Objective
It has been hypothesized that Lewy pathology initiates in the enteric nervous system years prior to debut of clinical motor symptoms in Parkinson disease patients. This study investigates ...whether Lewy pathology is present in various gastrointestinal tract tissues from Parkinson disease patients in the prodromal phase.
Methods
We used the Danish National Pathology Registry to identify archived paraffin‐embedded tissue blocks from 57 Parkinson disease patients (98 blocks) and 90 control subjects (98 blocks). We employed 2 different immunohistochemistry techniques visualizing aggregated α‐synuclein and phosphorylated α‐synuclein.
Results
Thirty‐nine Parkinson disease patients contributed tissues obtained in the prodromal disease phase, whereas 18 Parkinson disease patients contributed tissues obtained solely after Parkinson diagnosis. Prodromal tissues were obtained on average 7.0 years prior to diagnosis (range = 20 years to 4 months), and postdiagnosis tissue on average 2.8 years after diagnosis (range = 2 days to 18 years). Phosphorylated α‐synuclein positivity was seen in 22 of 39 (56%) prodromal Parkinson disease subjects and 30 of 67 (45%) prodromal tissue blocks. These fractions were significantly higher compared to control subjects (p = 0.0001 and p = 0.0032, respectively). In contrast, no significant difference was seen in the positivity rate between prodromal Parkinson disease patients and controls when using the aggregated α‐synuclein immunohistochemistry technique.
Interpretation
We detected Lewy pathology in the gastrointestinal tract of patients up to 20 years prior to their Parkinson disease diagnosis. These findings are in accordance with a hypothesized prodromal disease phase spanning 10 to 20 years. Ann Neurol 2016;79:940–949
BACKGROUND: Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How ...these signatures relate to one another in biological and prognostic contexts remains to be clarified. RESULTS: To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. CONCLUSIONS: These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.
Background & Aims Sessile serrated adenomas/polyps (SSA/Ps) and traditional serrated adenomas (TSAs) are now distinguished from hyperplastic polyps and recognized as precursors to colorectal cancer ...(CRC). We studied CRC risks associated with serrated polyps. Methods By using Danish databases (1977–2009), we conducted a nationwide population-based, case-control study nested within individuals who had received colonoscopies (n = 272,342), and identified 2045 CRC cases and 8105 CRC-free individuals (controls). For each case and control, we identified the first colorectal polyp(s) that underwent a biopsy or were excised during or after the initial colonoscopy, and obtained tissue blocks for hyperplastic lesions. Four expert pathologists reviewed these lesions using current terminology for serrated polyps. We used logistic regression to compute odds ratios (ORs) to associate the risk of CRC with polyp type and estimated the absolute risks by multiplying the risk in patients with no polyps by these ORs. Results Seventy-nine cases and 142 controls had SSA/Ps (OR, 3.07; 95% confidence interval CI, 2.30–4.10). SSA/Ps with cytology markers of dysplasia were associated with a particularly high OR (4.76; 95% CI, 2.59–8.73). Women with SSA/P had a higher risk for CRC than men with SSA/P (OR for women, 5.05; 95% CI, 3.05–8.37 vs OR for men, 2.18; 95% CI, 1.24–3.82); patients with SSA/P proximal to the splenic flexure had the highest risk for CRC (OR, 12.42; 95% CI, 4.88–31.58). The OR for CRC was 4.84 in the 14 cases vs 17 controls with TSAs (95% CI, 2.36–9.93), 2.51 in the 757 cases vs 1698 controls with conventional adenomas (95% CI, 2.25–2.80), and 1.30 in the 55 cases vs 235 controls with hyperplastic polyps (95% CI, 0.96–1.77). The 10-year risk for CRC was 4.4% for patients with SSA/P with dysplasia, 4.5% for patients with TSAs, and 2.3% for patients with conventional adenomas. Conclusion Patients with SSA/P or TSA are at increased risk for CRC; their level of risk is similar to or higher than that of patients with conventional adenomas.
Summary
We analysed a large cohort of Hodgkin lymphoma (HL) patients in order to characterize: (1) the pattern of late recurrence of lymphoid malignancies (LR) after initial treatment for HL over a ...35‐year period; (2) the clinicopathological parameters influencing the risk of LR; and (3) the outcome of patients experiencing LR. We reviewed data of 3350 HL patients diagnosed in Denmark between 1982 and 2018 and registered in the Danish National Lymphoma Registry (LYFO). LR was defined as a recurrence of lymphoid malignancy at least five years after initial diagnosis. LR occurred in 58 patients, with a cumulative incidence at 10, 15 and 20 years of 2.7%, 4.0% and 5.4% respectively. LR was more frequently observed in patients with nodular lymphocyte‐predominant HL (NLPHL) hazard ratio (HR) 4.5; 95% confidence interval (CI): 2.4–8.4, p < 0.001. In classical HL (cHL) patients, older age and lymphocytopenia were risk factors for LR with HRs of 1.04 per additional year (95% CI: 1.02–1.06) and 5.6 (95% CI: 2.7–11.5) respectively. Mixed cellularity histological subtype was a risk factor for LR, but only in females, with a HR of 5.4 (95% CI: 1.4–20.4, p = 0.014). In contrast to what was observed in NLPHL, LR in cHL was associated with an almost threefold increased risk of death compared with patients in continuous complete remission. Approximately one fifth (22.4%) of patients with LR experienced a second relapse.
