Peri-implantitis is an inflammatory disease affecting soft and hard tissues surrounding dental implants. As the global number of individuals that undergo restorative therapy through dental implants ...increases, peri-implantitis is considered as a major and growing problem in dentistry. A randomly selected sample of 588 patients who all had received implant-supported therapy 9 y earlier was clinically and radiographically examined. Prevalence of peri-implantitis was assessed and risk indicators were identified by multilevel regression analysis. Forty-five percent of all patients presented with peri-implantitis (bleeding on probing/suppuration and bone loss >0.5 mm). Moderate/severe peri-implantitis (bleeding on probing/suppuration and bone loss >2 mm) was diagnosed in 14.5%. Patients with periodontitis and with ≥4 implants, as well as implants of certain brands and prosthetic therapy delivered by general practitioners, exhibited higher odds ratios for moderate/severe peri-implantitis. Similarly, higher odds ratios were identified for implants installed in the mandible and with crown restoration margins positioned ≤1.5 mm from the crestal bone at baseline. It is suggested that peri-implantitis is a common condition and that several patient- and implant-related factors influence the risk for moderate/severe peri-implantitis (ClinicalTrials.gov NCT01825772).
Treatment outcomes in implant dentistry have been mainly assessed as implant survival rates in small, selected patient groups of specialist or university clinical settings. This study reports on loss ...of dental implants assessed in a large and randomly selected patient sample. The results were aimed at representing evaluation of effectiveness of implant dentistry. Using the national data register of the Swedish Social Insurance Agency, 4,716 patients were randomly selected. All had been provided with implant-supported restorative therapy in 2003. Patient files of 2,765 patients (11,311 implants) were collected from more than 800 clinicians. Information on patients, treatment procedures, and outcomes related to the implant-supported restorative therapy was extracted from the files. In total, 596 of the 2,765 subjects, provided with 2,367 implants, attended a clinical examination 9 y after therapy. Implant loss that occurred prior to connection of the supraconstruction was scored as an early implant loss, while later occurring loss was considered late implant loss. Early implant loss occurred in 4.4% of patients (1.4% of implants), while 4.2% of the patients who were examined 9 y after therapy presented with late implant loss (2.0% of implants). Overall, 7.6% of the patients had lost at least 1 implant. Multilevel analysis revealed higher odds ratios for early implant loss among smokers and patients with an initial diagnosis of periodontitis. Implants shorter than 10 mm and representing certain brands also showed higher odds ratios for early implant loss. Implant brand also influenced late implant loss. Implant loss is not an uncommon event, and patient and implant characteristics influence outcomes (ClinicalTrials.gov NCT01825772).
A balanced constitutional reciprocal translocation (RT) is a mutual exchange of terminal segments of two non-homologous chromosomes without any loss or gain of DNA in germline cells. Carriers of ...balanced RTs are viable individuals with no apparent phenotypical consequences. These animals produce, however, unbalanced gametes and show therefore reduced fertility and offspring with congenital abnormalities. This cytogenetic abnormality is usually detected using chromosome staining techniques. The aim of this study was to test the possibilities of using paired end short read sequencing for detection of balanced RTs in boars and investigate their breakpoints and junctions.
Balanced RTs were recovered in a blinded analysis, using structural variant calling software DELLY, in 6 of the 7 carriers with 30 fold short read paired end sequencing. In 15 non-carriers we did not detect any RTs. Reducing the coverage to 20 fold, 15 fold and 10 fold showed that at least 20 fold coverage is required to obtain good results. One RT was not detected using the blind screening, however, a highly likely RT was discovered after unblinding. This RT was located in a repetitive region, showing the limitations of short read sequence data. The detailed analysis of the breakpoints and junctions suggested three junctions showing microhomology, three junctions with blunt-end ligation, and three micro-insertions at the breakpoint junctions. The RTs detected also showed to disrupt genes.
We conclude that paired end short read sequence data can be used to detect and characterize balanced reciprocal translocations, if sequencing depth is at least 20 fold coverage. However, translocations in repetitive areas may require large fragments or even long read sequence data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus ...(EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies.
Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses.
Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich ‘hot’ CIN GEAs were often from Western patients, while immunological ‘cold’ CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1.
These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.
•There is large heterogeneity in the immune contexture of gastroesophageal adenocarcinoma (GEA) subtypes.•Chromosomal instable GEAs are often T cell excluded, which is associated with enhanced MYC and cell cycle pathways.•Genome stable cancers, contrarily, often have tertiary lymphoid structures.•This study argues for more personalized immunotargeting strategies in gastroesophageal cancer treatment.
Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments ...and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.
