Daniel Martin

Serum Autotaxin Is a Parameter for the Severity of Liver Cirrhosis and Overall Survival in Patients with Liver Cirrhosis – A Prospective Cohort Study

Background Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients. Methods Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry. Results 270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017). Conclusion Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.

Human papilloma virus load and PD-1/PD-L1, CD8+ and FOXP3 in anal cancer patients treated with chemoradiotherapy: Rationale for immunotherapy

ABSTRACT We examined the prognostic role of immune markers programmed cell death protein-1 (PD-1) and its ligand (PD-L1), CD8+ tumor-infiltrating lymphocytes (TILs), FOXP3+ Tregs and phosphorylated Caspase-8 (T273) in patients with anal squamous cell cancer (ASCC) treated with standard chemoradiotherapy (CRT). The baseline immunohistochemical expression of immune markers was correlated with clinicopathologic characteristics, and cumulative incidence of local failure, disease-free survival (DFS) and overall survival (OS) in 150 patients, also in the context of human papilloma virus 16 (HPV16) DNA load and p16INK4a expression. After a median follow-up of 40 mo (1–205 mo), the 5-y cumulative incidence of local failure and DFS was 19.4% and 67.2%, respectively. Strong immune marker expression was significantly more common in tumors with high HPV16 viral load. In multivariant analysis, high CD8+ and PD-1+ TILs expression predicted for improved local control (p = 0.023 and p = 0.007, respectively) and DFS (p = 0.020 and p = 0.014, respectively). Also, high p16INK4a (p = 0.011) and PD-L1 (p = 0.033) expression predicted for better local control, whereas high FOXP3+ Tregs (p = 0.050) and phosphorylated Caspase-8 (p = 0.031) expression correlated with superior DFS. Female sex and high HPV16 viral load correlated with favorable outcome for all three clinical endpoints. The present data provide, for the first time, robust explanation for the favorable clinical outcome of HPV16-positive ASCC patients harboring strong immune cell infiltration. Our findings are relevant for treatment stratification with immune PD-1/PD-L1 checkpoint inhibitors to complement CRT and should be explored in a clinical trial.

The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy

Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world, and 70-90% of all cases originate from infection with human papilloma viruses (HPV). Primary chemoradiotherapy (CRT) is the standard treatment for ASCC, but local and/or distant failure still occurs in up to 30% of patients. HPV-associated ASCC and tumors with a higher density of tumor infiltrating lymphocytes (TIL) carry a better prognosis. Furthermore, HPV can render tumors more immunogenic, whereas it correlates with elevated TIL densities. This comprehensive review highlights the progress made in understanding the immune microenvironment of anal intraepithelial neoplasias and ASCC in the context of HPV. Here, we discuss the immunomodulatory potential of CRT, the prognostic impact of immune checkpoint markers, and the rationale for including immunotherapies to further improve the clinical outcome in patients with ASCC.

Peripheral Leukocytosis Is Inversely Correlated with Intratumoral CD8+ T-Cell Infiltration and Associated with Worse Outcome after Chemoradiotherapy in Anal Cancer

Peripheral blood leukocytosis has been implicated in promoting tumor progression leading to worse survival, but the mechanisms behind this phenomenon remain unexplored. Here, we examined the prognostic role of pretreatment white blood cell (WBC) count and clinicopathologic parameters in the context of CD8+ tumor-infiltrating lymphocytes (TIL) and myeloperoxidase+ tumor-associated neutrophils (TANs) in patients with anal squamous cell carcinoma (ASCC) treated with definitive chemoradiotherapy (CRT). After a median follow-up of 26 months, leukocytosis correlated with advanced T-stage (p < 0.001) and N-stage (p < 0.001), and predicted for worse distant-metastasis-free survival (p = 0.006), disease-free-survival (DFS, p = 0.029), and overall survival (p = 0.013). Importantly, leukocytosis was associated with a lower intraepithelial CD8+ TIL density (p = 0.014), whereas low CD8+ TIL expression in the intraepithelial compartment was associated with worse DFS (p = 0.028). Additionally, high TAN expression in the peritumoral compartment was associated with a significantly lower density of CD8+ TIL (p = 0.039), albeit, TAN expression lacked prognostic value. In conclusion, leukocytosis constitutes an important prognostic marker in ASCC patients treated with CRT. In conjunction with intratumoral TIL and TAN, these data provide for the first time important insight on the correlation of peripheral blood leukocytosis with the intratumoral immune contexture and could be relevant for future patient stratification using immunotherapies in ASCC.

