Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, vascular ...homeostasis and inflammation. In addition, PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. PPARGs role in cancer is a matter of debate, as pro- and anti-tumour properties have been described in various tumour entities. Currently, the specific role of PPARG in patients with colorectal cancer (CRC) is not fully understood.
The prognostic impact of PPARG expression was investigated by immunohistochemistry in a case-control study using a matched pair selection of CRC tumours (n = 246) with either distant metastases to the liver (n = 82), lung (n = 82) or without distant metastases (n = 82). Its effect on proliferation as well as the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU) was examined after activation, inhibition, and transient gene knockdown of PPARG in the CRC cell lines SW403 and HT29.
High PPARG expression was significantly associated with pulmonary metastasis (p = 0.019). Patients without distant metastases had a significantly longer overall survival with low PPARG expression in their tumours compared to patients with high PPARG expression (p = 0.045). In the pulmonary metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumour (p = 0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a significant dose-dependent increase in proliferation of CRC cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it.
The prognostic effect of PPARG expression depends on the metastasis localization in advanced CRC patients. Activation of PPARG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensitivity towards the chemotherapeutic agent 5-FU. Based on this finding, a combination therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a promising strategy which should be further investigated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC).
Methods
AIO-PK0104 was a phase III ...trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc).
Results
KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (
p
= 0.40), but KRAS wildtype patients had an improved OS (HR 1.68,
p
= 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (
p
= 0.10) for the OSc.
Conclusion
This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.
Molecular differences in colorectal cancer (CRC) are associated with the metastatic route. Patient survival is mainly driven by metastatic spread thus it is imperative to understand its key drivers ...to develop biomarkers for risk stratification, follow-up protocols and personalized therapy. Thus, this study aimed to identify genes associated with the metastatic route in CRC.
CRC patients resected at our clinic from 2005 to 2014 and with a minimum 5-year follow-up were included in this analysis and grouped into CRC with hepatic (HEP), peritoneal (PER) or without distant metastases (M0), and HEP/PER. Firstly, tumor RNA of 6 patients each was isolated by microdissection from formalin-fixed paraffin-embedded specimens and analyzed by a NanoString analysis. Subsequently, these results were validated with immunohistochemistry and correlated to clinicopathological parameters in a larger collective of CRC patients (HEP n = 51, PER n = 44, M0 n = 47, HEP/PER n = 28).
Compared to M0, HEP tumors showed 20 differentially expressed genes associated with epithelial-mesenchymal transition (EMT) and angiogenesis. Compared to M0, PER tumors had 18 differentially expressed genes. The finding of different gene signatures was supported by the multidimensional principal component clustering analysis. Tumor perforation did not influence the metastatic route. CIB1 was homogenously and significantly overexpressed in HEP compared to M0 (p < 0.001), but not in PER. Furthermore, immunohistochemical validation demonstrated that the mean CIB1 expression in HEP was 80% higher than in M0 (p < 0.001).
Gene expression analysis revealed that CIB1 is significantly overexpressed in CRC leading to liver metastases compared to M0 and PER. Thus, the present results suggest that CIB1 may play a crucial role for hematogenous spread to the liver but not for peritoneal carcinomatosis. Consequently, CIB1 seems to be a promising prognostic marker and a potential tool for future targeted therapies as well as early diagnostics and follow-up.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We describe one of the first cases of a Posterior reversible encephalopathy syndrome (PRES) under tocilizumab as treatment of Giant cell arteritis (GCA).
A 65-year-old female with known GCA and ...treatment with Tocilizumab (TCZ) developed a convulsive epileptic seizure for the first time. MRI was suggestive of PRES and an associated left sided occipital hemorrhage. Extensive high blood pressure values were not detected. The patient recovered within a week and no further seizures occurred under anticonvulsive medication.
PRES during the treatment with Tocilizumab hasn't been described in GCA so far. There are single reports of an association between TCZ and PRES in other entities. Thus, a link between interleukin-6 and the integrity of the vasculature could be considered. The clinical consequence should be a stringent blood pressure monitoring in the ambulant setting of patients receiving TCZ.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Though peritoneal carcinomatosis reflects a late stage of colorectal cancer (CRC), only few patients present with synchronous or metachronous liver metastases alongside their peritoneal ...carcinomatosis. It is hypothesized that this phenomenon may be causally linked to molecular characteristics of the primary CRC. This study used miRNA profiling of primary CRC tissue either metastasized to the liver, to the peritoneum or not metastasized at all thus to identify miRNAs potentially associated with defining the site of metastatic spread in CRC.
