Validation of Selected Head and Neck Cancer Prognostic Markers from the Pathology Atlas in an Oral Tongue Cancer Cohort.

The Pathology Atlas is an open-access database that reports the prognostic value of protein-coding transcripts in 17 cancers, including head and neck cancer. However, cancers of the various head and neck anatomical sites are specific biological entities. Thus, the aim of the present study was to validate promising prognostic markers for head and neck cancer reported in the Pathology Atlas in oral tongue squamous cell carcinoma (OTSCC). We selected three promising markers from the Pathology Atlas (CALML5, CD59, LIMA1), and analyzed their prognostic value in a Norwegian OTSCC cohort comprising 121 patients. We correlated target protein and mRNA expression in formalin-fixed, paraffin-embedded cancer tissue to five-year disease-specific survival (DSS) in univariate and multivariate analyses. Protein expression of CALML5 and LIMA1 were significantly associated with five-year DSS in the OTSCC cohort in univariate analyses (p = 0.016 and p = 0.043, respectively). In multivariate analyses, lymph node metastases, tumor differentiation, and CALML5 were independent prognosticators. The prognostic role of the other selected markers for head and neck cancer patients identified through unbiased approaches could not be validated in our OTSCC cohort. This underlines the need for subsite-specific analyses for head and neck cancer.

Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas.

Early trials for immune checkpoint inhibitors in sarcomas have delivered mixed results, and efforts to improve outcomes now look to combinatorial strategies with novel immunotherapeutics, including some that target macrophages. To enhance our understanding of the sarcoma immune landscape, we quantified and characterized tumor-associated macrophage infiltration and expression of the targetable macrophage-related immune checkpoint CD47/SIRPα across sarcoma types. We surveyed immunohistochemical expression of CD68, CD163, CD47, and SIRPα in tissue microarrays of 1242 sarcoma specimens (spanning 24 types). Non-translocation sarcomas, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had significantly higher counts of both CD68+ and CD163+ macrophages than translocation-associated sarcomas. Across nearly all sarcoma types, macrophages outnumbered tumor-infiltrating lymphocytes and CD163+ (M2-like) macrophages outnumbered CD68+ (M1-like) macrophages. These findings were supported by data from The Cancer Genome Atlas, which showed a correlation between increasing macrophage contributions to immune infiltration and several measures of DNA damage. CD47 expression was bimodal, with most cases showing either 0% or >90% tumor cell staining, and the highest CD47 scores were observed in chordoma, angiosarcoma, and pleomorphic liposarcoma. SIRPα scores correlated well with CD47 expression. Given the predominance of macrophage infiltrates over tumor-infiltrating lymphocytes, the bias toward M2-like (immunosuppressive) macrophage polarization, and the generally high scores for CD47 and SIRPα, macrophage-focused immunomodulatory agents, such as CD47 or IDO-1 inhibitors, may be particularly worthwhile to pursue in sarcoma patients, alone or in combination with lymphocyte-focused agents.

More tendon degeneration in patients with shoulder osteoarthritis.

PURPOSE: Tendon disorders are a major problem in the general population. It is known that rotator cuff tendinopathy contributes to osteoarthritis (OA) of the shoulder. The aim of the study was to analyse the presence of tendinopathy in patients with shoulder OA and an intact rotator cuff, using a multimodal approach. METHODS: Thirteen consecutive patients median age 67 (52-84) years, with OA of the shoulder, and 13 consecutive control patients, with a fracture of the proximal humerus, median age 70 (51-84) years, underwent an open biopsy procedure from the biceps and subscapularis tendon in conjunction with shoulder arthroplasty. In addition to a macroscopic evaluation, the samples underwent histologic, morphologic and ultrastructural analyses in light and transmission electron microscopy. RESULTS: Macroscopic degeneration was found in 15 of 26 specimen in the OA group but in seven of 25 in the control group (p = 0.048). The histologic analysis revealed a non-significant difference for the total degeneration score (TDS) between the study groups. The morphologic evaluation of the samples revealed that the OA group had significantly more samples with non-homogeneous extracellular matrix (ECM), (p = 0.048). Ultrastructurally, the OA group revealed a significantly larger fibril diameter in the biceps tendon (p < 0.0001) but not in the subscapularis tendon compared with the control group. CONCLUSION: A significantly worse macroscopic appearance and significantly more morphologically inhomogeneous ECM, indicating more tendon degeneration, were found in the OA group compared with the control group. This indicates that it could be beneficial to treat the tendinosis in an early stage to decrease symptoms from the OA. STUDY DESIGN: Level of evidence, III.