Anal squamous cell carcinoma – State of the art management and future perspectives

Anal squamous cell carcinoma (ASCC) is associated with infection with high-risk strains of human papilloma virus (HPV) in 70-90% of cases and a rise in incidence has been observed in the last decades. Definitive chemoradiotherapy (CRT) using 5-fluorouracil and mitomycin C constitutes the standard treatment for localized disease, but about 30% of patients do not respond or relapse locally. Phase I/II trials testing targeted agents, such as epidermal-growth-factor receptor (EGFR) inhibitors, have failed to improve clinical outcome and resulted in increased toxicities. Modern imaging methods and biomarkers, also in the context of HPV status, should be further explored to improve patient stratification. In the present review, we will discuss the current clinical evidence and future perspectives in the management of ASCC. HPV-positive ASCC is more immunogenic with a higher density of tumor infiltrating lymphocytes that correlate with better response to CRT and more favorable prognosis compared to HPV-negative tumors. Immunotherapies including immune checkpoint inhibitors have brought new hope and promising results were recently demonstrated in metastatic ASCC. The addition of immunotherapies to CRT for localized disease is tested in early phase trials, and these results could have a profound impact on the way we treat ASCC in near future. Further research and novel approaches are expected to enhance our understanding of tumor biology and immunology, and improve patient stratification and treatment adaptation in the context of personalized medicine.

Nivolumab für das vorbehandelte metastasierte Analkarzinom: Blockade von Immuncheckpoints auch in Kombination mit Radiochemotherapie sinnvoll

Hintergrund und Ziel der Arbeit Ein Großteil der Patienten mit Analkarzinom kann durch eine definitive Radiochemotherapie geheilt werden. Allerdings kommt es bei bis zu 25% der Patienten zu Fernmetastasen, für die es keine Standardtherapie gibt. Die meisten Analkarzinome werden durch eine Infektion mit dem humanen Papillomavirus (HPV) ausgelöst. HPV-Infektionen lösen eine immunogene Reaktion aus und sorgen für die Infiltration des Tumors mit Lymphozyten. Die Hochregulierung des PD-L1 („programmed death ligand“ 1) auf Tumorzellen hemmt allerdings über Bindung an den PD-1 („programmed death receptor“ 1) die Aktivität dieser tumorinfiltrierenden Lymphozyten. Bei Nivolumab handelt es sich um einen humanisierten monoklonalen Antikörper gegen PD-1, der diese Interaktion hemmen und somit die tumorizide Wirkung der T-Lymphozyten fördern soll. Dieser Antikörper wird bereits bei mehreren soliden Tumoren, wie den Kopf-Hals-Tumoren oder den malignen Melanomen, erfolgreich in der Monotherapie eingesetzt. Bei der vorliegenden Arbeit handelt es sich um eine Phase-II-Studie bei chemotherapeutisch vorbehandelten Patienten mit Metastasen des Analkarzinoms.

Chemoradiotherapy as Definitive Treatment for Elderly Patients with Head and Neck Cancer

Background With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients. Patients and Methods We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years. Results RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS (p = 0.004) and PFS (p = 0.048). Conclusion Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.

Wie lange sollte bis zur Beurteilung des Therapieansprechens nach Radiochemotherapie des Analkarzinoms gewartet werden? How long should we wait upon completion of chemoradiotherapy before assessment of tumor response in anal cancer?

Hintergrund und Ziel Bisherige Leitlinien zur Therapie des Analkarzinoms sahen vor, dass 6–12 Wochen nach Beginn der Radiochemotherapie (RCT) die Beurteilung des Therapieansprechens erfolgen sollte. Bei unzureichender Regression des Tumors wäre die Salvage-Operation vorgesehen. Die vorliegende Post-hoc-Analyse der ACT-II-Studie untersuchte den optimalen Zeitpunkt zur Beurteilung des Therapieansprechens an einem großen, homogen behandelten Patientenkollektiv.

Prognostic impact of RITA expression in patients with anal squamous cell carcinoma treated with chemoradiotherapy

BACKGROUND RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signalling pathway and its deregulation is involved in the pathogenesis of several tumour entities. RITAs impact on the response of anal squamous cell carcinoma (SCC) to anticancer treatment, however, remains elusive. MATERIALS AND METHODS In our retrospective study immunohistochemical evaluation of RITA was performed on 140 pre-treatment specimens and was correlated with clinical and histopathologic characteristics and clinical endpoints cumulative incidence of local control (LC), distant recurrence (DC), disease-free survival (DFS) and overall survival (OS). RESULTS We observed significant inverse correlations between RITA expression and tumour grading, the levels of HPV-16 virus DNA load, CD8 (+) tumour infiltrating lymphocytes and programmed death protein (PD-1) immunostaining. In univariate analyses, elevated levels of RITA expression were predictive for decreased local control (p = 0.001), decreased distant control (p = 0.040), decreased disease free survival (p = 0.001) and overall survival (p < 0.0001), whereas in multivariate analyses RITA expression remained significant for decreased local control (p = 0.009), disease free survival (p = 0.032) and overall survival (p = 0.012). CONCLUSION These data indicate that elevated levels of pretreatment RITA expression are correlated with unfavourable clinical outcome in anal carcinoma treated with concomitant chemoradiotherapy.