Tissue of the primary tumor stemming from CRC patients diagnosed for either liver metastasis (LM; n = 10) or peritoneal carcinomatosis (PER; n = 10) was analyzed in this study. Advanced CRC cases without metastasis (M0; n = 3) were also included thus to select on those miRNAs most potentially associated with determining metastatic spread in general. miRNA profiling of 754 different miRNAs was performed in each group. MiRNAs being either differentially expressed comparing PER and LM or even triple differentially expressed (PER vs. LM vs. M0) were identified. Differentially expressed miRNAs were further validated by in silico and functional analysis.
Comparative analysis identified 41 miRNAs to be differentially expressed comparing primary tumors metastasized to the liver as opposed to those spread to the peritoneum. A set of 31 miRNAs was significantly induced in primary tumors that spread to the peritoneum (PER), while the remaining 10 miRNAs were found to be repressed. Out of these 41 miRNAs a number of 25 miRNAs was triple-differentially expressed (i.e. differentially expressed comparing LM vs. PER vs. M0). The latter underwent in silico analysis. Finally, we demonstrated that miR-31 down-regulated c-MET in DLD-1 colon cancer cells.
This study demonstrates that CRC primary tumors spread to the peritoneum vs. metastasized to the liver display significantly different miRNA profiles. Larger patient cohorts will be needed to validate whether determination of e.g. miR-31 may aid to predict the course of disease and whether this may help to create individualized follow up or treatment protocols. To determine whether certain miRNAs may be involved in regulating the metastatic potential of CRC, functional studies will be essential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Microscopy of mummified visceral tissue from a Medici family member in Italy identified a potential blood vessel containing erythrocytes. Giemsa staining, atomic force microscopy, and ...immunohistochemistry confirmed Plasmodium falciparum inside those erythrocytes. Our results indicate an ancient Mediterranean presence of P. falciparum, which remains responsible for most malaria deaths in Africa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Chronic inflammation is a significant factor in colorectal cancer (CRC) development, especially in colitis-associated CRC (CAC). T-cell exhaustion is known to influence inflammatory bowel ...disease (IBD) progression and antitumor immunity in IBD patients. This study aimed to identify unique immune infiltration characteristics in CAC patients. Methods: We studied 20 CAC and 20 sporadic CRC (sCRC) patients, who were matched by tumor stage, grade, and location. Immunohistochemical staining targeted various T-cell markers (CD3, CD4, CD8, and FOXP3), T-cell exhaustion markers (TOX and TIGIT), a B-cell marker (CD20), and a neutrophil marker (CD66b) in tumor and tumor-free mucosa from both groups. The quantification of the tumor immune stroma algorithm assessed immune-infiltrating cells. Results: CAC patients had significantly lower TOX+ cell infiltration than sCRC in tumors (p = 0.02) and paracancerous tissues (p < 0.01). Right-sided CAC showed increased infiltration of TOX+ cells (p = 0.01), FOXP3+ regulatory T-cells (p < 0.01), and CD20+ B-cells (p < 0.01) compared to left-sided CAC. In sCRC, higher tumor stages (III and IV) had significantly lower TIGIT+ infiltrate than stages I and II. In CAC, high CD3+ (p < 0.01) and CD20+ (p < 0.01) infiltrates correlated with improved overall survival. In sCRC, better survival was associated with decreased TIGIT+ cells (p < 0.038) and reduced CD8+ infiltrates (p = 0.02). Conclusion: In CAC, high CD3+ and CD20+ infiltrates relate to improved survival, while this association is absent in sCRC. The study revealed marked differences in TIGIT and TOX expression, emphasizing distinctions between CAC and sCRC. T-cell exhaustion appears to have a different role in CAC development.
Due to improvements in both the quality and availability of intracranial imaging as well as the evolution of surgical and endovascular techniques during the last decade, the number of treatments of ...unruptured intracranial aneurysms (UIA) has increased steadily. However, it is not generally known that vasospasm can arise after an uneventful clipping.
