Beyond Immune Checkpoint Inhibitors: Emerging Targets in Melanoma Therapy.

PURPOSE OF REVIEW: This review provides a comprehensive update on recent advancements in melanoma treatment by highlighting promising therapeutics with an aim to increase awareness of novel interventions currently in development. RECENT FINDINGS: Over the last decade there has been considerable expansion of the previously available treatment options for patients with melanoma. In particular, novel immunotherapeutics have been developed to expand on the clinical advancements brought by BRAF targeting and immune checkpoint inhibitors. Despite the success of checkpoint inhibitors there remains an unmet need for patients that do not respond to treatment. This review delves into the latest advancements in novel checkpoint inhibitors, cytokines, oncolytic viruses, vaccines, bispecific antibodies, and adoptive cell therapy. Preclinical experiments and early-stage clinical trials studies have demonstrated promising results for these therapies, many of which have moved into pivotal, phase 3 studies.

Utilisation of Chronic Disease and Mental Health Management Services and Cardioprotective Medication Prescriptions in Primary Care for Patients With Cardiovascular Diseases and Cancer: A Cross-Sectional Study.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among cancer survivors. Mental health is considered an important risk factor affecting the treatment of cardiovascular disease. However, little is known about the use of secondary prevention strategies for CVD in patients with both cancer and CVD. This study aimed to compare the utilisation of primary care chronic disease management plans, mental health care and guideline-indicated cardioprotective medications among CVD patients with and without cancer. METHODS: Retrospective cross-sectional study utilising clinical data of patients with CVD from 50 Australian primary care practices. Outcomes included the use of chronic disease management plans, mental health care, guideline-indicated cardioprotective medications and influenza vaccination. Logistic regression, accounting for demographic and clinical covariates and clustering effects by practices, was used to compare the two groups. RESULTS: Of the 15,040 patients with CVD, 1,486 patients (9.9%) concurrently had cancer. Patients with cancer, compared to those without, were older (77.6 vs 71.8 years, p<0.001), more likely to drink alcohol (62.6% vs 55.7%, p<0.001), have lower systolic (130.3±17.8 vs 132.5±21.1 mmHg, p<0.001) and diastolic (72.2±11 vs 75.3±34 mmHg, p<0.001) blood pressure. Although suboptimal for both groups, patients with cancer were significantly more likely to have general practice management plans (GPMPs) (51.4% vs 43.2%, p<0.001), coordination of team care arrangements (TCAs) (46.2% vs 37.0%, p<0.001), have a review of either GPMP or TCA (42.8% vs 34.7%, p<0.001), have a mental health treatment consultation (15.4% vs 10.5%, p=0.004) and be prescribed blood pressure-lowering medications (70.1% vs 66.0%, p=0.002). However, there were no statistical differences in the prescription of lipid-lowering or antiplatelet medications. After adjustments for covariates and multiple testing, patients with cancer did not show a difference in GPMPs, TCAs, and a review of either, but were more likely to receive mental health treatment consultations than those without cancer (odds ratio 1.76; 95% confidence interval 1.42-2.19). CONCLUSIONS: Less than half of patients with CVD had a GPMP, TCA or review of either. Although those patients with cancer were more likely to receive these interventions, still around half the patients did not. Medicare-funded GPMPs, TCAs and a review of either GPMP or TCA were underutilised, and future studies should seek to identify ways of improving access to these services.

Identification of SKOR2 IgG as a novel biomarker of paraneoplastic neurologic syndrome.

Introduction: The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples. Methods: Stored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization. Results: PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2-specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative. Discussion: SKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy.

Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum are prognostic of melanoma patient outcomes.

Background: Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics. Methods: Levels of TLS-kines in patients' sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas melanoma cohort (TCGA-SKCM) and a Moffitt Melanoma cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed. Results: Serum of 95 patients with melanoma were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 tumor transcripts was significantly associated with improved OS in TCGA-SKCM (HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt Melanoma patients (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL13 and CXCL10 tumor transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). Melanoma differentially expressed genes positively associated with high APRIL/CXCL10/CXCL13 tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types. Conclusion: Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted.

Immunotherapy in Melanoma: Recent Advances and Future Directions.

