The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory ...tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of pro-tumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased Natural Killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL-37. MARCO-expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) by antibody or CRISPR knockout of IL-37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK and T cell anti-tumor activities.
Objectives: Immunohistochemical staining against thyroid transcription factor 1 (TTF-1) is often used to distinguish lung adenocarcinoma from squamous cell carcinoma and pulmonary metastasis.
...Methods: TTF-1 expression was examined using the antibody clones 8G7G3/1, SPT24, and SP141 on tissue microarrays from 665 cases of resected lung cancers and 428 pulmonary metastases.
Results: Most lung adenocarcinomas, 89%, 93%, and 93%, were positive with TTF-1 clones 8G7G3/1, SPT24, and SP141, respectively. The corresponding figures for lung squamous cell carcinomas were 0%, 6%, and 8%. In total, five (2%), 19 (7%), and 21 (8%) of the pulmonary metastases from colorectal adenocarcinomas were positive with clones 8G7G3/1, SPT24, and SP141, respectively. Other TTF-1-positive pulmonary metastases (n = 8) were thyroid, urothelial, pancreatic, small bowel, and cervix carcinomas.
Conclusions: TTF-1 expression in lung cancer and pulmonary metastases differs between clones, with 8G7G3/1 being more specific but less sensitive compared with SPT24 and SP141.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). ...FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10−11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10−4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of ...harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.
BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.
The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient ICC = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).
BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
Whipple's disease is a chronic infectious disease that primarily affects the small intestine, but several organs can be involved simultaneously. The disease is caused by a gram-positive bacterium ...called Tropheryma whipplei. The disease is difficult to suspect because it is rare, and produces unspecific and long-term symptoms. Whipple's disease can lead to death if not treated. We here present a case of a man who presented with gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy and who was finally diagnosed with Whipple's disease 4 years after the occurrence of manifestations from the joints. The diagnosis was made both with 16S rRNA against Tropheryma whipplei and histopathologically from biopsy taken from the duodenum and distal ileum. The purpose of this case report is to raise awareness of a very rare disease that presented with a combination of symptoms similar to other and significantly more common diseases.
Whipples sjukdom är en kronisk infektionssjukdom som orsakas av bakterien Tropheryma whipplei.
Sjukdomen drabbar primärt tunntarmen, men flera organ kan vara engagerade.
Det är svårt att misstänka Whipples sjukdom både på grund av att den är sällsynt och att den ger ospecifika och långvariga symtom.
Vanliga symtom är migrerande artralgi/artrit med eller utan feber, viktnedgång, diarré, buksmärtor, lymfadenopati, hypoalbuminemi och anemi.
Sjukdomen är progredierande med letal utgång om den inte upptäcks och behandlas i tid; därför bör man ha den i åtanke som en viktig differentialdiagnos vid långvariga ospecifika symtom, särskilt i kombination med feber.
Solitary rectal ulcer syndrome (SRUS) is a rare disorder likely to be caused by a traumatic and ischemic mucosal injury related to latent or overt rectal prolapse. Mucosal damage can vary between ...erythema and up to intractable ulceration. The typical symptoms of SRUS may resemble those of inflammatory bowel disease (IBD)-related proctitis or rectal malignancy with mucus- and blood-mixed defecation with urgency and sometimes transient incontinence. The purpose of this paper is to raise awareness of this rare, quality-of-life impacting and difficult-to-treat disease and the not so well-known argon plasma coagulation (APC) treatment that can provide very good and long lasting symptom relief.
Solitärt rektalt ulkussyndrom (SRUS) är ett tillstånd som kan leda till besvärliga rektala symtom.
För diagnostiken krävs endoskopi och histopatologi för att utesluta andra sjukdomar.
Det finns hittills ingen etablerad tillfredsställande medicinsk behandling.
Argonplasmakoagulation är inte etablerad, men en effektiv behandlingsmetod som bör utnyttjas i behandlingsresistenta fall.
The main objective of the MCL3 study was to improve outcome for patients not in CR before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. 160 consecutive, ...untreated stage II-IV MCL patients < 66 years received rituximab (R)- maxi-CHOP alternating with R-high-dose Ara-C (6 cycles total), followed by high-dose BEAM or BEAC and autologous stem cell transplantation 2005-2009. Zevalin (0.4 mCi/kg) was given to responders in only CRu/PR prior to high-dose therapy. The overall response rate (ORR) pre-transplant was 97%. After a median follow-up of 4.4 years the outcome did not differ from that of the historic control, the MCL2 trial with the same treatment except for Zevalin. Overall (OS), event free (EFS), and progression-free survival (PFS) at 4 years were 78, 62 and 71%, respectively. For patients in CRu/PR before transplant who received Zevalin duration of response was shorter than in the CR group. Inferior PFS, EFS- and OS were predicted by PET-positivity pre-transplant and detectable minimal residual disease (MRD) before and after transplant. In conclusion, a positive PET prior to transplant and MRD are strong predictors of outcome. Late intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant.
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