Predictive factors of collateral vessel development induced by oxaliplatin-based chemotherapy.

BACKGROUND AND AIM: Oxaliplatin can lead to hepatic sinusoidal injury, called hepatic sinusoidal obstruction syndrome (SOS), resulting in portal hypertension-related complications. This could worsen the clinical course of the patients treated with oxaliplatin. Early diagnosis is challenging. We explored predictive markers of oxaliplatin-induced collateral vessels. METHODS: Patients who received oxaliplatin-based chemotherapy were retrospectively screened. We evaluated their laboratory findings and spleen size on computed tomography immediately before oxaliplatin-based chemotherapy and after 6 months of treatment. The primary outcome was collateral vessel development, as a surrogate marker for oxaliplatin-induced SOS in patients who underwent oxaliplatin-based chemotherapy. The secondary outcome was the identification of factors that predicted the development of collateral vessels. RESULTS: We enrolled 161 patients who received oxaliplatin-based chemotherapy. They had a median age of 69 years, and 63.3% were men. Collateral vessels developed in nine (5.6%) patients during the study period. After oxaliplatin-based chemotherapy, the spleen size increased in 104 patients (64.6%), with a ≥ 30% increase in 19.4% of the patients. Univariate analysis showed that the Fibrosis-4 (FIB-4) index (≥ 1.76; OR 9.17), aspartate aminotransferase:platelet ratio index (APRI) (≥ 0.193; OR 9.62), cumulative dose of oxaliplatin (≥ 1000 mg; OR 8.43), and increase in spleen size (≥ 30%; OR 6.01) were significant risk factors for collateral vessel development. Multivariate analysis after stepwise selection revealed that the FIB-4 index and spleen size were significant independent predictive factors. CONCLUSION: A ≥ 1.76 increase in the FIB-4 index and a ≥ 30% increase in spleen size after 6 months of oxaliplatin-based chemotherapy were significant predictive markers for collateral vessel development.

Contrast-Enhanced Ultrasound Imaging Features of Focal Chemotherapy-Induced Sinusoidal Injury in Patients With Colorectal Cancer: Initial Experience.

OBJECTIVES: Increasing studies have reported focal chemotherapy-induced sinusoidal injury (CSI) mimicking colorectal liver metastasis (CRLM) on imaging studies, resulting in unnecessary lobectomy. This study aimed to investigate the contrast-enhanced ultrasound (CEUS) imaging features of focal CSI. METHODS: We retrospectively evaluated 16 patients who had a pathologic diagnosis of focal CSI and underwent CEUS between January 2013 and January 2019. The images were compared with those obtained from 27 patients with CRLM. RESULTS: On CEUS, 14 (87.5%) focal CSIs showed heterogeneous isoenhancement, 1 (6.3%) peripheral hyperenhancement, and 1 (6.3%) homogeneous hyperenhancement during the arterial phase. Compared with the adjacent liver parenchyma, the initial enhancement time of focal CSI was earlier in 2 (12.5%), simultaneous in 9 (56.3%), and later in 5 (31.3%) patients. In the portal and late phases, all of the focal CSI cases showed hypoenhancement compared with the adjacent liver parenchyma. Focal CSI had the following CEUS findings, which were different from those of CRLM: (1) heterogeneous isoenhancement in the arterial phase (87.5% versus 0%; P < .001); (2) an initial enhancement time later than that of the liver parenchyma (mean ± SD, 0.5 ± 1.5 versus -1.5 ± 1.9; P < .001); (3) a longer time to peak (30.5 ± 5.6 versus 22.5 ± 4.4 seconds; P < .001); and (4) a later time to wash-out (51.0 ± 12.5 versus 35.0 ± 6.2 seconds; P = .002). CONCLUSIONS: Focal CSI usually shows heterogeneous isoenhancement in arterial phase and hypoenhancement in portal and late phases on CEUS, with slow contrast wash-in and wash-out, which can be helpful in the differential diagnosis with CRLM.

Increase in spleen volume as a predictor of oxaliplatin toxicity.

