An Attribution of Value Framework for Combination Treatments

Statins directly inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, while γ-tocotrienol, an isoform of vitamin E, enhances the degradation and reduces the cellular levels of HMGR in various tumor cell lines. Since treatment with statins or γ-tocotrienol alone induced a dose-responsive inhibition, whereas combined treatment with subeffective doses of these agents resulted in a synergistic inhibition in +SA mammary tumor cell growth, studies were conducted to investigate the role of the HMGR pathway in mediating the antiproliferative effects of combined low-dose statin and γ-tocotrienol treatment in +SA cells. Cells were maintained in serum-free defined media containing EGF (10 ng/mL) and insulin (10 µg/mL) as co-mitogens. Treatment with 8 μM simvastatin alone inhibited +SA cell growth and isoprenylation of Rap1A and Rab6, and supplementation with 2 µM mevalonate reversed these effects, indicating that simvastatin inhibits +SA cell growth by suppressing mevalonate synthesis. Also, treatment with 4 μM γ-tocotrienol alone inhibited +SA cell growth but had no effect on the isoprenylation of Rap1A and Rab6, and supplementation with 2 µM mevalonate had no effect on cell growth or isoprenylation, suggesting that γ-tocotrienol inhibits +SA cell growth through mechanisms independent of mevalonate suppression. The confocal immunofluorescence imaging revealed that treatment with subeffective doses of simvastatin (0.25 μM), lovastatin (0.25 μM), mevastatin (0.25 μM), pravastatin (10 μM), or γ-tocotrienol (2 μM) alone had no effect on the positive Ki-67 staining, while combined low-dose statin and γ-tocotrienol treatments markedly suppressed the positive Ki-67 staining in +SA cells as compared with control. Treatment with same subeffective doses of these statins or γ-tocotrienol alone had no effect on protein prenylation or mitogenic signaling, whereas combined treatment with these agents resulted in a significant inhibition in +SA cell growth, and a corresponding decrease in the relative levels of total HMGR, Rap1A and Rab6 prenylation, phosphorylated (active) MAPK, and cyclin D1, as compared with respective controls. However, these inhibitory effects on +SA cell growth, prenylation and mitogenic signaling were completely reversed by mevalonate supplementation. These findings demonstrate that the synergistic antiproliferative effects of combined low-dose statin and γ-tocotrienol treatment are directly related to an inhibition in HMGR activity and subsequent suppression in mevalonate synthesis. Since HMGR activity is characteristically elevated in cancer, these results strongly suggest that combination therapy with statins and γ-tocotrienol may be effective in suppressing the growth of breast cancer in women. Supported by grants from NIH (CA 86833) and First Tech International Ltd. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5417.

Most hypolipidemic drugs can not normalize plasma cholesterol and LDL levels in type II hyperlipoproteinemia (HLP) when used alone. Furthermore, combinations of many hypolipidemic agents can have additive effects.In this study, we investigated the effects of niceritrol-probucol combination therapy on serum lipid and apoprotein concentrations in type II HLP.Thirty one type II HLP (28; IIa, 3; IIb) patients were treated with probucol (500mg/day) for more than 12 weeks, then niceritrol (500-1, 500mg/day) was added to the treatment regimen. In six patients, medication of niceritrol was ferminated after combined treatment.Total cholesterol (TC) was reduced from 307mg/dl to 273mg/dl (10% of reduction) by probucol alone and further reduced to 235mg/dl (14% of further reduction) by combination therapy with niceritrol. Total reduction rate of TC was 23% by combination therapy. Additionally, LDL-c was reduced 9% by probucol alone and a further 14% by combination treatment. Total reduction rate of LDL-c was 23% by combination therapy. HDL-c was reduced 23% by probucol alone, but no further reduction was observed in the combination period. Hence, the atherogenic Index (AI) was reduced 16% by combination therapy. Serum TG did not show significant change by probucol alone, but was reduced 9% by combination therapy. Serum concentration of apoB was reduced 11% by combination therapy.These data indicated that combined niceritrolprobucol therapy for type II HLP is very useful.

It has been shown that Caspy2, a zebrafish active caspase, can efficiently suppress the growth of malignant tumor. The present study was designed to test whether combined gene therapy with IP-10, a potent antitumor chemokine, and Caspy2 would improve therapy efficacy. Recombinant plasmid expressing both Caspy2 and IP-10 genes was mixed with DOTAP-cholesterol nanoparticles. Immunocompetent mice bearing CT26 colon carcinoma, B16-F10 melanoma, and 4T1 breast carcinoma were treated with the complex. We found that the combined gene therapy more efficiently inhibited tumor growth, while efficiently prolonging the survival of tumor-bearing animals, compared with monotherapy. Moreover, a significant reduction in spontaneous lung metastasis could be observed in the 4T1 breast carcinoma model. Infiltration of CD8(+) T lymphocytes was also observed. In addition, apoptotic cells were widely detected by TUNEL assay and caspase-3 immunostaining in coadministered tumor tissues. The combination treatment also successfully inhibited angiogenesis and tumor cell proliferation as assessed by CD31 and Ki-67 immunostaining, respectively. Furthermore, depletion of CD8(+) T lymphocytes could significantly abrogate the antitumor activity, whereas the depletion of CD4(+) cells or natural killer cells showed partial abrogation. Rechallenged CT26 tumors were rejected in all of the surviving mice treated by combination therapy. Our results suggest that combined therapy with Caspy2 and IP-10 can significantly enhance antitumor activity by acting as an immune response initiator, apoptosis inducer, and angiogenesis inhibitor, which may be important for further applications in clinical cancer therapy.