Diagnostic histological and cytological specimens are routinely stored in pathology department archives. These biobanks are a valuable research resource for many diseases, particularly if they can be ...linked to high quality population-based health registries, allowing large retrospective epidemiological studies to be carried out. Such studies are of significant importance, for example in the search for novel prognostic and predictive biomarkers in the era of personalized medicine. Denmark has a wealth of highly-regarded population-based registries that are ideally suited to conduct this type of epidemiological research. We describe two recent additions to these databases: the Danish National Pathology Registry (DNPR) and its underlying national online registration database, the Danish Pathology Data Bank (DPDB). The DNPR and the DPDB contain detailed nationwide records of all pathology specimens analyzed in Denmark since 1997, and an incomplete but nonetheless valuable record of specimens from some pathology departments dating back to the 1970s. The data are of high quality and completeness and are sufficient to allow precise and efficient localization of the specimens. We describe the relatively uncomplicated procedures required to use these pathology databases in clinical research and to gain access to the archived specimens.
Aims
Macrophage infiltration has been associated with prognosis in several cancers, including lymphoma, but has not been assessed systematically in anaplastic large cell lymphoma (ALCL). The aim of ...the study was to correlate expression of the macrophage‐associated antigens CD68 and CD163 with pre‐therapeutic parameters and outcome in a cohort of treatment‐naive ALCL patients.
Methods and results
Pre‐therapeutic tumour specimens from 52 patients with ALCL were included in a tissue microarray. The intratumoral macrophage content was assessed by immunohistochemical staining for CD68 and CD163, and quantified using digital image analysis. Anaplastic lymphoma kinase (ALK)‐positive patients were significantly younger and had a favourable outcome compared with ALK‐negative ALCL patients (median age: 42 versus 59 years; P = 0.008). However, ALK expression was not a significant predictor when adjusting for age. Although classical risk factors were distributed evenly between the compared groups, high intratumoral content of CD68 and/or CD163 correlated with poor outcome, in both univariate and multivariate analyses. High intratumoral CD163 content showed the strongest adverse association with both overall and progression‐free survival in ALK‐negative patients (P < 0.001).
Conclusions
A high content of intratumoral CD68‐ and/or CD163‐positive macrophages correlates with an adverse outcome in ALK‐negative ALCL.
Summary
18F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography (FDG‐PET/CT) is used for staging classical Hodgkin lymphoma (cHL) with high sensitivity for skeletal involvement. ...However, it is unclear whether a single bone lesion carries the same adverse prognosis as multifocal lesions and if this is affected by type of chemotherapy ABVD (adriamycin, bleomycin, vincristine, dacarbazine) versus BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). We reviewed the clinico‐pathological and outcome data from 209 patients with newly diagnosed cHL staged by FDG‐PET/CT. Patterns of skeletal/bone marrow uptake (BMU) were divided into ‘low’ and ‘high’ diffuse BMU (i.e. without focal lesions), and unifocal or multifocal lesions. Additional separate survival analysis was performed, taking type of chemotherapy into account. Forty patients (19·2%) had skeletal lesions (20 unifocal, 20 multifocal). The 3‐year progression‐free‐survival (PFS) was 80% for patients with ‘low BMU’, 87% for ‘high BMU’, 69% for ‘unifocal’ and 51% for ‘multifocal’ lesions; median follow‐up was 38 months. The presence of bone lesions, both uni‐ and multifocal, was associated with significantly inferior PFS (log rank P = 0·0001), independent of chemotherapy type. Thus, increased diffuse BMU should not be considered as a risk factor in cHL, whereas unifocal or multifocal bone lesions should be regarded as important predictors of adverse outcome, irrespective of the chemotherapy regimen used.
Plasma circulating tumor DNA (ctDNA) with tumor-specific mutations is an attractive biomarker. The telomerase reverse transcriptase (TERT) C228T promoter mutation is the most prevalent ...tumor-associated mutation in hepatocellular carcinoma (HCC). We evaluated the presence and prognostic value of the TERT C228T mutation in plasma and tissue in a Danish HCC cohort.