We present a case of a 69-year-old woman who suffered from vasospasm and delayed cerebral ischemia that occurred after an uneventful clipping of a UIA. The aneurysm of the right middle cerebral artery was found incidentally via magnetic resonance imaging ordered after the patient complained of a short period of slight gait disturbances. To avoid a subarachnoid hemorrhage and consecutive complications like vasospasms, the patient elected microsurgical treatment. Clipping was managed by keyhole approach. Temporal clipping of the M1 was not necessary. After clip placement, appropriate flow in all distal segments was confirmed by indocyanine green video-angiography and micro-Doppler. The patient was discharged seven days after surgery without neurological deficits. After 12 days, the patient developed at home a sudden drooping on the left side of the face. Upon admission to the emergency room, the patient was alert but slightly confused. Neurological examination revealed a left-sided hemiparesis and motor speech disorder. In contrast to the preoperative transfemoral catheter angiography, the subsequent right internal carotid angiogram showed clear signs of vasospasm along the M1 and M2 segments of the right middle cerebral artery. Antithrombotic treatment with acetylsalicylic acid was begun. In accordance with guidelines for the treatment of subarachnoid hemorrhage and vasospasm, nimodipine was added. After 11 days the patient was discharged with no symptoms.
Cerebral vasospasm as a cause of ischemic stroke after uneventful surgery for a UIA seems to be a rare but possibly underestimated etiology that demands particular attention with respect to providing appropriate treatment. In future, it may be prudent to perform follow-up transcranial ultrasonography testing after the clipping of a UIA, especially considering the availability of potentially neuroprotective medications like nimodipine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The transcription factor SOX2, which is involved in the induction of pluripotent stem cells and contributes to colorectal carcinogenesis, is associated with a poor prognosis in colon cancer (CC). ...Furthermore, SOX2 is a repressor of the transcriptional activity of β-catenin in vitro. Since the majority of CC develop via an activation of the Wnt/β-catenin signalling pathway, indicated by nuclear expression of β-catenin, we wanted to investigate the expression patterns of SOX2 and β-catenin and correlate them with the occurrence of lymph node and distant metastases as indicators of malignant progression.
The expression of SOX2 and β-catenin was investigated in a case control study utilizing a matched pair collection (N = 114) of right-sided CCs with either corresponding distant metastases (N = 57) or without distant spread (N = 57) by applying immunohistochemistry.
Elevated protein expression of SOX2 significantly correlated with the presence of lymph node- (p = 0.006) and distant metastases (p = 0.022). Nuclear β-catenin expression correlated significantly only with distant metastases (p = 0.001). Less than 10% of cases showed a coexpression of high levels of β-catenin and SOX2. The positivity for both markers was also associated with a very high risk for lymph-node metastases (p = 0.007) and distant spread (p = 0.028).
We demonstrated that increased expression of either SOX2 or nuclear β-catenin are associated with distant metastases in right-sided CC. Additionally, SOX2 is also associated with lymph-node metastases. These data underline the importance of stemness-associated markers for the identification of CC with high risk for distant spread.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer is the third most common cancer and a major cause of cancer-related deaths. Early detection of colonic lesions can reduce the incidence and mortality of colorectal cancer. ...Colonoscopy is the screening test for colorectal cancer with the highest efficacy, but its acceptance in the general public is rather low. To identify suitable tumor-derived markers that could detect colorectal cancer in blood samples, we analyzed the methylation status of a panel of genes in sera of affected patients.
Using methylation-specific quantitative PCR, we analyzed the methylation of ten marker genes in sera of healthy individuals and patients with colorectal cancer.
Only HLTF, HPP1/TPEF, and NEUROG1 DNA methylation was detectable in at least 50% of patients with colorectal cancers. Whereas HLTF and HPP1/TPEF preferentially detected advanced and metastasized colorectal cancers, NEUROG1 methylation was detectable in UICC stages I-IV at a similar rate. Compared with other methylation markers, such as ALX4, SEPT9, and vimentin, NEUROG1 shows a higher sensitivity for colorectal cancer at UICC stages I and II. At a specificity of 91%, NEUROG1 reached a sensitivity of 61% (confidence interval, 50.4-70.6%) for the detection of colorectal cancers. Furthermore, detection of NEUROG1 methylation was independent of age and gender.
Methylation of the NEUROG1 gene is frequently found in sera of patients with colorectal cancers independent of tumor stage. The quantitative detection of NEUROG1 DNA methylation in serum is a suitable approach for the non-invasive screening for asymptomatic colorectal cancer.
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