"Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients?

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors ≤2 cm ("very early") in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a "very early" iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the "very early" iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2 cm or multinodular tumors, p = 0.02. The 1-, 3- and 5-year actuarial survival of those in the "very early" iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA ≤2 cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.

Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study.

OBJECTIVE: To evaluate the outcome of patients with hepatocellular-cholangiocarcinoma (HCC-CC) or intrahepatic cholangiocarcinoma (I-CC) on pathological examination after liver transplantation for HCC. BACKGROUND: Information on the outcome of cirrhotic patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study is limited. METHODS: Multicenter, retrospective, matched cohort 1:2 study. STUDY GROUP: 42 patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study; and control group: 84 patients with a diagnosis of HCC. I-CC subgroup: 27 patients compared with 54 controls; HCC-CC subgroup: 15 patients compared with 30 controls. Patients were also divided according to the preoperative tumor size and number: uninodular tumors 2 cm or smaller and multinodular or uninodular tumors 2 cm or larger. Median follow-up: 51 (range, 3-142) months. RESULTS: The 1-, 3-, and 5-year actuarial survival rate differed between the study and control groups (83%, 70%, and 60% vs 99%, 94%, and 89%, respectively; P < 0.001). Differences were found in 1-, 3-, and 5-year actuarial survival rates between the I-CC subgroup and their controls (78%, 66%, and 51% vs 100%, 98%, and 93%; P < 0.001), but no differences were observed between the HCC-CC subgroup and their controls (93%, 78%, and 78% vs 97%, 86%, and 86%; P = 0.9). Patients with uninodular tumors 2 cm or smaller in the study and control groups had similar 1-, 3-, and 5-year survival rate (92%, 83%, 62% vs 100%, 80%, 80%; P = 0.4). In contrast, patients in the study group with multinodular or uninodular tumors larger than 2 cm had worse 1-, 3-, and 5-year survival rates than their controls (80%, 66%, and 61% vs 99%, 96%, and 90%; P < 0.001). CONCLUSIONS: Patients with HCC-CC have similar survival to patients undergoing a transplant for HCC. Preoperative diagnosis of HCC-CC should not prompt the exclusion of these patients from transplant option.

[Interferon-alpha toxicity and reversible bilateral optical neuropathy: a timely withdrawal of the drug]. / Toxicidad por interferón alfa y neuropatía óptica bilateral reversible: una retirada a tiempo.

Clinical case A patient with chronic, painless, bilateral loss of vision, after significant intake of interferon (IFNα) and ribavirina due to liver transplant. Ocular fundus is normal. A suspected retrobulbar optic neuropathy is confirmed by a prolongation of the latency of the patient's visual evoked potential. There being no prior record of risk factors and with the patient's systemic analysis giving normal results, the clinical improvement and the electro-physiological tests conducted after the drug was withdrawn point to interferon as negatively affecting the bilateral optic nerve. Discussion Interferon-α is used in the treatment of viral and neoplastic illnesses. Currently the drug is formulated as Interferon alfa pegilado (IFNα-p) in order to reduce toxicity and increase tolerance. The most common secondary effects are flu symptoms, asthenia and weigh loss. Affected ocular tissue is rare and optic neuropathy is also an infrequent complication: retinopathy at the beginning of treatment is, however, more frequent. The most widely accepted hypothesis as to the cause of toxicity is the presence of circulating immune complexes. It is, therefore, essential for ophthalmologists to be aware of the toxicity of this drug in order to be able to withdraw it in good time, thus preventing potentially irreversible sight loss.

Exclusions and deaths on the liver transplant waiting list.

OBJECTIVE: To analyze the characteristiscs, evolution and survival of patients included on the waiting list (WL) for liver transplantation (OLT). PATIENTS AND METHODS: Between February 2002 and April 2009, 254 patients were included on WL to receive a first graft. Two hundred twenty-two patients (87.4%) were transplanted (group T); 7 (2.8%) died on the WL and 25 (9.8%) were excluded, namely, 13 (52%) due to improvement (group IE) and 12, for other reasons (group OE). Data collected prospectively were analyzed retrospectively. RESULTS: Indications for transplant were cirrhosis (58%), hepatocellular carcinoma (HCC; 29%) and other etiologies (13%.) Average time on the WL was 60.3 +/- 62.9 days. Significant differences were not observed among the groups with respect to age, gender, or indication for OLT. The probability for exclusion due to progression and/or death was not significantly greater among patients included for HCC than for other reasons (P = .6). Survivals at 1, 3, and 5 years after WL inclusion were 81.2%, 73.3%, and 68.6%, respectively, in the whole series; and 85,4%, 76,9%, and 71.7% in group T. All group OE patients died before the first year, while group IE showed a survival of 100%, 91.7% and 91.7% at 1, 3, and 5 years, respectively. Survival was not different between groups T and IE (P = .03), but was lower in group OE than in groups T or IE (P < .001). CONCLUSION: The list mortality rate in our series was low, probably in relation to the short waiting time. The rate of exclusion from WL was 10%. Patient with hepatocellular carcinoma were not at an increased risk of WL exclusion. Patients excluded due to improvement displayed excellent survivals during the 5 years following exclusion.

Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma.

BACKGROUND: Several studies have suggested the significance of some metalloproteases in the malignant behaviour of hepatocellular carcinoma. AIMS: To evaluate the liver expression of MMPs and their tissular inhibitors in patients with HCC. METHODS: An immunohistochemical study using tissue microarrays on samples obtained from 30 HCC patients, with antibodies against MMPs (1, 2, 7, 9, 11, 13 and 14) and TIMPs (1, 2 and 3) was performed. Results were correlated with various clinico-pathological findings and with overall survival. RESULTS: MMP-1 is mainly expressed by stromal cells, and MMP-13, TIMP-1 and TIMP-2 by inflammatory cells. A positive correlation between MMP-1 expression and larger size tumours (p<0.01) was found. Increased TIMP-2 expression was associated with higher preoperative serum levels of alpha-fetoprotein (p<0.01). Unsupervised hierarchical clustering for total score values designated two groups, one of them characterised by high MMPs and TIMPs expressions, including 21 cases (70%) for tumour cell clustering, 5 cases for fibroblasts (16.6%) and 6 cases for inflammatory cells (20%). All patients showing elevated MMPs and TIMPs expression in stromal cells presented a poor prognosis (p<0.05). CONCLUSIONS: High liver MMPs and TIMPs expressions in peritumour stromal cells are related to a poorer prognosis in HCC.

Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma.

AIM: To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis. METHODS: We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls) to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitative score based on their intensity, and the percentage of immunostained cells was measured. RESULTS: A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However, the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis. CONCLUSION: Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.