A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial).

BACKGROUND: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO). PATIENTS AND METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year. RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9). CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

Isolated hepatic perfusion for ocular melanoma metastasis: registry data suggests a survival benefit.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 35% of the patients, with the liver being the most common site for metastases. These metastases are generally refractory to systemic chemotherapy, and the median survival for patients with liver metastases is about 6 months. This phase II trial reports the experience of isolated hepatic perfusion (IHP) as a treatment option. METHOD: A total of 34 patients with isolated liver metastasis from ocular melanoma underwent IHP. An overall survival comparison was made using data retrieved from the National Patient Register managed by the Swedish National Board of Health and Welfare. RESULTS: An overall radiological response was seen in 68% of the patients, with 12% having a complete response. Time to local progression was 7 months; 68% of the patients developed extrahepatic metastases after a median of 13 months, and the median overall survival was 24 months. There was a significant survival advantage of 14 months (p = 0.029) when comparing these patients with a control group consisting of the longest surviving patients in Sweden with uveal melanoma liver metastases not treated with IHP. CONCLUSIONS: IHP is a treatment option with a high response rate and a potential survival benefit of more than 1 year. IHP should be considered an option in the treatment of uveal melanoma metastases. A randomized trial comparing IHP and best alternative care will start during 2013 (the SCANDIUM trial, ClinicalTrials.gov identifier NCT01785316).

Excellent liver transplantation survival and prevention of hepatitis B recurrence using hepatitis B immunoglobulin and nucleoside or nucleotide analogue along with treating physician adherence to treatment protocol.

INTRODUCTION: The introduction of hepatitis B immunoglobulin (HBIG) in the early 1990s dramatically reduced recurrence of hepatitis B after orthotopic liver transplantation (OLT) and thus improved survival. Today a combination of HBIG and a nucleoside or nucleotide analogue (NUC) is recommended as prophylaxis. The optimal protocol is yet to be commonly agreed upon. The aim of this study was to review our results over 25 years. PATIENTS AND METHODS: All 56 patients (45 males and 11 females) who underwent OLT due to hepatitis B infection between 1985-2009 were included in the review. Median age at transplantation was 51 years (range, 18-66). Seventeen patients (30%) had hepatocellular carcinoma (HCC) at transplantation. RESULTS: The 1- and 5-year overall survival rates were 89% and 77%, respectively. The 23 patients who underwent transplantation before 2000 showed 1- and 5-year survival rates of 82% and 61%, respectively; the 33 who underwent transplantation between 2000 and 2009, the rates were 94% and 90%, respectively (P < .01). There was no difference in the 5-year survival rate between patients who had or did not have been HCC (75% vs 78%, respectively). Recurrence of hepatitis B, defined as seroconversion to HBsAg positivity, was observed in 9 patients. Three transplantation cases before 1992 consequently did not receive HBIG. The remaining 6, who all underwent OLT between 1993 and 2001, were administered HBIG. In all 6 cases periods of low anti-HBs titers were registered prior to recurrence; treating physician noncompliance with the protocol may have contributed to the low anti-HBs titers. No recurrence was registered after 2001. CONCLUSION: With a combination of HBIG and NUC, excellent OLT results can be achieved for hepatitis B. It is, however, still important to maintain sufficient anti-HBs titers to prevent recurrence.

Extended right-sided liver resection for colorectal liver metastases--impact of percutaneous portal venous embolisation.

AIM: To compare the outcome after extended right liver lobe resection (ERL) for patients with liver metastases from colorectal cancer with preceding portal vein embolisation (PVE) with a non-PVE-group. METHODS: Nineteen patients underwent ERL (resection of segment 4-8) for colorectal liver metastases after PVE. They were compared with 21 patients that underwent an ERL without embolisation. A comparison was made with 84 patients undergoing right lobe liver resection during the same time period. Survival, post-operative morbidity and mortality were recorded and the volume of the future remnant liver (FRL) was measured with CT. RESULTS: There were major complications in 1/19 patients in the PVE-group and in 6/21 in the non-PVE-group (p=0.04). No post-operative deaths were observed in the PVE-group, compared to three deaths in the non-PVE-group (p=0.09). The median survival in the PVE-group was 32 months, which did not differ from the non-PVE-group. In 21% of the patients that underwent PVE, progression occurred during the time between embolisation and surgery. There was no difference in survival for patients that underwent PVE followed by ERL, compared to patients that underwent standard right lobe liver resection. CONCLUSION: The survival of patients after ERL is comparable with patients that undergo standard right lobe resection and have less liver tumour.

Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia.

