Universal molecular screening does not effectively detect Lynch syndrome in clinical practice

Background: Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecular screening for diagnosis of LS in a regional center. Methods: We conducted a prospective, consecutive case series study of universal IHC testing on cases of resected CRC from September 2004–December 2013. Referred cases with abnormal IHC results that attended a familial cancer clinic were assessed according to modified Bethesda criteria (until 2009) or molecular criteria (from 2009). Results: 1612 individuals underwent resection for CRC in the study period and had MMR testing by IHC. Of these, 274 cases (16.9%) exhibited loss of expression of MMR genes. The mean age at CRC diagnosis was 68.1 years (± standard deviation 12.7) and the mean age of those with an IHC abnormality was 71.6 (± 11.8). A total of 82 (29.9%) patients with an abnormal result were seen in a subspecialty familial cancer clinic. Patients aged under 50 (p = 0.009) and those with loss of MSH6 staining (p = 0.027) were more likely to be referred and to attend. After germ-line sequencing, 0.6% (10 of 82) were identified as having a clinically significant abnormality. A further eight probands with pathogenic germ-line mutations were identified from other referrals to the service over the same time period. Conclusions: While technically accurate, the yield of ‘universal’ IHC in detecting new Lynch probands is limited by real-world factors that reduce referrals and genetic testing. We propose an alternative approach for universal, incident case detection of Lynch syndrome with ‘one-stop’ MMR testing and sequencing.This work was supported by a grant from the Canberra Hospital Private Practice Fund (to DT)

MMP2 and MMP9 associate with crescentic glomerulonephritis

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple organ involvement. Lupus nephritis (LN) is a common manifestation with a wide variety of histological appearances. Matrix metalloproteinases (MMP) 2 and 9 are gelatinases capable of degrading glomerular basement membrane type IV collagen, which have been associated with LN. We examine the expression of MMP2 and MMP9 in different classes of LN. Methods: MMP2 and MMP9 expression was detected by immunohistochemistry in sections from renal biopsy specimens with class III, class IV and class V LN (total n = 31), crescentic immunoglobulin A nephropathy (n = 6), pauci-immune glomerulonephritis (n = 7), minimal change disease (n = 2), mesangiocapillary glomerulonephritis (n = 7), diabetic nephropathy (n = 12) and histologically normal controls (n = 8). Results: MMP2 and MMP9 were not expressed in all classes of LN, but were observed in LN with cellular and fibrocellular crescents. MMP2/MMP9 was expressed in cellular and fibrocellular crescents regardless of glomerulonephritis but not observed in inactive fibrous crescents or with mesangial proliferation. This suggests that MMP2 and MMP9 are involved in the development of extracapillary proliferative lesions. Conclusions: MMP2/MMP9 is expressed with active extracapillary proliferation. Further study is necessary to define whether the expression of MMP2/MMP9 reflects a role in glomerular repair after injury, a role in organ-level immune responses or a role as a marker of epithelialization

Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.(1,2) We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1(+/-) mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE

A Time to Pause and Reflect: When a Patient with Autoimmune Hepatitis Stops Responding to Corticosteroids

Drug-induced liver injury (DILI) with features of autoimmunity (AI) is a challenging diagnosis to make particularly due to its apparent corticosteroid responsiveness. We present the case of a 74-year-old woman who presented with a 2-week history of jaundice and fatigue. She was initially diagnosed with autoimmune hepatitis (AIH) based on biochemical and histological characteristics and prompt response with budesonide but a biochemical relapse occurred soon after inadvertent rechallenge with irbesartan, a drug that she had discontinued prior to her presentation but was not initially considered to be a cause of her symptoms

Adult pilomyxoid astrocytoma presenting in the temporal lobe

Pilomyxoid astrocytoma (PMA) is a rare variant of astrocytoma that is usually present in the hypothalamic and chiasmatic areas in the paediatric population. PMA shares many similar histopathological features to Pilocytic astrocytoma (PA), with some notable differences in its radiological and histopathological findings. On the contrary, PMA has been reported to behave more aggressively in its clinical progression than PA. Here, we describe a rare case of PMA in a 25-year-old female involving the temporal lobe, presenting with recurrent partial seizures. To our knowledge, this is the first reported case of PMA presenting in the temporal lobe in an adult female with an atypical location of the tumour, uncommon age group, and unusual radiological features being unique in this case report

Accurate identification of interval colorectal cancers: results from a single Australian jurisdiction