Correction to: More tendon degeneration in patients with shoulder osteoarthritis.

Unfortunately, the given name and the family name of the authors were incorrectly identified in the original article. The author names are corrected here by this correction paper. The original article has been corrected.

Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma.

Oral squamous cell carcinomas are associated with a poor prognosis, which may be partly due to functional impairment of the immune response. Lymphocyte recruitment to the tumor site is facilitated by high-endothelial venules, whereas expression of programmed-death ligand 1 (PD-L1) can impair T-cell function. Thus, we hypothesize that these factors are important in shaping the immune response in oral squamous cell carcinoma. In the present study, we characterized the immune infiltrate in formalin-fixed, paraffin-embedded tumor samples from 75 oral squamous cell carcinoma patients. We used immunohistochemistry to determine the distribution of immune cell subsets, high-endothelial venules, and PD-L1, as well as quantitative real-time polymerase chain reaction to assess the expression of inflammatory cytokines and chemokines associated with lymphocyte trafficking. Finally, we calculated correlations between the presence of immune cell subsets, the gene expression patterns, high-endothelial venules, PD-L1, and the clinicopathological parameters, including patient survival. The presence of high-endothelial venules correlated with increased number of CD3+ T cells and CD20+ B cells, higher levels of the chemokines CXCL12 and CCL21, and lower levels of CCL20, irrespective of the tumors' T stage. In univariate analysis, high levels of CD20+ B cells and CD68+ macrophages, positive high-endothelial venule status, and low T and N stages predicted longer patient survival. However, only the presence of high-endothelial venules and a low T stage were independent positive prognosticators. This indicates that high-endothelial venules are important mediators and a convenient marker of an antitumor immune response in oral squamous cell carcinoma. Our findings suggest that these vessels are a potential immunomodulatory target in this type of cancer. PD-L1 staining in tumor cells correlated with lower T stage, increased infiltration of CD4+ cells, and higher expression of several inflammation-related cytokines. Thus, oral squamous cell carcinomas rich in CD4+ cells may preferentially respond to PD-1/PD-L1 blockade therapy.

The natural course of Helicobacter pylori infection on endoscopic findings in a population during 17 years of follow-up: the Sørreisa gastrointestinal disorder study.

The natural course of Helicobacter pylori (H. pylori) is poorly understood, as most research in the field has been on patient populations. We studied the natural course of H. pylori and its associations to morphological changes of the gastric mucosa, peptic ulcer, and reflux oesophagitis in a prospective cohort study of subjects with and without dyspepsia. A total of 361 adults (201 men/160 women, mean age 41/42 years) in Sørreisa municipality, Norway who in 1987 were subjected to upper endoscopy and assessed for gastrointestinal symptoms and H. pylori status were followed up in 2004. H. pylori was strongly associated with neutrophilic (odds ratio [OR] 23.79; 95% confidence interval [CI] 11.64:48.61) and mononuclear infiltration (OR 9.43; CI 5.12:17.36), moderately with atrophy of the antrum (OR 1.98; CI 1.17:3.34), but not with atrophy of the gastric body or intestinal metaplasia. Elimination of H. pylori was associated with regression of gastric inflammation and atrophy, whereas intestinal metaplasia progressed. H. pylori was positively associated with peptic ulcer (OR 2.69; CI 1.2:6.02) but not significantly negatively associated with oesophagitis (OR 0.62; CI 0.35:1.09). This is the first prospective study including endoscopic findings of subjects without dyspepsia, to show that the impact of H. pylori on gastric atrophy is only modest, and that eliminating H. pylori does not cause regression of intestinal metaplasia. However, inflammation of the gastric mucosa regresses after H. pylori elimination. H. pylori is only a moderate risk factor for peptic ulcer, and other explanatory factors deserve more attention.