We analyzed ctDNA from 95 HCC patients and 45 liver cirrhotic patients without HCC for the TERT mutation using droplet digital polymerase chain reaction. We also analyzed DNA from the corresponding primary tumor tissues in 34 HCC patients.
The plasma TERT C228T mutation was detected in 42/95 HCC patients (44%) but in none of the non-HCC patients. The TERT mutation was detected in 23/34 tumor samples (68%). The TERT mutation was associated with increased mortality when detected in plasma (adjusted HR 2.16 (1.20-3.88), p = .010) but not in tumor tissue (adjusted HR 1.11 (0.35-3.56), p = .860). There was a positive correlation between the presence of the TERT mutation in plasma and an advanced TNM stage (p < .0001) and vascular invasion (p = .005). Analysis of the TERT mutation in plasma and tumor DNA from the same patient was concordant in 21/34 samples (62%; kappa value 0.31, p = .014). Non-concordance was associated with an early TNM stage.
The plasma TERT mutation was detected in 44% of HCC patients and in none of non-HCC cirrhotic patients; and was associated with increased mortality. We propose the TERT C228T mutation in ctDNA as a promising HCC biomarker for prognosis.
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•Experimental and human NASH is associated with reduced urea cycle enzyme expression.•Hypermethylation of urea cycle enzymes is a potential underlying mechanism.•The functional ...changes of urea synthesis in NASH are associated with hyperammonemia.•Hyperammonemia can cause progression of liver injury and fibrosis.•Ammonia is a potential novel target for prevention of progression of NASH.
In non-alcoholic steatohepatitis (NASH), the function of urea cycle enzymes (UCEs) may be affected, resulting in hyperammonemia and the risk of disease progression. We aimed to determine whether the expression and function of UCEs are altered in an animal model of NASH and in patients with non-alcoholic fatty liver disease (NAFLD), and whether this process is reversible.
Rats were first fed a high-fat, high-cholesterol diet for 10 months to induce NASH, before being switched onto a normal chow diet to recover. In humans, we obtained liver biopsies from 20 patients with steatosis and 15 with NASH. Primary rat hepatocytes were isolated and cultured with free fatty acids. We measured the gene and protein expression of ornithine transcarbamylase (OTC) and carbamoylphosphate synthetase (CPS1), as well as OTC activity, and ammonia concentrations. Moreover, we assessed the promoter methylation status of OTC and CPS1 in rats, humans and steatotic hepatocytes.
In NASH animals, gene and protein expression of OTC and CPS1, and the activity of OTC, were reversibly reduced. Hypermethylation of Otc promoter genes was also observed. Additionally, in patients with NAFLD, OTC enzyme concentration and activity were reduced and ammonia concentrations were increased, which was further exacerbated in those with NASH. Furthermore, OTC and CPS1 promoter regions were hypermethylated. In primary hepatocytes, induction of steatosis was associated with Otc promoter hypermethylation, a reduction in the gene expression of Otc and Cps1, and an increase in ammonia concentration in the supernatant.
NASH is associated with a reduction in the gene and protein expression, and activity, of UCEs. This results in hyperammonemia, possibly through hypermethylation of UCE genes and impairment of urea synthesis. Our investigations are the first to describe a link between NASH, the function of UCEs, and hyperammonemia, providing a novel therapeutic target.
In patients with fatty liver disease, the enzymes that convert nitrogen waste into urea may be affected, leading to the accumulation of ammonia, which is toxic. This accumulation of ammonia can lead to scar tissue development, increasing the risk of disease progression. In this study, we show that fat accumulation in the liver produces a reversible reduction in the function of the enzymes that are involved in detoxification of ammonia. These data provide potential new targets for the treatment of fatty liver disease.
Summary
In this study we investigated the dynamics of hepatocyte hyperplasia and hypertrophy in rats subjected to increasing sizes of partial hepatectomy (PH). A total of 104 rats were randomized ...according to the size of PH. On postoperative days (PODs) 1, 3 and 5, blood was drawn and the remnant liver removed for stereological analysis. Liver parameters and regeneration rate were significantly affected by size of PH. On POD 1, hepatocyte volumes had increased significantly in all PH groups. On POD 3, all groups showed hepatocyte volumes approximating baseline. On POD 5, hepatocyte volumes were significantly lower in PH (90) than in baseline, sham and PH (30) rats. Increasing hepatocyte proliferation was not observed following PH (30). Following PH (70), cell proliferation was significantly elevated on PODs 1 and 3, and following PH (90) on PODs 3 and 5. In conclusion, general hypertrophy of hepatocytes after different size of PH was followed by hepatocyte proliferation only in the liver remnant of PH (70) and PH (90).
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