for KSHV. Numerous factors, several related to parasitic coinfections, were associated with detection of either virus or with VL. These findings may help better understand the interplay between the two gammaherpesviruses and generally among copathogens contributing to cancer burden in sub-Saharan Africa.

HiQuant: Rapid Postquantification Analysis of Large-Scale MS-Generated Proteomics Data.

Recent advances in mass-spectrometry-based proteomics are now facilitating ambitious large-scale investigations of the spatial and temporal dynamics of the proteome; however, the increasing size and complexity of these data sets is overwhelming current downstream computational methods, specifically those that support the postquantification analysis pipeline. Here we present HiQuant, a novel application that enables the design and execution of a postquantification workflow, including common data-processing steps, such as assay normalization and grouping, and experimental replicate quality control and statistical analysis. HiQuant also enables the interpretation of results generated from large-scale data sets by supporting interactive heatmap analysis and also the direct export to Cytoscape and Gephi, two leading network analysis platforms. HiQuant may be run via a user-friendly graphical interface and also supports complete one-touch automation via a command-line mode. We evaluate HiQuant's performance by analyzing a large-scale, complex interactome mapping data set and demonstrate a 200-fold improvement in the execution time over current methods. We also demonstrate HiQuant's general utility by analyzing proteome-wide quantification data generated from both a large-scale public tyrosine kinase siRNA knock-down study and an in-house investigation into the temporal dynamics of the KSR1 and KSR2 interactomes. Download HiQuant, sample data sets, and supporting documentation at http://hiquant.primesdb.eu .

Pop goes the O2: a case of popper-induced methaemoglobinamia.

A 39-year-old man presented to the emergency department after falling downstairs after he consumed a large quantity of alcohol. On examination, he had altered mental state (GCS 14), central cyanosis and low oxygen saturation of 86%, despite 100% oxygen being administered. His arterial blood gas confirmed diagnosis of methaemoglobinaemia with a methaemoglobin percentage of 14.08. He was treated successfully with methylthioninium chloride. The patient later admitted to use of recreational poppers (amyl nitrates) the previous evening. The emergency physician is challenged by the presentation of a patient with altered mental state and unexplained low oxygen saturation with concurrent alcohol intoxication but must have a high index of suspicion for methaemoglobinaemia particularly with a history of recreational drug ingestion.