Oxaliplatin toxicity presenting as a liver nodule - case report.

BACKGROUND: Oxaliplatin based chemotherapy is often used as adjuvant therapy in colon and rectal cancer. A reported side effect is Sinusoidal Obstruction Syndrome which is characterized by a spectrum of pathologic changes, from sinusoidal dilation, peri-sinusoidal haemorrhage, peliosis and nodular regenerative hyperplasia. Very rarely it can cause the development of liver nodules mimicking liver metastases. Herein, we report a case of Sinusoidal Obstruction Syndrome causing a liver nodule suspicious of liver metastasis on imaging. This is the third reported case of this complication of oxaliplatin toxicity, in which resection was performed and pathological diagnosis confirmed. CASE PRESENTATION: We report the case of a 59 year old man with stage III colon cancer who underwent sigmoidectomy followed by adjuvant chemotherapy with oxaliplatin. One year after surgery a liver nodule was detected and the patient underwent right hepatectomy. Pathology showed no liver nodule and diagnosed sinusoidal obstruction syndrome. CONCLUSION: We describe the third reported case of a liver lesion mimicking a liver metastasis after oxaliplatin-based chemotherapy for colon cancer. We suggest that in patients heavily treated with oxaliplatin with de novo liver nodules, this differential diagnosis should be considered. In particular, in this population of patients an intense imagiologic evaluation and even a preoperative biopsy should be pursued to confirm the diagnosis of malignancy and avoid overtreatment.

[Denture impaction in the thoracic esophagus: surgical treatment - a case report]. / Impactação de prótese dentária no esófago torácico: tratamento cirúrgico. A propósito de um caso clínico.

Esophageal foreign body impaction is mostly managed with endoscopic retrieval. However, in cases of large or irregularly shaped foreign bodies, or in cases of long standing impaction, this technique carries a high risk of perforation and a surgical approach is often mandatory.The authors report the case of a 55 year old woman, with a past history of mental retardation, presenting with dysphagia for solid food and regurgitation beginning one month earlier. After failed extraction by flexible esophagoscopy,the denture was removed by esophagotomy through a postero-lateral thoracotomy. In the postoperative period the patient developed a leakage of the suture line with resultant esophago-pleural fistula which was managed with double esophageal exclusion. She was discharged on the 40th postoperative day on semi-solid diet and is presently (eight months after the first surgery) symptom free.

[The impact of selective clamping of portal vein in hepatocellular function. An experimental study]. / Estudo experimental do impacto da clampagem selectiva da veia porta na função hepatocelular.

UNLABELLED: The influence of selective clamping of the elements of hepatic pedicle in the hepatocellular function and viability were evaluated in our department. AIM: Study the effect of selective clamping of the portal vein (CPV) in hepatocellular function in an animal model with normal liver. METHOD: Three groups of Wistar rats (males, 2 months) were subjected a CPV for 60 min: group A (n=21) submitted to a continuous inflow occlusion; group B (n=12) underwent to a CPV for 30 min with 5 min of reperfusion; group C (n=10) underwent a CPV for 15 min with 5 min of reperfusion. The group D (n=9) was not subjected to a CPV. A hepatic biopsy was done at the end of surgery. The degree of tissue injury was evaluated using: 1) blood markers: AST, ALT, total bilirubin (TB), GGT alkaline-phosphatase, LDH and hepatic extraction fraction (HEF) by radioisotopic methods three days before laparotomy (BS) and after surgery (AS); 2) apoptosis, necrosis were investigated after collagenase cell isolation from hepatectomy pieces by flow-cytometry using the followed probes: propidium-iodide and annexin-V. STATISTICAL ANALYSIS: variance analysis, post-hoc comparisons by Turkey-test (p<0.05). RESULTS: 1) Mortality: Group A - 62%, Group B - 17%, Group C - 30%, Group D - 0% (p<0.03). 2) We observed statistical differences in these parameters: ALT (p<0,025) and LDH (p<0,002) preferentially in groups A but without differences between the A,B,C and D Groups (ns). 3) We also verified a significant decrease in HEF values (p<0,0001) preferentially in group A without differences between the groups. 4) No difference were observed when analysed apoptosis and necrosis and cell viability between the groups. CONCLUSIONS: Postoperative liver failure is the leading cause of mortality after hepatectomy, however selective clamping of the portal vein, is reflected in an increase in cell viability and a decrease in the type of cell death (necrosis ou apoptosis) compared to studies carried out previously by us and thus may be regarded as an alternative to the Pringle maneuver. However, selective clamping of the portal vein for periods above 30' should be avoided, given the high mortality verified.

Functional Impairment of Circulating FcεRI+ Monocytes and Myeloid Dendritic Cells in Hepatocellular Carcinoma and Cholangiocarcinoma Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most common primary liver malignancies whose outcome is influenced by the immune response. METHODS: In this study, we have functionally characterized, by flow cytometry, circulating myeloid dendritic cells (mDCs) and FcεRI+ monocytes in a group of healthy individuals (n = 10) and in a group of patients with HCC (n = 19) and CCA (n = 8), at the time point of the surgical resection (T0) and once the patient had recovered from surgery (T1). Moreover, we proceeded to a more in depth phenotypic characterization of the FcεRI+ monocyte subpopulation. RESULTS: A significant decrease in the frequency of TNFα producing FcεRI+ monocytes and mDCs in HCC and CCA patients when compared to the group of healthy individuals was observed, and a close association between FcεRI+ monocytes and mDCs dysfunction was identified. In addition, the phenotypic characteristics of FcεRI+ monocytes from healthy individuals strongly suggest that this population drives to mDCs, which matches with the fact that both populations are functionally affected. CONCLUSIONS: The frequency and the function of circulating mDCs and FcεRI+ monocytes are affected in both HCC and CCA patients, and FcεRI+ monocytes could represent those fated to become mDCs. © 2019 International Clinical Cytometry Society.

