Cyclooxygenase activity and tumor progression

Invasive growth of malignant tumors is associated with local and systemic inflammation, which may promote progression and metastases. Inflammation is also responsible for appearing manifestations of advanced cancer as fatigue, anorexia and wasting with eicosanoids, proinflammatory cytokines and nitric oxide as mediators. The aim of the present work was to extend information on the significance of cyclooxygenase activity in local and systemic progression of tumor disease. Methods: Murine tumor models (MCG-101, K1735-M2), human carcinomas xenontransplanted to nude mice, tumor cell cultures and tissue samples from human colorectal adenocarcinomas were used. Inhibitors of cyclooxygenase and nitric oxide synthase, antibodies against IL-6 and recombinant IL-12 were used to evaluate effects on tumor growth, inflammation (SAP, CRP, ESR) and host wasting (anorexia, body composition). Expression of proteins was evaluated by immunohistochemistry, western blot and RT-PCR. Signal molecules were quantified by RIA, ELISA and immunoelectrophoresis. Eicosanoids and polyamines were fractionated by HPLC. Cell proliferation was estimated by mitotic counting and flow cytometry. Results: Inhibition of prostaglandin synthesis (indomethacin) reduced tumor growth, attenuated host wasting and prolonged survival in MCG-101 bearing mice with high tumor production of PGE2. By contrast, no such effects were seen in K1735-M2 bearing mice with insignificant PGE2 production. Indomethacin also reduced growth of human tumors on nude mice. There was no clear-cut correlation between overall COX-2 expression in tumors and sensitivity to indomethacin treatment, although COX-2 expression was significantly correlated to tumor PGE2 production; factors that predicted reduced survival in colon carcinoma. IL-6 deficient mice showed reduced tumor growth and wasting. Indomethacin reduced plasma PGE2 levels and wasting in all groups of cytokine knockout mice, but only IL-12 knockouts showed concomitant reduction in tumor growth. Recombinant IL-12 reduced tumor growth in wild type mice, but not so in IFN- deficient mice. Cytokine knockout tumor-bearing mice experienced anorexia to the same extent as wild types. Our results suggested subtype EP receptors to explain effects by PGE2 exposure to tumor and stroma cells. Systemic inflammation was related to tumor cell proliferation evaluated by p15, TGFb3 and Bcl-2 in tumor tissue. Indomethacin treatment increased tumor tissue expression of IL-6, TNF-, GM-CSF, TGF, cNOS decreased expression of b-FGF, angiogenin, vWF and blood vessel density, whereas EGF, VEGF, PDGF A, B, IL-1, transferrin receptors were unchanged. Cell cycle was prolonged in vivo but not in vitro by indomethacin. NSAID inhibition of tumor growth and host-wasting was not simply related to COX specificity. NOS-inhibitors reduced tumor growth in both MCG-101 and K1735-M2 tumors expressing high amounts of cNOS and iNOS. Synergism between COX- and NOS-inhibition was not observed. NOS inhibition attenuated host wasting to the same extent as indomethacin in MCG-101 bearing mice. Conclusion: Results in the present study demonstrate that cyclooxygenase activity is central in tumor progression with well-recognized host stigmata of systemic inflammation both in experimental and clinical cancer. Such effects are connected to classic tumor growth factors, cytokines and nitric oxide, where redundancy among cytokines was pronounced in development of host deteriorations (cachexia)

Surgical treatment for gallbladder cancer – a systematic literature review

<p><b>Objective:</b> To evaluate existing evidence regarding surgical treatments for gallbladder cancer in a Health Technology Assessment. A specific aim was to evaluate whether extended surgery regarding liver, lymph nodes, bile duct, and adjacent organs compared with cholecystectomy alone in the adult patient with gallbladder cancer in early and late stages implies improved survival.</p> <p><b>Methods:</b> In April 2015 and updated in June 2016, a systematic literature search was conducted in PubMed, Embase, and the Cochrane Library. Two authors independently screened titles, abstracts, and full-text articles. The certainty of evidence was evaluated according to GRADE.</p> <p><b>Main results:</b> Forty-four observational studies (non-randomised, controlled studies) and seven case series were included. Radical resection, including liver and lymph node resection, compared with cholecystectomy alone showed significantly better survival for patients with stages T1b and above. All studies had serious study limitations and the certainty of evidence was very low (GRADE ⊕○○○). A survival benefit seen in patients with stage T1b or higher with lymph node resection, was most evident in stage T2, but the certainty of evidence was low (GRADE ⊕⊕○○). It is uncertain whether routine bile duct resections improve overall survival in patients with gallbladder cancer stage T2–T4 (GRADE ⊕○○○).</p> <p><b>Conclusion:</b> Data indicate that prognosis can be improved if liver resection and lymph node resection is performed in patients with tumour stage T1b or higher. There is no evidence supporting resection of the bile duct or adjacent organs if it is not necessary in order to achieve radicality.</p

Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial) : study protocol for a randomized controlled trial

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 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). Methods/Design: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Discussion: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.Correction in: TRIALS, Volume: 16, Article Number: 334DOI: 10.1186/s13063-015-0809-8</p

Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial) : study protocol for a randomized controlled trial

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 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). Methods/Design: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Discussion: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.Errata Trials (2015), 16, 334. DOI: 10.1186/s13063-015-0809-8</p