DNA damage predicts prognosis and treatment response in colorectal liver metastases superior to immunogenic cell death and T cells

Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear. Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33). DNA damage (gammaH2AX), RNA and DNA sensors (RIG-I, DDX41, cGAS, STING), ER stress response (p-PKR, p-eIF2alpha, CALR), type I and type II IFN- induced proteins (MxA, GBP1), mature dendritic cells (CD208), and cytotoxic and memory T cells (CD3, CD8, CD45RO) were investigated by an immunohistochemistry whole-slide tissue scanning approach and further correlated with recurrence-free survival (RFS), overall survival (OS), radiographic and pathologic therapy response. Results: gammaH2AX is a negative prognostic marker for RFS (HR 1.32, 95% CI 1.04-1.69, p=0.023) and OS (HR 1.61, 95% CI 1.23-2.11, p<0.001). A model comprising of DDX41, STING and p-PKR predicts radiographic therapy response (AUC=0.785, p=0.002). gammaH2AX predicts prognosis superior to the prognostic value of CD8. CALR positively correlates with GBP1, CD8 and cGAS. A model consisting of gammaH2AX, p-eIF2alpha, DDX41, cGAS, CD208 and CD45RO predicts pathological therapy response (AUC=0.944, p<0.001). Conclusion: In contrast to preclinical models, DNA damage inversely correlated with ICD and its associated T cell infiltrate and potentially serves as a therapeutic target in CLM

Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial.

BACKGROUND: Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting. METHODS: Patients aged 18-75 years, PS 0-1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg(-1) followed by irinotecan 180 mg m(-)(2), leucovorin 200 mg m(-)(2), 5-fluorouracil 400 mg m(-)(2) bolus and 5-fluorouracil 2400 mg m(-)(2) 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required. RESULTS: From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8-80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6-76.6). Median PFS and OS were 14 (95% CI: 11-24) and 38 (95% CI: 28-NA) months, respectively. CONCLUSION: Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance

Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer

Background: Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin. Methods: In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR. Results: Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate-severe) SOS (P=0.026). Conclusion: The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment

Relationship between microvessel count and postoperative survival in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: The present study aimed to elucidate the relationship between microvessel count (MVC) according to CD34 expression and prognosis in intrahepatic cholangiocarcinoma (ICC) patients who underwent hepatectomy based on our preliminary study. METHODS: Relationships between MVC and clinicopathological factors were examined in 37 ICC patients. CD34 expression was analyzed using immunohistochemical methods. RESULTS: Median MVC for ICC patients was 140/mm(2), which was applied as a cutoff value. Lower MVC was significantly associated with larger tumor size, periductal infiltrating type, and advanced Japanese tumor-node-metastasis stage (p < 0.05). Univariate survival analysis identified higher carcinoembryonic antigen level, periductal infiltrating type, poor histological differentiation, and lower MVC as significantly associated with lower 5-year survival rates. The 5-year survival rate in the higher-MVC group was significantly greater than that in the lower-MVC group (44% vs. 7%, p = 0.048). According to Cox multivariate survival analysis, only periductal infiltrating type on macroscopic examination was identified as a significant independent risk factor for poor survival after hepatectomy (risk ratio 4.8; p = 0.006), not MVC (1.1; p = 0.82). CONCLUSION: Tumor MVC might offer a useful prognostic marker of ICC patient survival after hepatectomy and further investigation in a larger series is warranted

Zufallsbefunde von Leber, Gallensystem, Pankreas und Milz bei asymptomatischen Patienten : Bewertung und Managementempfehlung

Klinisches Problem Die vermehrte Verwendung hoch entwickelter bildgebender Verfahren wie Multidetektorcomputertomographie und Magnetresonanztomographie hat zu einer beträchtlichen Zunahme asymptomatischer und unerwarteter Befunde geführt. Radiologische Standardverfahren Besonders betroffen sind abdominelle CT-Untersuchungen mit einer Vielzahl inzidenteller Befunde. Dieses wertvolle Diagnoseverfahren birgt auch die Gefahr aufwendiger und auch kostenintensiver Folgeuntersuchungen mit z. T. invasiven Verfahren. Bewertung Vor diesem Hintergrund stellt sich für den Radiologen immer häufiger die schwierige Aufgabe, diese Läsionen korrekt einzuschätzen, über die Notwendigkeit einer weiteren Abklärung zu entscheiden und den Patienten umfassend über die klinische Relevanz zu informieren. Empfehlung für die Praxis Das Ziel dieses Artikels ist es, die am häufigsten vorkommenden abdominellen Zufallsbefunde zu beschreiben sowie Hilfestellung bei ihrer Interpretation und Differenzialdiagnose mit Empfehlungen für das weitere Management zu geben.Clinical issue The increased use of highly developed imaging procedures, such as multidetector-row computed tomography and magnetic resonance imaging has led to a substantial increase of asymptomatic and unexpected findings. Standard radiological methods Abdominal CT investigations are particularly affected with a large number of incidental findings. This valuable diagnostic procedure also entails the risk of complex and cost-intensive subsequent investigations with partly invasive procedures. Achievements For this reason radiologists are more often confronted with the difficult task of correctly assessing these lesions, to decide on the need for additional investigations and to inform the patient in detail about the clinical relevance. Practical recommendations The aims of this article are to describe the most common abdominal incidentalomas, to assist with the interpretation and differential diagnosis and to give recommendations for further management.(VLID)353372

Der Radiologe / Zufallsbefunde von Niere, Nebenniere, Adnexen, Gastrointestinaltrakt, Mesenterium und Lymphknoten : Bewertung und Managementempfehlung

Klinisches Problem Neben den parenchymatösen Oberbauchorganen hat der zunehmende Einsatz von Schnittbildverfahren zu einer vermehrten Anzahl von Zufallsbefunden der Nieren, Nebennieren, Adnexe, des Gastrointestinaltrakts, Mesenteriums und der intraabdominellen Lymphknoten geführt. Radiologische Standardverfahren Abdominelle CT-Untersuchungen zeigen häufig unerwartete Befunde ohne korrelierende Symptomatik. Die steigende klinische Relevanz ist einerseits auf die Zunahme inzidenteller Pathologien und andererseits auf ein wachsendes Bewusstsein ethischer und sozioökonomischer Faktoren zurückzuführen. Bewertung Bei der radiologischen Interpretation sind neben morphologischen Kriterien sowohl die Einbeziehung der individuellen Risikofaktoren des Patienten als auch der klinische Gesamtkontext von großer Bedeutung. Empfehlung für die Praxis Das Ziel dieses Artikels ist eine Beschreibung und Bewertung der in der Computertomographie detektierten genannten Zufallsbefunde sowie weiterer Managementempfehlungen.Clinical issue Besides the upper abdominal parenchymal organs, the increasing application of cross-sectional imaging has also led to a rising number of incidental findings in the kidneys, adrenal glands, adnexa uteri, the gastrointestinal tract, mesentery and abdominal lymph nodes. Standard radiological methods Abdominal computed tomography investigations often show unexpected findings without any correlating symptoms. The growing clinical relevance is due to the large number of incidental findings as well as an increasing awareness of ethical and socioeconomic factors. Achievements When interpreting radiological findings not only morphological criteria but also individual risk factors of the patient and the clinical context are of great importance. Practical recommendations The aims of this article are the description and evaluation of frequent incidental findings detected by computed tomography and to provide information about management recommendations.(VLID)353373