In vivo selective and distant killing of cancer cells using adenovirus-mediated decorin gene transfer.

Decorin is a well-known, ubiquitous proteoglycan that is a normal component of the ECM. Upon transgenic expression of decorin, tumor cells with diverse histogenetic background overexpress p21WAF1, a potent inhibitor of cyclin-dependent kinase activity, become arrested in G1, and fail to generate tumors in immunocompromised animals. Because decorin is a secreted protein, it has been recently suggested that decorin could act as an autocrine and paracrine regulator of tumor growth. Here, we demonstrate that adenovirus (Ad)-mediated transfer and expression of human decorin cDNA induced in vivo apoptosis of xenograft tumor cells in nude mice. This oncolytic activity was observed when the Ad vector encoding the decorin cDNA was injected intratumorally (i.t.) or i.v. Importantly, i.t. injection of the decorin Ad vector led to growth inhibition of the injected tumor associated with similar growth inhibition of a distant contralateral tumor, demonstrating a distant decorin antitumoral effect. Immunochemistry against human decorin and decorin quantitation in tumors confirmed that decorin migrated to the tumor distant site. Furthermore, decorin effect was specific to tumor cells, because neither apoptosis nor growth inhibition were observed in nontumoral human cells such as hepatocytes, endothelial cells, and fibroblasts, despite p21 overexpression.

HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the PKA signaling pathway.

The HIP/PAP (=human Reg-2) C-type lectin encoding gene is activated in primary liver cancers. In normal liver, the protein is undetectable in normal mature hepatocytes and found only in some ductular cells, representing potential hepatic progenitor cells. The aim of this study was to examine the consequences of human HIP/PAP expression in the liver of transgenic mice. We demonstrated that HIP/PAP stimulated liver regeneration after partial hepatectomy. To further investigate the enhanced liver regeneration observed in vivo, primary cultures of hepatocytes were used to evaluate the mitogenic and anti-apoptotic properties of HIP/PAP. HIP/PAP increased hepatocyte DNA synthesis and protected hepatocytes against TNF-alpha plus actinomycin-D-induced apoptosis. HIP/PAP anti-apoptotic effects against TNF-alpha were clearly demonstrated when protein kinase A activity was specifically inhibited by KT5720, and HIP/PAP stimulated PKA-dependent phosphorylation of the proapoptotic Bad protein at Ser-112, suggesting that HIP/PAP may compete with cAMP to stimulate PKA activity. Overall, our results led us to propose a new role for a C-type lectin, HIP/PAP, as a hepatic cytokine that combines mitogenic and anti-apoptotic functions regarding hepatocytes, and consequently acts as a growth factor in vivo to enhance liver regeneration.

Paracrine in vivo inhibitory effects of hepatitis B virus X protein (HBx) on liver cell proliferation: an alternative mechanism of HBx-related pathogenesis.

The role of the hepatitis B virus X protein (HBx) in the pathogenesis of hepatitis B virus (HBV) infection remains unclear. HBx exhibits pleiotropic biological effects, whose in vivo relevance is a matter for debate. In the present report, we have used a combination of HBx-expressing transgenic mice and liver cell transplantation to investigate the in vivo impact of HBx expression on liver cell proliferation and viability in a regenerative context. We show that moderate HBx expression inhibits liver regeneration after partial hepatectomy in HBx-expressing transgenic mice. We also demonstrate that the transplantation of HBx-expressing liver cells, isolated from HBx transgenic mice, is sufficient to inhibit overall recipient liver regeneration after partial hepatectomy. Moreover, the injection of serum samples drawn from HBx-expressing transgenic mice mimicked the inhibitory effect of HBx on liver regeneration. Finally, the incubation of primary rat hepatocytes with the supernatant of HBx-expressing liver cells inhibits cellular DNA synthesis. Taken together, our results demonstrate a paracrine inhibitory effect of HBx on liver cell proliferation and lead us to propose HBV as one of the few viruses implicated in human cancer which act, at least in part, through paracrine biological pathways.

A highly efficient, stable, and rapid approach for ex vivo human liver gene therapy via a FLAP lentiviral vector.

Allogenic hepatocyte transplantation or autologous transplantation of genetically modified hepatocytes has been used successfully to correct congenital or acquired liver diseases and can be considered as an alternative to orthotopic liver transplantation. However, hepatocytes are neither easily maintained in culture nor efficiently genetically modified and are very sensitive to dissociation before their reimplantation into the recipient. These difficulties have greatly limited the use of an ex vivo approach in clinical trials. In the present study, we have shown that primary human and rat hepatocytes can be efficiently transduced with a FLAP lentiviral vector without the need for plating and culture. Efficient transduction of nonadherent primary hepatocytes was achieved with a short period of contact with vector particles, without modifying hepatocyte viability, and using reduced amounts of vector. We also showed that the presence of the DNA FLAP in the vector construct was essential to reach high levels of transduction. Moreover, transplanted into uPA/SCID mouse liver, lentivirally transduced primary human hepatocytes extensively repopulated their liver and maintained a differentiated and functional phenotype as assessed by the stable detection of human albumin and antitrypsin in the serum of the animals for months. In conclusion, the use of FLAP lentiviral vectors allows, in a short period of time, a high transduction efficiency of human functional and reimplantable hepatocytes. This work therefore opens new perspectives for the development of human clinical trials based on liver-directed ex vivo gene therapy.