Introduction: Interval colorectal cancers (CRCs) are those diagnosed within 5 years of a negative colonoscopy. We investigated the proportion of interval CRCs that develop within 6–60 months of colonoscopy, and their clinical and molecular characteristics. Methods: We performed a cohort study of all individuals who underwent colonoscopy between 2001 and 2008 at a single large teaching hospital. These records were linked with (i) the regional cancer registry using probabilistic record linkage and (ii) the hospital medical record using deterministic linkage. Matches were verified, and pathology, tumor stage and mismatch repair status were extracted. Results: A total of 10 854 individuals had a colonoscopy at our centre in the period. Linkage to ACT and NSW Cancer Registries detected 384 and 98 CRCs for notification dates of 2001–2013 (ACT) and 2001–2010 (NSW). The second match process identified a further 55 CRCs from a search of the hospital electronic medical records using relevant ICD‐10 diagnosis codes. A total of 404/537 CRCs (58% male) were included in this study after excluding cases that did not have a colonoscopy between 2001–2008, diagnosis of carcinoid tumor, metastatic malignancy of unknown primary and cases that could not be verified by pathological or clinical records. There were seventeen (4.2%) interval cancers. Individuals with interval cancers were more likely to have diverticulosis at the index colonoscopy (p = 0.019), and the index colonoscopy was more likely to be performed by a trainee (p = 0.044). Interval cancers were somewhat more likely to have mucinous histology (p = 0.059). There were no differences with respect to CRC site, stage, mismatch repair or BRAF mutation status. Conclusions: In our population‐based cohort study in Australia, 4.2% of patients with CRC had interval cancers. The data show that improvement is possible in colonoscopy training and surveillance in diverticulosis. These data are comparable to rates of interval cancers from other population studies and establish a benchmark for Australian jurisdictions

PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma

Aim There is currently a need to identify prognostic biomarkers to assist in a risk adopted approach in treatment of malignant pleural mesothelioma (MPM). Expression of programmed death ligand 1 (PD-L1) has been studied as a prognostic biomarker in a number of tumors given its central role in antitumoral immune response evasion. Four previously published analyses found PD-L1 positivity to be an adverse survival prognostic factor in MPM. This study aims to further investigate the relationship between PD-L1 expression in mesothelioma tissues and survival outcome. Methods Clinical data of MPM patients from a single institution between 2006 and 2016 were reviewed. Patient's archived tissues were stained with PD-L1 (Clone Ventana SP263). PD-L1 positivity was defined as > 1% membranous staining regardless of intensity. Results Data from fifty eight patients were analyzed. Median age was 73, majority was male (49, 84%) and had ECOG between 0 and 2 (46, 79%). Most common histopathological subtype was epithelioid (42, 72%), 9 (16%) biphasic subtype and 7 (12%) sarcomatoid. Thirty one patients (53%) received best supportive care and twenty seven patients (47%) received chemotherapy or combination treatment. Forty-two patients had positive PD-L1 expression (72.4%). The median survival time for PD-L1 negative group is 15.5 months and 6 months for the positive group. Positive PD-L1 expression is independently correlated with worse prognosis (HR = 2.02; 95% CI, 1.005–4.057; P-value = 0.0484). Conclusions Our analysis found a higher percentage of MPM patients with positive PD-L1 (> 1%) compared to other studies. Highly positive PD-L1 expression was associated with statistically significantly lower median survival time

Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo

The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cance

Histological remission (NANCY index) is superior to endoscopic mucosal healing in predicting relapse-free survival in patients with ulcerative colitis in clinical and endoscopic remission

Background Histological grade is increasingly recognised as an important predictor of relapse in ulcerative colitis (UC) patients. Current treatment targets aim at mucosal healing, however many patients continue to have histological activity. We aimed to assess histological activity using the validated Nancy histological activity score as a predictor of future relapse in UC patients in endoscopic and clinical remission. Methods Patients with UC attending the inflammatory bowel disease clinic at a single tertiary centre between 2015 and 2018 were included. Patients in clinical and endoscopic remission who underwent a surveillance colonoscopy between 2009 and 2017 were identified. Clinical remission was defined by partial Mayo score (MSp) 2, initiation of steroids, hospitalisation, and escalation or alteration of therapy. Results 74 patients in both clinical and endoscopic remission were included in the study. Median follow-up time was 42 months (IQR 26–63 months) with median relapse free period of 30 months (IQR 18–48 months). Patients with MES 0 (p = 0.02, Figure 1) and histological remission (p ≤ 0.0001, Figure 2) demonstrated significantly longer relapse free survival. On multi-variate analysis only histological activity remained as an independent risk factor of future clinical relapse (hazard ratio 4.36, 95% CI 1.68–11.27; p = 0.002)