Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases?

Hubert, Catherine; Sempoux, Christine; Horsmans, Yves; Rahier, Jacques; Humblet, Yves; Machiels, Jean‐Pascal; Ceratti, A.; Canon, Jean-Luc; Gigot, Jean‐François

doi:10.1111/j.1478-3231.2007.01511.x

Cited by 71 publications

(41 citation statements)

References 25 publications

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“…In our two patients to these consideration the multinodular pattern has further biased the diagnostic conclusion. Indeed, only Hubert et al [11] previously reported two cases of multiple FNHs occurred in similar circumstances while other authors described patients with single lesions [5,6,9] . Our experience is conveying a further peculiarity, which could be useful for further discussion and experiences in this sense.…”

Section: Discussionmentioning

confidence: 99%

“…The natural history of FNH remains unknown, too. Few spontaneous regressions after the suspension of the chemotherapy have been reported as well as some protective effects of bevacizumab on the development of this toxicity [5,11,12] . From the clinical standpoint their proper diagnosis is a delicate matter, since they occur in oncological patients with generally well-documented, and extensive negative At microscopy the lesions were characterized by several fibrous septa highlighted by special stains (Masson staining), and they showed a typical patter at glutamine synthetase immunostaining; D: At higher magnification they contained several dystrophic vessels.…”

Section: Discussionmentioning

confidence: 99%

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Multiple focal nodular hyperplasias induced by oxaliplatin-based chemotherapy

Donadon

Tommaso

Roncalli

et al. 2013

WJH

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Focal nodular hyperplasia (FNH) is a benign condition that affects normal liver with low prevalence. Recently, the extensive use of oxaliplatin to treat patients with colorectal cancer has been reported to be associated with the development of different liver injuries, as well as focal liver lesions. The present work describes two patients with multiple bilateral focal liver lesions misdiagnosed as colorectal liver metastases, and treated with liver resection. The first patient had up to 15 small bilateral focal liver lesions, with magnetic resonance imaging consistent with colorectal liver metastases (CLM), and fluorodeoxyglucose (FDG)-positron emission tomography (PET) negative. The second patient had up to 5 small focal liver lesions, with computed tomography consistent with CLM, and FDG-PET negative. They had parenchyma sparing liver surgery, with uneventful postoperative course. At the histology the diagnosis was multiple FNHs. The risks of oxaliplatinbased chemotherapy regimens in development of liver injuries, such as FNH, should not be further denied.The value of the modern multidisciplinary management of patients with colorectal cancer relies also on the precise estimation of the risk/benefit for each patient.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multiple focal nodular hyperplasias induced by oxaliplatin-based chemotherapy

Donadon

Tommaso

Roncalli

et al. 2013

WJH

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“…In fact, since our initial report (1), several groups have confirmed the existence of oxaliplatin-related SOS in 25% to 36% of treated patients. This has led to concerns that oxaliplatin-associated hepatotoxicity may decrease the chances of curative liver surgery by increasing morbidity through preoperative hemorrhage, postoperative liver failure, delayed regeneration, and portal hypertension (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Rare fatal cases have been reported, inducing a group of experts to publish a cautionary note on the use of chemotherapy before surgical liver resection (14).…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Rubbia‐Brandt

Tauzin

Brézault

et al. 2011

Molecular Cancer Therapeutics

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Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

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“…Previous studies reported that the formation of marked nodular hyperplasia may induce portal hypertension [41,42] . In addition, Hubert et al [43] reported that 5-FU-oxaliplatin-based chemotherapy had the potential to induce nodular hyperplasia in patients suffering from colorectal liver metastases. In this study, the portal pressure of the rats in the AEE788-treated group remained within the normal range.…”

Section: Nrh Nrhmentioning

confidence: 99%

Effect and Risk of AEE788, a Dual Tyrosine Kinase Inhibitor, on Regeneration in a Rat Liver Resection Model

Deng

Huang²,

Dirsch³

et al. 2010

Eur Surg Res

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Background: AEE788, a dual tyrosine kinase inhibitor, has antiproliferative effects on diverse tumor models in mice. We aimed to investigate whether AEE788 blocks liver regeneration and causes drug-related side effects. Methods: Rats treated orally with 50 mg/kg AEE788 or solvent every 2 days were subjected to 70% partial hepatectomy (PH) and sacrificed on postoperative days 1, 2, 7, and 28. Liver regeneration was evaluated using liver weight to body weight ratio, BrdU-staining, mitotic index, and PCR for PCNA (proliferating cell nuclear antigen). Side effects on the gastrointestinal system and liver were assessed using clinical chemistry, histology, silver staining, and immunohistochemistry. Plasma and liver tissue levels of AEE788 were measured using spectrometry. Results: AEE788 treatment did not inhibit liver regeneration. No obvious drug-related systemic or hepatic side effects were observed. Restoration of liver architecture during liver regeneration was not obviously impaired, even after 4 weeks’ AEE788 treatment. After a 1-week treatment, AEE788 concentrations in plasma and liver tissue in the PH group were 3-fold and 8-fold higher than the non-PH group, respectively. Conclusion: Its antiproliferative properties, good tolerance, and lack of inhibition on liver regeneration make AEE788 a potential candidate for clinical study with oncological PH, but one that carries the risk of overexposure in the early postoperative phase.

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Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases?

Abstract: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery.

Cited by 71 publications

References 25 publications

Multiple focal nodular hyperplasias induced by oxaliplatin-based chemotherapy

Multiple focal nodular hyperplasias induced by oxaliplatin-based chemotherapy

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Effect and Risk of AEE788, a Dual Tyrosine Kinase Inhibitor, on Regeneration in a Rat Liver Resection Model

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