Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer ...cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.
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•mTRAIL-R promotes KRAS-driven lung and pancreatic cancer growth and metastasis•Human TRAIL-R2 promotes tumor growth, migration, invasion, and metastasis•Endogenous mTRAIL-R constitutively activates Rac1 in vivo in tumors•TRAIL-R2 expression positively correlates with the onset of metastasis in patients
von Karstedt et al. show that mouse TRAIL-R and human TRAIL-R2, but not TRAIL-R1, are important for the progression, invasion, and metastasis of KRAS-mutant tumors through the regulation of Rac-1.
We aimed to characterize clinical and prognostical factors of primary head and neck squamous cell carcinoma (HNSCC) in 85 young patients (≤39 years, median age: 37 years; between 2000-2018) in ...comparison with 140 institutional general HNSCC patients (median age: 61.5 years). The patient's medical records were collected from the institutional database. The prevalence of smoking and alcohol consumption (65.8% and 48.1%) in the young group exceeded the regional population average but was below the institutional (86.4% and 55%) general HNSCC patient population. Primary tumor sites in the group of young patients were as follows: oral cavity (56.4%), oropharynx (17.6%), hypopharynx (11.7%), and larynx (14.1%). Cumulative five-year overall survival was 44.2% in the young group, but significantly better with early T (T1-2 vs. T3-4: 52.6% vs. 26.7%;
= 0.0058) and N0 status (N0 vs. N+: 65.2% vs. 32.3%;
= 0.0013). Young age, abstinence, earlier stage and laryngeal tumor site might predict a better prognosis. The age distribution and the high prevalence of traditional risk factors among the young patients as well as the predominance of oral cavity tumor localization suggest that the early onset of tumor development could be originated from the premature failure of the intrinsic protective mechanisms.
Current guidelines lack comprehensive information on the metastatic site-specific role of KRAS mutation in lung adenocarcinoma (LADC). We investigated the effect of KRAS mutation on overall survival ...(OS) in this setting. In our retrospective study, 500 consecutive Caucasian metastatic LADC patients with known KRAS mutational status were analyzed after excluding 32 patients with EGFR mutations. KRAS mutation incidence was 28.6%. The most frequent metastatic sites were lung (45.6%), bone (26.2%), adrenal gland (17.4%), brain (16.8%), pleura (15.6%) and liver (11%). Patients with intrapulmonary metastasis had significantly increased KRAS mutation frequency compared to those with extrapulmonary metastases (35% vs 26.5%, p = 0.0125). In contrast, pleural dissemination and liver involvement were associated with significantly decreased KRAS mutation incidence (vs all other metastatic sites; 17% (p < 0.001) and 16% (p = 0.02) vs 33%, respectively). Strikingly, we found a significant prognostic effect of KRAS status only in the bone metastatic subcohort (KRAS-wild-type vs KRAS-mutant; median OS 9.7 v 3.7 months; HR, 0.49; 95% CI, 0.31 to 0.79; p = 0.003). Our study suggests that KRAS mutation frequency in LADC patients shows a metastatic site dependent variation and, moreover, that the presence of KRAS mutation is associated with significantly worse outcome in bone metastatic cases.
Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), ...tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1).
After exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival.
The 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26-0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis.
High ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.
The prognostic value of histological phenomena tumor budding (TB) and poorly differentiated clusters (PDCs) have been less studied in gastric cancer (GAC) and the data provided so far are ...controversial. In our study, 290 surgically resected GAC cases were evaluated for TB according to the criteria of International Tumor Budding Consensus Conference (ITBCC) and PDC, and both parameters were scored on a three-grade scale as described for colorectal cancer previously (0: Grade0, 1–4: Grade1, 5–9: Grade2 and ≥10: Grade3) and classified as low (Grade0–2) and high (Grade3) TB/PDC. High TB/PDC was associated with diffuse-type morphology, higher pT status, incomplete surgical resection, poor tumor differentiation and perineural and lymphovascular invasion. Multivariable survival analyses have shown an independent prognostic role of high TB with poorer overall survival in the total cohort (p = 0.014) and in intestinal-type adenocarcinomas (p = 0.005). Multivariable model revealed high TB as an independent predictor for lymph node metastasis in both the total cohort (p = 0.019) and in the intestinal type adenocarcinomas (p = 0.038). In contrast to tumor budding, no significant association was found between PDC and the occurrence of lymph node metastasis and tumor stage and even survival. In conclusion, tumor budding is an independent prognostic factor of survival in gastric cancer, especially in intestinal-type adenocarcinomas.
Assessment of population-based cancer survival may provide the most valuable feedback about the effectiveness of oncological surveillance and treatment.
Based on the database of the Hungarian ...National Cancer Registry, standardized incidence rates of lung, breast, colorectal, prostate and cervical cancer were compared to standardized mortality data of the Hungarian Central Statistical Office in the period between 2001 and 2015. Then survival analysis was performed on cleansed database.
The incidence of colorectal, breast and prostate cancer increased, while standardized rates of lung and cervical cancer declined. The survival of colorectal, breast and prostate cancer showed improvement. Contrarily, lung cancer exhibited a mild decline, while that of cervical cancer did not change significantly. In earlier stages survival was improved among almost every studied tumor type, while in advanced stages improvement was not observed. Comparison of stage distribution revealed that in the 2011-2015 period colorectal, breast and prostate cancer cases were diagnosed at earlier stages, while lung and cervical cancer patients were typically discovered at more advanced stages.
The outcome of advanced cancer treatments is better in earlier stages, which highlighted the importance of screening network. However, growth of oncological treatment costs with longer patient survival imposes a constantly increasing burden on society.