The use of immunotherapy in the treatment of advanced and high-risk melanoma has led to a striking improvement in outcomes. Although the incidence of melanoma has continued to rise, median survival has improved from approximately 6 months to nearly 6 years for patients with advanced inoperable stage IV disease. Recent understanding of the tumor microenvironment and its interplay with the immune system has led to the explosive development of novel immunotherapy treatments. Since the approval of the therapeutic cytokines interleukin-2 and interferon alfa-2 in the 1990s, the development of novel immune checkpoint inhibitors (ICIs), oncolytic virus therapy, and modulators of the tumor microenvironment have given way to a new era in melanoma treatment. Monoclonal antibodies directed at programmed cell death protein 1 receptor (PD-1) and its ligand (PDL-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) have provided robust activation of the adaptive immune system, restoring immune surveillance leading to host tumor recognition and destruction. Multiple other immunomodulatory therapeutics are under investigation to overcome resistance to ICI therapy, including the toll-like receptor-9 (TLR-9) and 7/8 (TLR-7/8) agonists, stimulator of interferon genes (STING) agonists, and fecal microbiota transplantation. In this review, we focus on the recent advances in immunotherapy for the treatment of melanoma and provide an update on novel therapies currently under investigation.

Multiple primary melanoma in association with other personal and familial cancers.

BACKGROUND: Multiple primary melanoma (MPM) is known to be associated with familial melanoma. However, the association between MPM and other personal and familial cancers is not well documented. The objective of this study was to evaluate the association between MPM and personal history of other cancers or cancer history among first-degree relatives (FDRs). METHODS: We performed a retrospective case-control study including cases with gender-matched MPM and single primary melanoma (SPM) at a 1:2 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The associations between MPM and other cancers were evaluated using univariable and multivariable logistic regression models. RESULTS: In total, 378 patients (44.2% men; median age 52 years) were enrolled, including 252 with SPM and 126 with MPM. In comparison to patients with SPM, patients with MPM were more likely to have squamous cell carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.001-3.79, p = 0.047) and prostate cancer (OR 2.72, 95% CI 1.07-7.01, p = 0.034). FDRs of patients with MPM had higher prevalence of melanoma (OR 2.37, 95% CI 1.31-4.28, p = 0.004) and prostate cancer (OR 2.92, 95% CI 1.47-6.14, p = 0.002) but not other cancers. In multivariable analysis, the association remained significant between MPM and squamous cell carcinoma (OR 2.18, 95% CI 1.08-4.39, p = 0.028), prostate cancer (OR 2.85, 95% CI 1.09-7.54, p = 0.032), FDR history of melanoma (OR 2.37, 95% CI 1.31-4.29, p = 0.004), and FDR history of prostate cancer (OR 3.26, 95% CI 1.59-6.83, p = 0.001). CONCLUSIONS: Patients with MPM have a higher prevalence of personal and FDR histories of nonmelanoma skin cancers and prostate cancer.

Sentinel Lymph Node Gene Expression Signature Predicts Recurrence-Free Survival in Cutaneous Melanoma.

We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with recurrence-free survival (RFS) were selected and a penalized regression function was used to select 12 genes with a non-zero coefficient. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and RFS. Among the 45 patients evaluated, 23 (51%) had a positive SLN. Twenty-one (46.7%) patients developed disease recurrence. For the top 25 differentially expressed genes (DEG), 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, DCTN1, ASPSCR1, CHRFAM7A, ZNF223, PDE6G, CXCL3, HEXIM1, HLA-DRB). This 12-gene signature score was significantly associated with RFS (p < 0.0001) and produced a bootstrap C index of 0.888. In univariate analysis, Breslow thickness, presence of primary tumor ulceration, SLN positivity were each significantly associated with RFS. After simultaneously adjusting for these prognostic factors in relation to the gene signature, the 12-gene score remained a significant independent predictor for RFS (p < 0.0001). This SLN 12-gene signature risk score is associated with melanoma recurrence regardless of SLN status and may be used as a prognostic factor for RFS.

MRI determined prostate volume and the incidence of prostate cancer on MRI-fusion biopsy: a systemic review of reported data for the last 20 years.