BACKGROUND: Oxaliplatin is a nonconventional third-generation platinum compound. It is an important chemotherapeutic agent in regimens used in gastrointestinal carcinomas as well as other malignancies. Oxaliplatin toxicity profile includes neurotoxicity, hepatotoxicity, and splenomegaly. The primary aim of this study was to measure the spleen volume of patients on oxaliplatin therapy before and during chemotherapy to detect any increase in splenic size as a biomarker for early oxaliplatin toxicity. METHODS: This was a prospective pilot study conducted at the American University of Beirut-Medical Center. Fifty patients newly started on oxaliplatin were included. The spleen volume was measured from the patients' baseline CT scan using the IntelliSpace Portal upgraded system (using Response Evaluation Criteria In Solid Tumors [RECIST]), for each follow-up CT scan. Side effects were evaluated at each patient visit and graded according to the severity. RESULTS: Thirty-seven (74%) patients developed an increase in spleen size. Thirty-three (66%) sampled patients developed peripheral neuropathy (all grades) at 3 months, whereas only two (4%) patients developed grade 3 neuropathy. Only one (3%) patient who developed an increase in spleen size also developed grade 3 peripheral neuropathy - a result that is significantly different (p<0.001) when comparing patients with an increase in spleen size who also developed peripheral neuropathy of other grades. CONCLUSION: An increase in spleen volume possibly precedes a significant peripheral neuropathy which could be a potential marker for oxaliplatin-induced toxicity.

Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice.

AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH). METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broad-spectrum MMP inhibitor were used to examine the role of MMP-9. RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P < 0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P < 0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P < 0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P < 0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P < 0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P < 0.05). CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

Chemotherapy-associated hepatopathy in korean colorectal cancer liver metastasis patients: oxaliplatin-based chemotherapy and sinusoidal injury.

BACKGROUND: Although chemotherapy-related hepatic injury has been reported in colorectal cancer liver metastasis (CRLM) patients, the morphologic changes caused by chemotherapeutic agents and the effect of chemotherapy on postoperative outcome remain ill-defined. A comprehensive review of the morphologic changes in the post-chemotherapy non-neoplastic liver was performed and the clinical effect of preoperative chemotherapy in CRLM patients was analyzed. METHODS: Hematoxylin-eosin, Masson's trichrome and reticulin-stained slides from non-neoplastic livers obtained from 89 CRLM patients were analyzed, and the clinicopathologic features were correlated with the status of chemotherapy exposure. RESULTS: Histopathologic features of sinusoidal injury (sinusoidal dilatation, centrilobular perivenular fibrosis, parenchymal extinction lesions, small vessel obliteration, and hepatocyte plate disruption) were significantly more frequent in oxaliplatin-exposed livers (p<0.05). The extent of sinusoidal dilatation was positively correlated with increasing numbers of chemotherapy cycles (p=0.022). Abnormal preoperative liver function tests were more frequently seen (p<0.05) and postoperative total bilirubin was higher in the chemotherapy group (p=0.008). Postoperative morbidity was more common in the chemotherapy group (p=0.044). CONCLUSIONS: Sinusoidal injury is frequently seen in oxaliplatin-treated livers, and its presence, especially when extensive, should be documented in surgical pathology practice. The recognition of sinusoidal injury may provide helpful guidelines for surgeons in deciding the extent of hepatic resection.

Chemotherapy-Associated Hepatopathy in Korean Colorectal Cancer Liver Metastasis Patients: Oxaliplatin-Based Chemotherapy and Sinusoidal Injury

BACKGROUND: Although chemotherapy-related hepatic injury has been reported in colorectal cancer liver metastasis (CRLM) patients, the morphologic changes caused by chemotherapeutic agents and the effect of chemotherapy on postoperative outcome remain ill-defined. A comprehensive review of the morphologic changes in the post-chemotherapy non-neoplastic liver was performed and the clinical effect of preoperative chemotherapy in CRLM patients was analyzed. METHODS: Hematoxylin-eosin, Masson's trichrome and reticulin-stained slides from non-neoplastic livers obtained from 89 CRLM patients were analyzed, and the clinicopathologic features were correlated with the status of chemotherapy exposure. RESULTS: Histopathologic features of sinusoidal injury (sinusoidal dilatation, centrilobular perivenular fibrosis, parenchymal extinction lesions, small vessel obliteration, and hepatocyte plate disruption) were significantly more frequent in oxaliplatin-exposed livers (p<0.05). The extent of sinusoidal dilatation was positively correlated with increasing numbers of chemotherapy cycles (p=0.022). Abnormal preoperative liver function tests were more frequently seen (p<0.05) and postoperative total bilirubin was higher in the chemotherapy group (p=0.008). Postoperative morbidity was more common in the chemotherapy group (p=0.044). CONCLUSIONS: Sinusoidal injury is frequently seen in oxaliplatin-treated livers, and its presence, especially when extensive, should be documented in surgical pathology practice. The recognition of sinusoidal injury may provide helpful guidelines for surgeons in deciding the extent of hepatic resection.