The introduction of immuno- and targeted therapeutic modalities meant a breakthrough step in the therapy of melanoma. As a checkpoint inhibitor, the more effective and less toxic anti-PD1 therapy ...followed an anti-CTLA4 approach.
From our patient pool, 222 advanced melanoma cases were selected, where anti-PD1 (pembrolizumab, nivolumab) therapy was initiated between March 2015 and December 2020. During our retrospective analysis, the efficacy and safety of the therapy were assessed.
The median follow-up was 16 months (interval: 0-64 months), and 150 patients (67.6%) received therapy in the first line, while second and third line therapy was performed among 72 patients (32.4%) for the median of 7.0 months (0-60). In 50 cases, BRAF mutations were detected. Ninety-six patients showed objective response (11.3% CR, 32.0% PR). The median PFS was 10.0 months (0-60), and the median OS was 23.0 months (0-64). Autoimmune side effects were found in 79 patients (35.5%); grade 3 occurred in 6.3% of the cases, while 1 patient died due to fulminant pneumonitis (0.25%).
Although the range of immunotherapeutic options is getting wider, in the management of melanoma patients, anti-PD1 monotherapy remains an important, effective, and safe method. However, significant correlation was found between the immune-related side effects and therapeutic efficacy.
Immune suppressing molecule CD73 is overexpressed in various cancers and associated with poor survival. Little is so far known about the predictive value of CD73 in pancreatic ductal adenocarcinoma ...(PDAC). The purpose of this study was to investigate the prognostic significance of CD73 in PDAC. The study material consisted of 110 radically treated patients for PDAC. Tissue microarray blocks were constructed and stained immunohistochemically using CD73 antibody. Staining intensity and numbers of stained tumour cells, inflammatory cells, stroma, and blood vessels were assessed. High-level CD73 expression in tumour cells was positively associated with PD-L1 expression, perineural invasion, and histopathological grade. CD73 positivity in tumour-infiltrating lymphocytes was significantly associated with lymph node metastasis. Lymphocytic CD73 positivity was also associated with staining positivity in both stroma and vascular structures. In addition, CD73 positivity in vascular structures and stroma were associated with each other. There were no significant associations between CD73 positive tumour cells and CD73 positivity in any other cell types. PD-L1 expression was associated with CD73 staining positivity in stroma (
p
= 0.007) and also with histopathological grade (
p
= 0.033) and T class (
p
= 0.016) of the primary tumour. CD73 positivity in tumour cells was significantly associated with poor disease-specific (
p
= 0.021) and overall survival (
p
= 0.016). In multivariate analysis, CD73 positivity in tumour cells was an independent negative prognostic factor together with histopathological grade, TNM stage, and low immune cell score. In conclusion, high CD73 expression in tumour cells is associated with poor survival in PDAC independently of the number of tumour-infiltrating lymphocytes or TNM stage.
Background Hereditary angioedema (HAE) is a rare, life-threatening disease. The knowledge about the molecular pathogenesis of HAE has derived mainly from investigating blood samples. However, limited ...data are available on the role of the molecular mechanisms in the affected tissues during HAE attack. Objective The aim of our study was to explore the histological changes occurring in HAE attacks. Methods Post mortem macro-, microscopic and immunohistological assessment of upper airway tissues of a patient with HAE due to C1 inhibitor deficiency (C1-INH-HAE) type 2 who died from laryngeal HAE attack was compared with a non-HAE patient who died from other condition without any signs of angioedema. Results Compared to the control patient, we demonstrated stronger T cell/monocyte infiltration and a more intense C1-INH staining in the C1-INH-HAE patient. The expression of both bradykinin receptors (B1/B2) was observed with a slightly lower level in the C1-INH-HAE patient than in the control patient. PAR1 expression was strongly reduced in the C1-INH-HAE patient suggesting overactivation of this hyperpermeability inducing receptor. Conclusion Our unique case and novel results correspond to the knowledge about C1-INH and BDKRs observed in plasma; however, it revealed new information about the pathomechanism of HAE attack focusing on the potential involvement of PAR1 in edema formation. This observation, if it is verified by subcutaneous biopsy studies, may designate a new therapeutic target in HAE. Keywords: Hereditary angioedema, C1-inhibitor deficiency, Immunohistochemistry, Laryngeal edema, Protease activated receptor 1, Bradykinin receptor
Cutaneous melanoma is the third most common type of skin cancer in the world. The incidence of melanoma is increasing in most countries, however, mortality seems to be slowly decreasing. The ...treatment of advanced cutaneous melanoma changed radically since 2011. The new therapeutic modalities, such as immuno- and targeted therapies give a chance to successfully reach more prolonged progression-free survival (PFS) and overall survival (OS) in patients with metastatic melanoma. Despite the great therapeutic benefit, most patients eventually develop resistance to these therapies, and the disease will progress. In some cases oligoprogression develops. In those cases local therapy, such as stereotactic radiotherapy can make it possible to continue the previously applied effective medical treatment for the benefit of patients. In our study of a total of 30 patients-20 of them received pre-treatment with systemic medical therapy-received stereotactic radiotherapy using various systems, in the National Institute of Oncology, Hungary, Budapest. We managed to prolong the systemic therapy for 12.5 months median period with the assistance of CyberKnife technique. Therapy related adverse events were mostly tolerable with only 3% of Grade 3 toxicity. We concluded that stereotactic radiotherapy and stereotactic radiosurgery, are safe, and effective therapeutic modalities for regional tumor control in cases of oligoprogression.
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