PURPOSE: Magnetic resonance imaging (MRI) is a precise, systemic and advantageous imaging technique when compared to transrectal ultrasound (TRUS) which is very operator dependent. The negative correlation between prostate volume and the incidence of prostate cancer (PCa) obtained by TRUS biopsy has been well documented in the literature. The purpose of this systemic review is analyzing the reported MRI-fusion study results on prostate biopsies regarding any correlation between prostate volume and the incidence of PCa. METHODS: After defining the inclusion and exclusion criteria an in-depth review were performed between 01.01.2000 and 02.08.2022 using the PubMed database and applying the "PRISMA" guidelines. RESULTS: Twelve studies qualified, and all showed an inverse/negative relationship between prostate volume and incidence of PCa. Sample sizes ranged from 33 to 2767 patients in single and multi-institutional studies. All studies showed a statistically significant inverse relationship with a p value < 0.05. The graph summarizing all of studies and using Fisher's method revealed a highly significant combined p level of 0.00001. Additionally, not one single study was found showing the contrary (a positive correlation between prostate size and the incidence of PCa). CONCLUSION: To our knowledge, this is the first systemic review of reported MRI-Fusion data on the incidence of PCa in correlation with prostate volume. This MRI review confirms previous TRUS-biopsy studies which demonstrated an inverse relationship between prostate volume and the incidence of PCa, and thus further supports the hypothesis that large prostates size may be protective against PCa when compared to smaller prostates.

Identification of Caveolae-Associated Protein 4 Autoantibodies as a Biomarker of Immune-Mediated Rippling Muscle Disease in Adults.

Importance: Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking. Objective: To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics. Design, Setting, and Participants: This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months. Exposures: Diagnosis of iRMD. Main Outcomes and Measures: Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features. Results: Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change. Conclusions and Relevance: The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.

Poorer survival outcomes in patients with multiple versus single primary melanoma.

BACKGROUND: Given equivocal results related to overall survival (OS) for patients with multiple primary melanomas (MPMs) compared with those with single primary melanomas (SPMs) in previous reports, the authors sought to determine whether OS differs between these 2 cohorts in their center using their UPCI-96-99 database. Secondary aims were to assess the differences in recurrence-free survival (RFS). In a subset of patients, transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) was performed to assess disease-associated genes of interest. METHODS: This retrospective case-controlled study included patients with MPMs and age-, sex-, and stage-matched controls with SPMs at a 1:1 ratio. Cox regression models were used to evaluate the effect of the presence of MPMs on death and recurrence. NanoString PanCancer Immune Profiling was used to assess peripheral blood immune status in patients. RESULTS: In total, 320 patients were evaluated. The mean patient age was 47 years; 43.8% were male. Patients with MPMs had worse RFS and OS (P = .023 and P = .0019, respectively). The presence of MPMs was associated with an increased risk of death (hazard ratio [HR], 4.52, P = .0006), and increased risk of disease recurrence (HR, 2.17; P = .004) after adjusting for age, sex, and stage. The degree of tumor-infiltrating lymphocytes (TILs) was different between the first melanoma of MPMs and SPMs. Expression of CXCL6 and FOXJ1 was increased in PBMCs isolated from patients with MPMs. CONCLUSIONS: Patients with MPMs had worse RFS and OS compared with patients with SPMs. Immunologic differences were also observed, including TIL content and expression of CXCL6/FOXJ1 in PBMCs of patients with MPMs, which warrant further investigation.

Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome.

OBJECTIVES: To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients. METHODS: Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen. RESULTS: IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25-87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration. CONCLUSIONS: This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

Aerosol Generation in Ear Canal and Air-Fluid Interface Suction.

OBJECTIVE: The identification of aerosol-generating procedures (AGPs) is important during the current SARS-CoV-2 pandemic due to aerosol-mediated virus transmission. Aerosol measurement during clinical procedures using particle counting may be confounded by variable natural background aerosol levels or limited by partial volume sampling. The study objective was to quantify any significant aerosol generated from simulated suction clearance procedures. STUDY DESIGN: Prospective quantification of aerosol generation during clinical suction simulation. SETTING: Clean chamber. METHODS: We created a clean environment for particle counting in a transparent neutralized polypropylene chamber. Air was passed through a HEPA 14 class filter to maintain a constant chamber inlet pressure. An optical particle counter was connected in line to the chamber exhaust vent to measure all of the vented particles. The chamber background count was 1 particle ≥0.3 µm per 15 minutes at a flow rate of 1 chamber air change per minute. We used this system to quantify very low aerosol counts generated from suction clearance of a silicone ear canal and at an open air-fluid interface. RESULTS: No clinically significant aerosol generation was found by particle counting of the whole chamber air volume during simulated suction procedures. CONCLUSION: Simulated ear suction clearance and air-fluid interface suction does not generate any significant aerosol. It appears likely that any aerosol potentially generated at the suction tube tip is entrained by incoming air flow. This is the first study to quantify aerosols generated by suction in a controlled environment; further research is required to determine its clinical implications.

