Per Lindnér

Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer

BackgroundHepatocellular cancer (HCC), as well as cholangiocellular cancer (CCC), has an extremely poor prognosis due to the extent of tumor at diagnosis and the underlying liver disease. Sirolimus is used in the transplantation setting as an immunosuppressive agent, but it also possesses antiproliferative and antiangiogenic properties. The objective of the study was to evaluate the effect of sirolimus on HCC and CCC.MethodsIn a prospective single-arm protocol, the tumor response to sirolimus as the primary endpoint was studied in 21 patients with advanced HCC and nine with CCC. Sirolimus was administered once daily by mouth, with the dose adjusted to a serum trough level between 4 and 15 μg/ml. Tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), according to the Response Evaluation Criteria in Solid Tumors (RECIST), every third month. Secondary measures were overall survival, time to tumor progression, tumor markers, and side effects.ResultsOf the patients with HCC, one had partial remission (PR) and fi ve patients had stable disease (SD) at 3 months. Of the patients with CCC, three had SD. The median survival for patients with HCC was 6.5 months (range, 0.2–36 months) and that for patients with CCC was 7 months (range, 2.6–35 months).ConclusionTreatment of HCC and CCC with sirolimus can induce temporary PD or SD. This pilot study indicates that sirolimus might be a promising drug for this treatment, but further clinical studies elucidating the biological effects are advocated.

Histamine in immunotherapy of advanced melanoma: a pilot study

Sixteen patients with advanced metastatic malignant melanoma were treated with a high-dose infusion of interleukin-2 (IL-2; 18×106 IU/m−2 day−1) together with daily subcutaneous (s.c.) injections of interferon α (IFNα; 3×106 U/m−2 day−1) in 5-day cycles. Nine of these patients were given histamine (1 mg s.c.) twice daily during treatment with IL-2 and IFNα. In the seven patients who did not receive histamine, one partial response (that is a reduction of more than 50% in the total tumour burden) was observed in a patient with skin and lymph node melanoma. In the eight histamine-treated patients evaluable for response, four partial responses were observed. Two other patients showed regression at one site of metastasis but tumours remained unchanged at other sites. Two histamine-treated patients showed complete resolution of extensive liver metastasis. Sites of response in histamine-treated patients also included the subcutis, lymph nodes, skeleton, spleen and muscle. Lung melanoma did not respond to histamine/IL-2/IFNα. Three patients with lung tumours responded with significant (more than 50%) reduction of the volume of soft-tissue tumours, suggesting that the response to histamine may be organotropic. Survival was significantly prolonged in patients receiving histamine. Our data suggest that treatment with histamine may improve the antitumour efficacy of immunotherapy in metastatic melanoma.

Liver transplantation for metastatic neuroendocrine tumor disease.

METASTASES from neuroendocrine tumors (NET) of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPT) can be limited to the liver for long periods and may have slow growth. The symptoms are often related to hormone overproduction and debulking surgery, for example, liver resection, is recommended to achieve tumor remission or symptom palliation. If liver resection is not feasable, hepatectomy and orthotopic liver transplantation (OLT) have been proposed. For EPT where the primary tumor is located in the head of the pancrea it may be advantageous to resect the primary tumor and the liver metastases en bloc and perform a multivisceral transplantation (MVTx).

MicroRNA in exosomes isolated directly from the liver circulation in patients with metastatic uveal melanoma.