Changes in the prevalence of dyspepsia and Helicobacter pylori infection after 17 years: the Sørreisa gastrointestinal disorder study.

Dyspepsia and Helicobacter pylori infection are two important public health issues in the field of gastroenterology, generating high expenditures in diagnosis and treatment. A causal relationship between H. pylori and dyspepsia is still debated. The aim of this study was to address changes in the prevalence of, and association between, dyspepsia and H. pylori infection in a general population. The study took place in the municipality of Sørreisa in Northern Norway. Data were collected in 1987 and 2004. The study included questionnaires on gastrointestinal disorders and risk factors, as well as H. pylori assessment. The prevalence of dyspepsia in 2004 was 31.9% in men and 31.7% in women (compared with 30.7 and 26.3% in 1987). In 2004, the prevalence of H. pylori infection in men with/without dyspepsia was 20.3/26.7% (compared with 47.0/32.7% in 1987), whereas the prevalence of H. pylori infection in women with/without dyspepsia was 31.3/20.8% (compared with 50.0/40.7% in 1987). Since 1987, the prevalence of H. pylori has decreased independently of dyspepsia, most pronounced in the younger age groups, thus indicating a cohort effect. Our findings of a decreasing prevalence of H. pylori, a persistently high prevalence of dyspepsia, and an uneven distribution of H. pylori infection with regard to dyspepsia in men and women, question the understanding of a causal relationship between dyspepsia and H. pylori.

Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum.

Cytokines have been suggested to be key factors in modulating immune response against tumorigenesis in the microenvironment. Therefore, characterization of cytokine expression along the colorectal adenoma-carcinoma sequence may add important information for understanding the immune-related mechanisms of the development of colorectal carcinoma (CRC). In this study, biopsies from 32 patients with colorectal adenoma (CRA), 20 patients with CRC and 18 healthy controls were examined. Cytokine gene expressions of interleukin-4 (IL-4), IL-10, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and its upstream inducers (IL-12A and IL-18) were measured at messenger RNA (mRNA) level with quantitative real-time PCR (Q-PCR). Cytokine expressing cells were characterized using immunohistochemistry (IHC). A distinct different cytokine profile between adenoma and CRC was observed: the Th1 cytokines (IFN-gamma, TNF-alpha, IL-12A and IL-18) were increased in local tissues of CRA and decreased in CRC. Consistent with the quantitative cytokine data, IHC examinations revealed slightly increased densities of Th1 cytokine-expressing cells in CRA and a remarkably decreased density of the Th1 cells in CRC. In CRA, the cytokine-expressing cells were highly polarized to the subepithelial stroma while the cells were evenly distributed through the stroma in CRC. In conclusion, distinct changes in the Th1 cytokine profile appear along the colorectal adenoma-carcinoma sequence. This may reflect a change in the host immune regulatory function in the adenoma-carcinoma sequence.

Trends in incidence and survival of mesenchymal neoplasm of the digestive tract within a defined population of northern Norway.

Population-based incidence and survival data for gastrointestinal stromal tumor (GIST) are sparse due to the fact that GIST is a rather novel entity both clinically and pathologically, and has not been registered as a separate entity in population-based cancer registries. The aim of the present study was to reclassify all mesenchymal tumors within a defined population of northern Norway over a time-span of 30 years with the purpose of estimating trends of incidence and survival. One hundred and forty-one patients with mesenchymal neoplasms of the digestive tract were identified: 102 as GISTs, 32 as leiomyomatous tumors, 4 as schwannomas, and 3 as fibromas. Incidence rates of GIST showed a significant increase over the whole period, which was not observed for the non-GIST cases. Analysis of GIST cases showed that cases with more than 5 mitoses per 50 high power fields had an increased expected mortality 4 times that of those with fewer mitoses, and the combination of mitotic count and size of tumor can be recommended for categorizing the tumors into different risk levels. The study confirms that GIST is by far the most frequent mesenchymal neoplasm of the digestive tract and that the incidence has increased over the last 30 years.