Esophageal cancer is a disease with poor overall survival. Despite advancements in therapeutic options, the treatment outcome of esophageal cancer patients remains dismal with an overall 5-year ...survival rate of approximately 20 percent. To improve treatment efficacy and patient survival, efforts are being made to identify the factors that underlie disease progression and that contribute to poor therapeutic responses. It has become clear that some of these factors reside in the tumor micro-environment. In particular, the tumor vasculature and the tumor immune micro-environment have been implicated in esophageal cancer progression and treatment response. Interestingly, galectins represent a family of glycan-binding proteins that has been linked to both tumor angiogenesis and tumor immunosuppression. Indeed, in several cancer types, galectins have been identified as diagnostic and/or prognostic markers. However, the role of galectins in esophageal cancer is still poorly understood. Here, we summarize the current literature with regard to the expression and potential functions of galectins in esophageal cancer. In addition, we highlight the gaps in the current knowledge and we propose directions for future research in order to reveal whether galectins contribute to esophageal cancer progression and provide opportunities to improve the treatment and survival of esophageal cancer patients.
Highlights • OS significantly longer in single organ metastatic disease compared to 2 or ⩾3 organs. • Single organ metastases also prognostic in subgroup of18 FDG-PET-staged patients. • Single organ ...metastases also prognostic in patients receiving anticancer treatment. • In single organ metastases, low local disease (i.e. T1–2 and N0–1) best prognosis.
To evaluate the long-term neurodevelopmental and behavioral outcome of antenatal allopurinol treatment during suspected fetal hypoxia.
We studied children born from women who participated in a ...randomized double-blind placebo controlled multicenter study (ALLO-trial). Labouring women in whom the fetus was suspected to have fetal hypoxia were randomly allocated to receive allopurinol or placebo. At 5 years of age, the children were assessed with 2 parent reported questionnaires, the Ages and Stages Questionnaire (ASQ) and the Child Behavior Checklist (CBCL). A child was marked abnormal for ASQ if it scored below 2 standard deviation under the normative mean of a reference population in at least one domain. For CBCL, a score above the cut-off value (95th percentile for narrowband scale, 85th percentile for broadband scale) in at least one scale was marked as abnormal.
We obtained data from 138 out of the original 222 mildly asphyxiated children included in the ALLO-trial (response rate 62%, allopurinol n = 73, placebo n = 65). At 5 years of age, the number of children that scored abnormal on the ASQ were 11 (15.1%) in the allopurinol group versus 11 (9.2%) in the placebo group (relative risk (RR) 1.64, 95% confidence interval (CI): 0.64 to 4.17, p = 0.30). On CBCL 21 children (30.4%) scored abnormal in de allopurinol group versus 12 children (20.0%) in the placebo group (RR 1.52, 95% CI: 0.82 to 2.83, p = 0.18).
We found no proof that allopurinol administered to labouring women with suspected fetal hypoxia improved long-term developmental and behavioral outcome. These findings are limited due to the fact that the study was potentially underpowered.
NCT00189007 Dutch Trial Register NTR1383.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•PD-L1 ≥ 1% is expressed in 16% of stage IV LCNEC, 5% has expression ≥50%.•PD-L1 staining in LCNEC is comparable to values in SCLC, but lower than in NSCLC.•No difference in PD-L1 expression is found ...in RB1 mutated and RB1 wildtype subgroups.•Expression of PD-L1 (tumor cells) and CD8 (tumor infiltrating cells) is associated.•Overall survival is prolonged in patients with PD-L1+ and CD8+ LCNEC.
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare tumor with high mutational burden. Two subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 group and the TP53 and STK11/KEAP1 group. We investigated PD-L1 and CD8 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes.
Immunohistochemical (IHC) analysis for PD-L1 and CD8 was performed on pathological reviewed pretreatment tumor samples for 148 stage IV LCNEC. Data about targeted next generation sequencing (TNGS) (TP53, RB1, STK11, KEAP1) and IHC for RB1 were available for most tumors. IHC staining for PD-L1 (DAKO 28-8) was performed and scored positive if tumors showed ≥1% membranous staining. CD8 was scored for intra-tumor T-cells and stromal cells.
PD-L1 IHC expression data could be generated in 98/148 confirmed LCNEC samples along with RB1 IHC (n = 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); 5 (5%) with ≥50%. PD-L1 expression was equal in RB1 mutated and RB1 wildtype tumors. None of STK11 mutated tumors (n = 7) expressed PD-L1. PD-L1 expression was correlated with superior overall survival (OS), hazard ratio 0.55 ((95% Confidence Interval 0.31-0.96), p = 0.038). Intra-tumor CD8 was associated with PD-L1 expression (p = 0.021) and stromal and intra-tumor CD8 were correlated with improved OS (p = 0.037 and p = 0.026 respectively).
PD-L1 expression was positive in 16% of stage IV LCNEC tumors. This was independent of molecular subtype but associated with CD8 expression. In LCNEC patients with PD-L1 and/or CD8 expression superior OS was observed.
•Carcinoids are characterized by well differentiated morphology and low proliferation.•LCNEC is characterized by poorly differentiated morphology and high proliferation.•We identified 7 pulmonary NEN ...with high proliferation but preserved differentiation.•pRb expression might be useful in this subgroup as a classifying or prognostic marker.
Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival.
Cases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression.
Seven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months.
A subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied.
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