BackgroundUveal melanoma is a tumour arising from melanocytes of the eye, and 30 per cent of these patients develop liver metastases. Exosomes are small RNA containing nano-vesicles released by most cells, including malignant melanoma cells. This clinical translational study included patients undergoing isolated hepatic perfusion (IHP) for metastatic uveal melanoma, from whom exosomes were isolated directly from liver perfusates. The objective was to determine whether exosomes are present in the liver circulation, and to ascertain whether these may originate from melanoma cells.MethodsExosomes were isolated from the liver perfusate of twelve patients with liver metastases from uveal melanoma undergoing IHP. Exosomes were visualised by electron microscopy, and characterised by flow cytometry, Western blot and real-time PCR. Furthermore, the concentration of peripheral blood exosomes were measured and compared to healthy controls.ResultsThe liver perfusate contained Melan-A positive and RNA containing exosomes, with similar miRNA profiles among patients, but dissimilar miRNA compared to exosomes isolated from tumor cell cultures. Patients with metastatic uveal melanoma had a higher concentration of exosomes in their peripheral venous blood compared to healthy controls.ConclusionsMelanoma exosomes are released into the liver circulation in metastatic uveal melanoma, and is associated with higher concentrations of exosomes in the systemic circulation. The exosomes isolated directly from liver circulation contain miRNA clusters that are different from exosomes from other cellular sources.

Isolated hepatic perfusion for liver metastases of malignant melanoma.

The objective was to analyze the outcome of three treatment strategies using isolated hyperthermic liver perfusion (IHP) with melphalan for liver metastases of malignant melanoma. It was designed as an exploratory study. The setting was a single-center study in a university hospital. The study was carried out on 27 patients. IHP was used with modifications during three different time periods (IHP I, IHP II and IHP III), in technique and temperature (amount of melphalan: 0.5, 1.0 and 2 mg/kg body weight in the perfusate; 41, 40 and 40°C). Tumor response was estimated according to WHO criteria with computed tomography or MRI. Mortality and morbidity were secondary measures. Six of 11 patients in the IHP I cohort experienced a partial response (PR). In the IHP II cohort, two patients of 11 experienced a complete response and five a PR. In the IHP III cohort, five of five patients experienced a PR. Six postoperative deaths were reported (27%) (three in the IHP I and three in the IHP II series), secondary to liver insufficiency and multiorgan failure. Treatment of liver metastases of malignant melanoma with isolated hyperthermic melphalan perfusion has shown an impressive tumor response rate, which seems to be higher than the response rates reported for other systemic chemotherapy regimens. The maximum tolerated dose for melphalan in the perfusate was surpassed with a 2 mg/kg body weight. By modifying the technique and restricting the allowed tumor burden, the response rate remained high and the mortality was reduced.

p53 Mutations in primary tumors and subsequent liver metastases are related to survival in patients with colorectal carcinoma who undergo liver resection

The appearance of p53 mutations in colorectal carcinoma was determined, independent of differentiation and tumor stage of the primary tumors, in relation to the survival of patients who were scheduled to undergo liver resection.

Impressive regression of primary liver cancer after treatment with sirolimus

Hepatocellular cancer (HCC) has an extremely poor prognosis due to the extent of the tumour and underlying liver disease. Except for liver transplantation and liver resection there is no proven therapy [1]. Although regarded as a chemoinsensitive tumour, chemoembolisation for selected patients offers a limited survival benefit [2]. For most patients only best supportive care is available. Sirolimus is established as an immunosuppressive agent used in kidney and liver-transplantation. It inhibits mTOR, downstream the Akt pathway, regulating cell-regulatory and nutrient proteins [3]. The activation of Akt seems to be important in HCC and correlates with prognosis [4]. Based on in vitro studies and animal experiments, showing restricted growth of a hepatoma when sirolimus was given, [5] a pilot study was undertaken. The study was approved by the Ehtics Commite of the Faculty of Medicine, University of Gothenburg. The first case included was a 58 year old Caucasian musician. He was admitted for consideration for liver resection or liver transplantation of a large central liver tumor. He had a positive Hepatitis C serology and was a heavy alcohol abuser. BMI was 43kg/m but he had a 10 kg weight loss during the last month. He ran a continuous fever above 38 centigrade. His alpha-fetoprotein at diagnosis was 25 300 mg/l. No histology confirmation of diagnosis was done as CT documented tumours in a cirrhotic liver and this level of alpha-fetoprotein is considered as proof for HCC. His liver function was classified as Child-Pugh A. MRI revealed a central liver tumor, diameter 11 cm and a portal vein thrombosis. He was rejected for surgery and was included in the Sirolimus study. His CT after 3 months was unchanged but an MRI after 6 months showed a remarkable tumor regression, the tumor diameter was reduced to 5 cm. This partial remission was confirmed after 9 months. Alpha-fetoprotein declined to the lowest value 10 900 mg/l after five months (and liver laboratory tests were normalized). After 3 months he returned to his job as a professional dance band musician but he did not discontinue his drinking habits. After nine months there was clinical evidence of tumor progression. The patient succumbed 20 months after the initiation of sirolimus treatment. This case suggests that sirolimus therapy could have a tumor effect in patients with advanced primary hepatocellular cancer. As a remarkable tumor regression was registered in this patient we were obliged at this premature time to inform about it.