Possible clinical implications of prostate capsule thickness and glandular epithelial cell density in benign prostate hyperplasia.

PURPOSE: The negative correlation between BPH-size and incidence of prostate cancer (PCa) is well-documented in the literature, however the exact mechanism is not well-understood. The present study uses histo-anatomical imaging to study prostate volume in correlation to prostate capsule thickness, and glandular epithelial cell density within the peripheral zone (PZ). MATERIALS AND METHODS: Specimens were selected from radical prostatectomies ranging from 20 to 160 mL based on ease of anatomical reconstruction by the slides. A total of 60 patients were selected and underwent quantitative measurements of prostate capsule thickness and glandular epithelial density within the PZ using computer-based imaging software. Pearson's correlation and a stepwise multiple linear regression analysis was conducted to determine the relationship between these measured parameters and the clinical characteristic of these patients. RESULTS: Pearson's correlation analysis revealed a strongly significant, negative correlation between prostate volume and glandular epithelial cell density (r(58)=-0.554, p<0.001), and a strongly significant, positive correlation between prostate volume and average capsule thickness (r(58)=0.462, p<0.001). Results of multiple regression analysis showed that average glandular epithelial cell density added statistically to this prediction (p<0.05). CONCLUSIONS: The results suggest that growth of the transition zone in BPH causes increased fibrosis of the PZ, leading to atrophy and fibrosis of glandular cells. As 80% of PCa originates from the glandular epithelium within the PZ, this observed phenomenon may explain the inverse correlation between BPH and PCa that is well-documented in the literature.

Gender Comparison of Receipt of Government-Funded Health Services and Medication Prescriptions for the Management of Patients With Cardiovascular Disease in Primary Care.

BACKGROUND: Cardiovascular disease (CVD) and risk factors remains a major burden in terms of disease, disability, and death in the Australian population and mental health is considered as an important risk factor affecting cardiovascular disease. A multidisciplinary collaborative approach in primary care is required to ensure an optimal outcome for managing cardiovascular patients with mental health issues. Medicare introduced numerous primary care health services and medications that are subsidised by the Australian government in order to provide a more structured approach to reduce and manage CVD. However, the utilisation of these services nor gender comparison for CVD management in primary care has been explored. Therefore, the aim is to compare the provision of subsidised chronic disease management plans (CDMPs), mental health care and prescription of guideline-indicated medications to men and women with CVD in primary care practices for secondary prevention. METHODS: De-identified data for all active patients with CVD were extracted from 50 Australian primary care practices. Outcomes included the frequency of receipt of CDMPs, mental health care and prescription of evidence-based medications. Analyses adjusted for demography and clinical characteristics, stratified by gender, were performed using logistic regression and accounted for clustering effects by practices. RESULTS: Data for 14,601 patients with CVD (39.4% women) were collected. The odds of receiving the CDMPs was significantly greater amongst women than men (preparation of general practice management plan [GPMP]: (46% vs 43%; adjusted OR [95% CI]: 1.22 [1.12, 1.34]). Women were more likely to have diagnosed with mental health issues (32% vs 20%, p<0.0001), however, the adjusted odds of men and women receiving any government-subsidised mental health care were similar. Women were less often prescribed blood pressure, lipid-lowering and antiplatelet medications. After adjustment, only an antiplatelet medication or agent was less likely to be prescribed to women than men (44% vs 51%; adjusted OR [95% CI]: 0.84 [0.76, 0.94]). CONCLUSION: Women were more likely to receive CDMPs but less likely to receive antiplatelet medications than men, no gender difference was observed in the receipt of mental health care. However, the receipt of the CDMPs and the mental health treatment consultations were suboptimal and better use of these existing services could improve ongoing CVD management.

Leucine Zipper 4 Autoantibody: A Novel Germ Cell Tumor and Paraneoplastic Biomarker.