MCG 101 tumors were implanted sc. on wild-type C57 Bl and gene knockout mice to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-12, IFNgamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] to explain local tumor growth, anorexia, and carcass weight loss in a well-defined model with experimental cachexia. Indomethacin was provided in the drinking water to explore interactions between host and tumor-derived prostaglandins and proinflammatory cytokines for tumor growth. Wild-type tumor-bearing mice developed cachexia because of rapid tumor growth, which were both attenuated in IL-6 gene knockouts. Similar findings were observed after provision of anti-IL-6 to wild-type tumor-bearing mice. Alterations in food intake were not directly related to systemic IL-6 but rather secondarily to IL-6-dependent tumor growth. The absence of host-derived IL-12, IFN-gamma, or the TNF receptor 1 or receptor 2 gene did not attenuate tumor growth or improve subsequent cachexia. Thus, carcass weight loss was not improved by the omission of host cytokine (TNF-alpha, IL-12, or IFN-gamma) except for IL-6. Systemic indomethacin provision decreased plasma prostaglandin E2 in five of six groups of gene knockout tumor-bearing mice, which was associated with improved carcass weight in these groups. Indomethacin seemed to improve food intake to a similar extent in both wild-type and gene knockouts, which agree with the speculation that eicosanoids are more important to explain anorexia than host cytokines. Our results demonstrate that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a more complex fashion than usually presented based on previous information in studies on either anti-cytokine experiments in vivo or on gene knockouts with respect to a "single cytokine model." Overall, host cytokines were quantitatively less important than tumor-derived cytokines to explain net tumor growth, which indirectly explains subsequent cachexia and anorexia.

Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids.

The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.

A novel tablet-based 13C urea breath test for Helicobacter pylori with enhanced performance during acid suppression therapy.

BACKGROUND: The urea breath test (UBT) can still be improved in terms of user-friendliness and accuracy during acid-suppression therapy. This study was designed to evaluate a novel, rapidly disintegrating 13C UBT tablet, which was supplemented with citric acid to facilitate diagnosis of Helicobacter pylori in the hypochlorhydric stomach. METHODS: The efficacy of a fasting 13C tablet-based UBT (TUBT) was compared with that of a standard 13C UBT (SUBT) during 40 min after dosing, and optimal sampling points were determined. The single-point TUBT was validated against a 'gold standard' (GS) including a TUBT, culture, histology, and a CLO test in 134 dyspeptic patients, and its optimal cut-off point was determined by means of a biometric method. In addition, 20 SUBT-positive patients were randomized to perform either the TUBT or the SUBT after 7 days of omeprazole therapy (20 mg twice daily). RESULTS: Compared with a SUBT, the TUBT gave a quicker and wider separation between positive and negative results and an earlier optimal sampling point (10 versus 40 min). At 10 min the TUBT correctly classified 40 of 42 GS-positive subjects (sensitivity, 95%) and all of 92 GS-negative patients (specificity, 100%), and the optimal cut-off point was 1.8 delta per mil. Furthermore, when optimal sampling points were used, the TUBT (t = 10 min) proved to be more accurate than the SUBT (t = 40 min) during omeprazole treatment, correctly identifying all of 10 and 3 of 9 H. pylori-infected patients, respectively. CONCLUSIONS: By supplying 13C urea and citric acid as a rapid-release tablet, it is possible to shorten the duration of the 13C UBT to 10 min, omit the test meal, and still maintain excellent accuracy, even during acid suppression therapy.

Effects related to indomethacin prolonged survival and decreased tumor-growth in a mouse-tumor model with cytokine dependent cancer cachexia.

Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor-bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells.

The superior laryngeal nerve in thyroid surgery.

Injury to the external branch of the superior laryngeal nerve (ESLN) during thyroid surgery can have serious consequences. A strategy for perioperative identification and preservation of the ESLN was clinically evaluated after postmortem anatomic observations. These showed that 20% of ESLNs run distally through the pharyngeal constrictor muscle, which necessitates intramuscular dissection for identification in the area around the superior thyroid pole. In 23% of the ESLNs identifiable without intramuscular dissection (18% of the total), a course partly lateral to the superior thyroid artery and its branches implied definite risk of injury during division of the superior pole vessels. In the clinical series, 72% of the ESLNs were identifiable without intramuscular dissection, and 19% of these (14% of the total) were partly lateral to the superior thyroid artery. Only one patient had signs of ESLN injury postoperatively, probably caused by diathermy to an adjacent vessel. Perioperative identification of ESLN with dissection into the pharyngeal constrictor muscle (about 20% of cases) appears to be inadvisable, but identification of ESLN with other courses is important, as around 20% are highly vulnerable during division of the superior thyroid artery and its branches.