Survival after liver transplantation for cholangiocarcinoma has increased during the last decade.

INTRAHEPATIC (IH) or peripheral cholangiocarcinoma (CCC), which arises from the IH bile ducts, is the second most common primary liver cancer after hepatocellular carcinoma. Extrahepatic (EH) CCC arises from the biliary tree outside the liver parenchyma; when it is centrally located in the proximal bile duct it is also known as Klatskin tumor. CCC is often unresectable due to its central location or involvment of portal structure. For these patients liver transplantation (LT) provides an opportunity for radical resection. CCC is, however, a rare indication for LT. The limited number of organs available makes LT for CCC controversial; many centers have reported a dismal prognosis; only few cases of long-term survival after liver transplantation have been reported. The purpose of this retrospective analysis was to study the results of LT for CCC and to determine prognostic variables that could improve the selection of recipients for this procedure.

Auxiliary liver and combined kidney transplantation prevents hyperacute kidney rejection in highly sensitized patients

THE PRESENCE of antibodies against donor HLA antigens often causes hyperacute rejection in a normal kidney transplant. Removal of antibodies before kidney transplantation can improve graft survival, although the efficacy of the treatment remains variable. Patients with multispecific HLA antibodies and renal failure therefore often remain on hemodialysis for many years, because the chance of finding a kidney for a patient with HLA antibodies against 90% of the population is small, despite all donors being tested to find “perfect” matches. In liver grafts, hyperacute rejection is seldom seen even in the presence of donor-reactive antibodies in the recipient serum (positive crossmatch). Cases have also been published with combined liver and kidney transplantation, where the renal graft was placed despite a positive crossmatch with obvious success. These observations encouraged us to test the hypothesis that a segmental liver graft, transplanted as an auxiliary graft, could absorb preformed antibodies against donor HLA antigens, thus making subsequent kidney transplantation from the same donor possible without hyperacute rejection of the kidney.

Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma

Abstract Purpose: The aim of the present study is to describe our experience with isolated limb perfusion (ILP) in the treatment of in-transit metastases of malignant melanoma and to determine prognostic factors for response, local progression, survival and toxicity. Materials and methods: A retrospective follow-up of all patients (n = 163) treated between January 1984 and December 2008 using data collected from individual patient records and the Swedish National Patient Register. Results: Clinical response was evaluable in 155 patients, 65% had a complete response (CR) and 20% had a partial response (PR). Local progression occurred in 63% of the patients after a median time of 16 months. Negative prognostic factors in univariate analyses were proximal location of the primary tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, proximal location of the primary tumour and no CR after ILP were significant prognostic factors. Median cancer-specific survival was 30 months, and negative prognostic factors in univariate analyses were male gender, positive lymph node status, systemic metastases, bulky tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, positive lymph node status, bulky tumour and no CR after ILP were significant prognostic factors. A majority (97%) of the patients had a Wieberdink grade II–III local toxicity. Four patients underwent limb amputation after a median of 19 months, none because of toxicity. Conclusion: We found that ILP is a safe method with a high response rate for the treatment of patients with in-transit metastases of malignant melanoma.