OBJECTIVE: This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). METHODS: Archival sera from patients with germ cell tumor-associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam-2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant-protein Western blot, enzyme-linked immunosorbent assay (ELISA), and cell-based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. RESULTS: Leucine zipper 4 (LUZP4)-immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28-84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11-IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer-evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole-body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T-cell-dendritic-cell cocultures from chronic immunosuppression-naïve LUZP4-IgG-seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle-exposed and healthy control cultures. INTERPRETATION: LUZP4-IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen-specific T-cell responses support a CD8+ T-cell-mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001-1010.

Mobilization and Exercise Intervention for Patients With Multiple Myeloma: Clinical Practice Guidelines Endorsed by the Canadian Physiotherapy Association.

OBJECTIVE: Individuals with multiple myeloma (MM) often have reduced functional performance due to the cancer itself or as a direct side effect of cancer treatments. Physical therapy is a part of cancer rehabilitation; however, no guidelines are available to provide information and direction for physical therapists managing patients with MM. The goal of this guideline is to provide recommendations based on a systematic review and consensus process that physical therapists can use to manage patients with MM. METHODS: A systematic review of the literature published until August 2018 was performed in 8 databases with 2 independent reviewers assessing quality. Seventeen articles were identified as relevant, and a draft guideline was developed in the form of action statements. A total of 10 physical therapists with hematology experience and 10 patients with MM were recruited for consensus process. A priori threshold of 80% agreement was used to establish a consensus for each statement. The draft guidelines were reviewed externally by 4 methodologists using the AGREE II tool and a stakeholder representing OH (Cancer Care Ontario) Program in Evidence Based Care, McMaster University. The final guideline was reviewed and officially endorsed by the Canadian Physiotherapy Association. RESULTS: A total of 30 action statements were developed that achieved consensus, indicating physical therapy recommendations based on physiological markers (ie, hemoglobin, platelet count), complete patient presentation, and the stage of medical treatment. CONCLUSION: These clinical practice guidelines were developed to aid physical therapists in implementing evidence-based and best-practice care for patients with MM to optimize rehabilitation outcomes. IMPACT: These guidelines fill an important knowledge gap and are the first to provide information specifically for physical therapist management of patients with MM.

QUality improvement in primary care to prevent hospitalisations and improve Effectiveness and efficiency of care for people Living with coronary heart disease (QUEL): protocol for a 24-month cluster randomised controlled trial in primary care.

BACKGROUND: Cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, is the leading cause of death and disability globally. A large proportion of mortality occurs in people with prior CHD and effective and scalable strategies are needed to prevent associated deaths and hospitalisations. The aim of this study is to determine if a practice-level collaborative quality improvement program, focused on patients with CHD, reduces the rate of unplanned CVD hospitalisations and major adverse cardiovascular events, and increases the proportion of patients achieving risk factor targets at 24 months. METHODS: Cluster randomised controlled trial (cRCT) to evaluate the effectiveness of a primary care quality improvement program in 50 primary care practices (n~ 10,000 patients) with 24-month follow-up. Eligible practices will be randomised (1:1) to participate in either the intervention (collaborative quality improvement program) or control (standard care) regimens. Outcomes will be assessed based on randomised allocation, according to intention-to-treat. The primary outcome is the proportion of patients with unplanned CVD hospitalisations at 2 years. Secondary outcomes are proportion of patients with major adverse cardiovascular events, proportion of patients who received prescriptions for guideline-recommended medicines, proportion of patients achieving national risk factor targets and proportion with a chronic disease management plan or review. Differences in the proportion of patients who are hospitalised (as well as binary secondary outcomes) will be analysed using log-binomial regression or robust Poisson regression, if necessary. DISCUSSION: Despite extensive research with surrogate outcomes, to the authors' knowledge, this is the first randomised controlled trial to evaluate the effectiveness of a data-driven collaborative quality improvement intervention on hospitalisations, CVD events and cardiovascular risk amongst patients with CHD in the primary care setting. The use of data linkage for collection of outcomes will enable evaluation of this potentially efficient strategy for improving management of risk and outcomes for people with heart disease. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12619001790134 (dated 20th December 2019).

Access to Palliative Care for Cancer Patients Living in a Northern and Rural Environment in Ontario, Canada: The Effects of Geographic Region and Rurality on End-of-Life Care in a Population-Based Decedent Cancer Cohort.

