Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia : a successfully managed with rituximab : case report and review of the literature

Background: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. Case presentation: We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. Conclusions: Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN

High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma

Aims: Mesothelin (MSLN) is a cancer-associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody–drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti-mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical-score (H-score). Methods and results: The MN1 anti-MSLN antibody was used to stain a formalin-fixed paraffin-embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H-score were evaluated. The correlation of H-score with prognosis was investigated. Sixty-six per cent of epithelioid tumours were MSLN-positive (with expression in > 5% tumour cells). Of MSLN-expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H-score as a continuous variable and an H-score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively). Conclusions: MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin-targeted personalised therapies, such as chimeric antigen receptor T cells

Molecular testing in stage I–III non-small cell lung cancer : approaches and challenges

Precision medicine in non-small cell lung cancer (NSCLC) is a rapidly evolving area, with the development of targeted therapies for advanced disease and concomitant molecular testing to inform clinical decision-making. In contrast, routine molecular testing in stage I–III disease has not been required, where standard of care comprises surgery with or without adjuvant or neoadjuvant chemotherapy, or concurrent chemoradiotherapy for unresectable stage III disease, without the integration of targeted therapy. However, the phase 3 ADAURA trial has recently shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, reduces the risk of disease recurrence by 80% versus placebo in the adjuvant setting for patients with stage IB–IIIA EGFR mutation-positive NSCLC following complete tumor resection with or without adjuvant chemotherapy, according to physician and patient choice. Treatment with adjuvant osimertinib requires selection of patients based on the presence of an EGFR-TKI sensitizing mutation. Other targeted agents are currently being evaluated in the adjuvant and neoadjuvant settings. Approval of at least some of these other agents is highly likely in the coming years, bringing with it in parallel, a requirement for comprehensive molecular testing for stage I–III disease. In this review, we consider the implications of integrating molecular testing into practice when managing patients with stage I–III non-squamous NSCLC. We discuss best practices, approaches and challenges from pathology, surgical and oncology perspectives

Targeting CD83 in mantle cell lymphoma with anti-human CD83 antibody

Objectives: Effective antibody–drug conjugates (ADCs) provide potent targeted cancer therapies. CD83 is expressed on activated immune cells including B cells and is a therapeutic target for Hodgkin lymphoma. Our objective was to determine CD83 expression on non-Hodgkin lymphoma (NHL) and its therapeutic potential to treat mantle cell lymphoma (MCL) which is currently an incurable NHL. Methods: We analysed CD83 expression on MCL cell lines and the lymph node/bone marrow biopsies of MCL patients. We tested the killing effect of CD83 ADC in vitro and in an in vivo xenograft MCL mouse model. Results: CD83 is expressed on MCL, and its upregulation is correlated with the nuclear factor κB (NF-κB) activation. CD83 ADC kills MCL in vitro and in vivo. Doxorubicin and cyclophosphamide (CP), which are included in the current treatment regimen for MCL, enhance the NF-κB activity and increase CD83 expression on MCL cell lines. The combination of CD83 ADC with doxorubicin and CP has synergistic killing effect of MCL. Conclusion: This study provides evidence that a novel immunotherapeutic agent CD83 ADC, in combination with chemotherapy, has the potential to enhance the efficacy of current treatments for MCL

Retrospective evaluation of the use of pembrolizumab in malignant mesothelioma in a real-world Australian population

Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. Results: A total of 98 patients were included with a median age of 70 years (range, 46–91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6–6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6–13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment

The novel 19G endobronchial USS (EBUS) needle samples processed as tissue "core biopsies" facilitate PD-L1 and other biomarker testing in lung cancer specimens : case report and the view point from the respiratory physician and the pathologist

The immunohistochemical expression of Programmed Death Ligand (PD-L1) predicts responses to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). PD-L1 testing is currently only recommended on tissue specimens; however, in many patients, cytology samples are the only specimens available. The introduction of the novel 19G "core-biopsy" needle has revolutionized the utility of endobronchial USS-guided biopsy (EBUS) by providing solid tissue "microbiopsies" rather than traditional liquid cytology samples. We report a case of metastatic adenocarcinoma with the only accessible site of biopsy being a hilar lymph node. Using the 19G core-biopsy needle and processing the microbiopsy samples in formalin provided more material for predictive biomarker testing, including PD-L1 immunohistochemistry, when traditional processing was inadequate. This case highlights the need for close multidisciplinary discussions between the pathologist and the respiratory physician regarding emerging biomarkers and novel biopsy techniques to obtain maximum utility of the tools and avoid repeated procedures for the patient

Molecular pathology in lung cancer

Increasing understanding of genomic changes in cancer is transforming the diagnosis and treatment of a subset of lung cancers. A significant proportion of lung adenocarcinomas harbour biologically relevant or targetable somatic genetic changes such as mutations, amplifications or translocations in a range of genes, including KRAS, EGFR, ALK, ROS1, MET and BRAF. This review highlights the key actionable somatic changes seen in lung cancer, with particular emphasis on epidermal growth factor receptor mutations and ALK gene rearrangements in adenocarcinoma, as well as identifying promising new targets in squamous cell carcinoma of the lung. Accurate and sensitive molecular testing is essential to ensure patients with this poor prognosis disease receive the correct therapy, but mutation testing in lung cancer poses particular challenges. As the majority of patients with lung cancer present with advanced disease that is unsuitable for resection, many biopsies submitted for molecular testing are small biopsies such as core biopsies and fine needle aspirate biopsies, often with only a very small amount of diagnostic material available for mutation analysis. This paper highlights the need for good communication between clinicians, radiologists and pathologists to ensure optimal samples for molecular testing and the benefits of testing for multiple genes in one assay

Molecular diagnosis in cytology and its place in the new classification : a pactical guide

The clinical importance of molecular testing for Epidermal Growth Factor Receptor (EGFR) mutations and ALK gene rearrangements in non-small cell lung cancer (NSCLC) is widely recognized. As most patients with NSCLC present with advanced stage disease not suitable for surgical resection, only cytology or small biopsy specimens are available for molecular testing in most cases. Although currently targetable genetic alterations are known to mostly occur in adenocarcinomas, accurate histological subtyping of NSCLC can be challenging in cytology and small biopsy samples. The recent IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma helps provide guidelines for histological subtyping in small samples and tissue management for molecular testing. This review places the use of cytology specimens in the new adenocarcinoma classification and highlights key issues for performing testing in these specimens

TERT gene : its function and dysregulation in cancer

In this review, we summarise the function and structure of telomerase reverse transcriptase (TERT) in humans, including its regulation. The dysregulation of telomerase through TERT promoter mutations across a range of cancers is discussed. The molecular mechanism activated by TERT promoter mutations is outlined. Finally, the timing of TERT promoter mutations during carcinogenesis is reviewed in the context of their potential utility as clinical biomarkers of malignant transformation