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Histopathological findings in colorectal liver metastases after electrochemotherapy.

ABSTRACT: Electrochemotherapy of colorectal liver metastases has been proven to be feasible, safe and effective in a phase I/II study. In that study, a specific group of patients underwent two-stage operation, and the detailed histopathological evaluation of the resected tumors is presented here. Regressive changes in electrochemotherapy-treated liver metastases were evaluated after the second operation (in 8-10 weeks) in 7 patients and 13 metastases when the treated metastases were resected. Macroscopic and microscopic changes were analyzed. Electrochemotherapy induced coagulation necrosis in the treated area encompassing both tumor and a narrow band of normal tissue. The area became necrotic, encapsulated in a fibrous envelope while preserving the functionality of most of the vessels larger than 5 mm in diameter and a large proportion of biliary structures, but the smaller blood vessels displayed various levels of damage. At the time of observation, 8-10 weeks after electrochemotherapy, regenerative changes were already seen in the peripheral parts of the treated area. This study demonstrates regressive changes in the whole electrochemotherapy-treated area of the liver. Further evidence of disruption of vessels less than 5 mm in diameter and preservation of the larger vessels by electrochemotherapy is provided. These findings are important because electrochemotherapy has been indicated for the therapy of metastases near major blood vessels in the liver to provide a safe approach with good antitumor efficacy.

SUBMITTER: Gasljevic G

PROVIDER: S-EPMC5501591 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Histopathological findings in colorectal liver metastases after electrochemotherapy.

Gasljevic Gorana G Edhemovic Ibrahim I Cemazar Maja M Brecelj Erik E Gadzijev Eldar M EM Music Maja M MM Sersa Gregor G

PloS one 20170707 7

Electrochemotherapy of colorectal liver metastases has been proven to be feasible, safe and effective in a phase I/II study. In that study, a specific group of patients underwent two-stage operation, and the detailed histopathological evaluation of the resected tumors is presented here. Regressive changes in electrochemotherapy-treated liver metastases were evaluated after the second operation (in 8-10 weeks) in 7 patients and 13 metastases when the treated metastases were resected. Macroscopic ...[more]

PMID: 28686650

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Project description:BackgroundElectrochemotherapy (ECT) is a combined treatment in which high voltage electroporation (EP) pulses are used to facilitate the uptake of a chemotherapeutic drug into tumor cells, thus increasing antitumor effectiveness of the drug. The effect of ECT of deep-seated tumors located close to the heart on functioning of the heart has not been previously investigated. In this study, we investigate the effects of intra-abdominal ECT of colorectal liver metastases on functioning of the heart during the early post-operative care period.MethodsFor ECT high voltage EP pulses with amplitudes of up to 3000 V and 30 A were delivered in synchronization with electrical activity of the heart. Holter electrocardiographic (ECG) signals were obtained from 10 patients with colorectal liver metastases treated with ECT. ECG was recorded during the periods of 24 hours before and after the surgical procedure involving ECT. Four-hour long night-time ECG segments from both periods exhibiting the highest level of signal stationarity were analyzed and compared. Changes in several ECG and heart rate variability (HRV) parameters were evaluated.ResultsNo major heart rhythm changes (i.e., induction of extrasystoles, ventricular tachycardia or fibrillation) or pathological morphological changes (i.e., ST segment changes) indicating myocardial ischemia were found. However, we found several minor statistically significant but clinically irrelevant changes in HRV parameters after ECT procedures: a decrease in median values of the mean NN interval, a decrease in the low-frequency and in the normalized low-frequency component, and an increase in the normalized high-frequency component.ConclusionsOnly minor effects of intra-abdominal ECT treatment on functioning of the heart were found. They were expressed as statistically significant but clinically irrelevant changes in heart rate and long-term HRV parameters and were as such not life-threatening to the patients. The nature of these changes is such that they can be attributed to the known effects of the drugs given to the patients in the post-operative care. Further investigation is still warranted to unambiguously resolve whether ECT with high voltage EP pulses applied in immediate vicinity of the heart is responsible for the observed effects.

Project description:Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour-liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β [95% confidence interval, CI]: 24.57 [18.28-30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β [95% CI]: 24.18 [18.70-29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β [95% CI]: 23.29 [1.78-44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

Project description:BackgroundIn patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.MethodsAll consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.ResultsIn total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen.ConclusionsThe current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.

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Histopathological findings in colorectal liver metastases after electrochemotherapy.

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Histopathological findings in colorectal liver metastases after electrochemotherapy.

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