BACKGROUND: Access to palliative care has been associated with improving quality of life and reducing the use of potentially aggressive end-of-life care. However, many challenges and barriers exist in providing palliative care to residents in northern and rural settings in Ontario, Canada. AIM: The purpose of this study was to examine access to palliative care and associations with the use of end-of-life care in a decedent cohort of northern and southern, rural and urban, residents. DESIGN: Using linked administrative databases, residents were classified into geographic and rural categories. Regression methods were used to define use and associations of palliative and end-of-life care and death in acute care hospital. SETTING/PARTICIPANTS: A decedent cancer cohort of Ontario residents (2007-2012). RESULTS: Northern rural residents were less likely to receive palliative care (adjusted odds ratio [OR] = 0.90, 95% confidence interval [CI]: 0.83-0.97). Those not receiving palliative care were more likely to receive potentially aggressive end-of-life care and die in an acute care hospital (adjusted OR = 1.20, 95% CI: 1.02-1.41). CONCLUSIONS: Palliative care was significantly associated with reduced use of aggressive end-of-life care; however, disparities exist in rural locations, especially those in the north. Higher usage of emergency department (ED) and hospital resources at end of life in rural locations also reflects differing roles of rural community hospitals compared with urban hospitals. Improving access to palliative care in rural and northern locations is an important care issue and may reduce use of potentially aggressive end-of-life care.

Evidence-based guidelines for physiotherapy management of patients with multiple myeloma: study protocol.

BACKGROUND: Patients with multiple myeloma (MM) are often treated with chemotherapy, radiation, and, if indicated, autologous stem cell transplant. In addition to side effects of the treatment, patients with MM often have bone pain, pathological fractures, spinal cord compressions, fatigue, and muscle weakness, which negatively impact functional performance and quality of life. Currently, there are no related guidelines for safe and effective physiotherapy (PT) management. Accordingly, the aim of the present study is to develop guidelines for effective physiotherapy management of patients with MM by systematically reviewing and evaluating the available evidence followed by a consensus process to specifically describe the research questions as detailed below. METHODS/DESIGN: Physiotherapy management guidelines for patients with multiple myeloma will be developed based on the results of a systematic search of the following databases: US National Library of Medicine Database (PubMed), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Elton B. Stephens Co. (EBSCO), Web of Science, Database of Abstracts of Reviews of Effects (DARE), Cochrane Database of Systematic Review, and Physiotherapy Evidence Database (PEDro). All articles will be screened for inclusion and exclusion criteria. Relevant potential articles will be identified and systematically reviewed for final phase of inclusion. Two independent reviewers will systematically review and analyze the quality of identified articles using standardized assessment tools. Scientific conclusions will be drawn and recommendations will be made based on a critical appraisal process. The guideline development will also be based on the team's judgment about the overall quality of the studies and a consensus process. DISCUSSION: Draft guidelines will be developed in the form of action statements based on the strength of evidence and grades of recommendations. The draft guidelines will be reviewed internally by two independent reviewers using AGREE II and externally by a methodological expert from Evidence-Based Care - Cancer Care Ontario and will be sent to the Canadian Physiotherapy Association (CPA) for feedback from physiotherapists. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017064056.

Alcohol screening and brief interventions in primary care - Evidence and a pragmatic practice-based approach.

BACKGROUND: Risky alcohol drinking is a common problem in adults presenting in Australian general practice. Preventive health guidelines recommend routine delivery of alcohol screening and brief intervention (ASBI) by general practitioners (GPs). However, ASBIs have rarely been implemented successfully in a sustainable manner. OBJECTIVE: In this article, we explain the current state of empirical evidence for the effectiveness of ASBI in primary care and describe a pragmatic interpretation of how this evidence applies to routine care. DISCUSSION: The empirical evidence surrounding ASBIs is complex. ASBIs are efficacious in research settings, but their effectiveness when compared with control interventions in real-world practice is less certain. Alcohol assessment within therapeutic doctor-patient relationships, rather than the specific formal tools, may be the 'active ingredient'. A pragmatic, practice-based approach to early detection of risky drinking is to focus on strategies that allow asking patients about their drinking more regularly, documenting it, and using quality improvement methodology to improve alcohol recording data completeness for the practice population.