Comparison of extended-release niacin and atorvastatin monotherapies and combination treatment of the atherogenic lipid profile in diabetes mellitus

BackgroundIt is important to simultaneously induce strong cell death and antitumor immunity in cancer patients for successful cancer treatment. Here, we investigated the cytotoxic and phenotypic modulation effects of the combination of ANT2 shRNA and human sodium iodide symporter (hNIS) radioiodine gene therapy in vitro and in vivo and visualized the antitumor effects in an immunocompromised mouse colon cancer model.MethodsA mouse colon cancer cell line co-expressing hNIS and the luciferase gene (CT26/hNIS-Fluc, named CT26/NF) was established. CT26/NF cells and tumor-bearing mice were treated with HBSS, scramble, ANT2 shRNA, I-131, and ANT2 shRNA + I-131. The apoptotic rates (%) and MHC class I and Fas gene expression levels were determined in treated CT26/NF cells using flow cytometry. Concurrently, the level of caspase-3 activation was determined in treated cells in vitro. For in vivo therapy, tumor-bearing mice were treated with scramble, ANT2 shRNA, I-131, and the combination therapy, and the anti-tumor effects were monitored using bioluminescence. The killing activity of cytotoxic T cells (CTLs) was measured with a lactate dehydrogenase (LDH) assay.ResultsFor the in vitro experiments, the combination of ANT2 shRNA and I-131 resulted in a higher apoptotic cell death rate compared with ANT2 shRNA or I-131 alone, and the levels of MHC class I and Fas-expressing cancer cells were highest in the cells receiving combination treatment, while single treatment modestly increased the level of MHC class I and Fas gene expression. The combination of ANT2 shRNA and I-131 resulted in a higher caspase-3 activation than single treatments. Interestingly, in vivo combination treatment led to increased gene expression of MHC class I and Fas than the respective mono-therapies; furthermore, bioluminescence showed increased antitumor effects after combination treatment than monotherapies. The LDH assay revealed that the CTL killing activity against CT26/NF cells was most effective after combination therapy.ConclusionsIncreased cell death and phenotypic modulation of cancer cells in vitro and in vivo were achieved simultaneously after combination therapy with ANT2 shRNA and I-131, and this combination therapy induced remarkable antitumor outcomes through improvements in CTL immunity against CT26/NF. Our results suggest that combination therapy can be used as a new therapeutic strategy for cancer patients who show resistance to single therapy such as radiation or immunotherapy.

To investigate the appropriate time for combination therapy in HBeAg positive chronic hepatitis B (CHB) patients with decompensated cirrhosis. Thirty HBeAg positive CHB patients with decompensated cirrhosis were enrolled in the study. All of the patients were given 48 wk combination therapy with lamivudine (LAM) and adefovir dipivoxil (ADV). Briefly, 10 patients were given the de novo combination therapy with LAM and ADV, whereas the other 20 patients received ADV in addition to LAM after hepatitis B virus (HBV) genetic mutation. Serum alanine aminotransferase and total bilirubin were both improved in the two groups at 4, 12, 24 and 48 wk after treatment. Serum albumin was also improved at 24 and 48 wk after combination therapy in both groups. The serum HBV DNA level was still detectable in every patient in the two groups at 4 and 12 wk after combination treatment. However, in the de novo combination group, serum HBV DNA levels in 4 (40%) and 9 (90%) patients was decreased to below 1×10(3) copies/mL at 24 and 48 wk after the combination treatment, respectively. In parallel, serum HBV DNA levels in 2 (20%) and 8 (40%) patients in the add-on combination group became undetectable at 24 and 48 wk after combination treatment, respectively. Furthermore, 6 (60%) patients in the de novo combination group achieved HBeAg seroconversion after 48 wk treatment, whereas only 4 (20%) patients in the add-on combination group achieved seroconversion. Child-Pugh score of patients in the de novo combination group was better than that of patients in the add-on combination group after 48 wk treatment. Moreover, patients in the de novo combination group had a significantly decreased serum creatinine level and elevated red blood cell counts. De novo combination therapy with LAM and ADV was better than add-on combination therapy in terms of Child-Pugh score, virus inhibition and renal function.

Background: In most studies comparing 5-fluorouracil (5-FU) monotherapy versus the combination of folinic acid and 5-FU in the treatment of advanced colorectal cancer, a low dose of 5-FU was given in monotherapy, possibly leading to impaired results in these groups. In a further study we therefore compared the combination treatment with an intensive 5-FU monotherapy regimen with a loading course followed by weekly injections. Patients and Methods: Patients were randomized to receive either 5-FU 370 mg/m2 i.v. days 1-5, followed by weekly administrations of 5-FU 600 mg/m2 or the same doses of 5-FU preceded by folinic acid 200 mg/m2. Because of toxicity, the weekly 5-FU dose in the combination treatment group was reduced to 500 mg/m2 in the second part of the study. Results: Overall, 144 patients were treated. 42 patients received combination therapy and 41 monotherapy before treatment dose modification (part 1). After dose reduction, 31 patients had combination therapy and 30 monotherapy (part 2). Treatment resulted in a complete or partial remission in 11 patients (26%) on combination therapy with the higher and 14 (45%) with the lower weekly dose of 5-FU as compared to 24 and 27%, respectively, treated with monotherapy. In the first part, neither time to progression nor overall survival was statistically different between the treatment groups. After treatment modification, time to progression was significantly longer with combination therapy compared to monotherapy. In both parts, there was no significant difference in survival time between the groups as a whole. However, patients with extensive metastatic disease had a survival benefit when treated with the modified combination therapy as compared to monotherapy. The main toxicity was diarrhea during weekly therapy. This was especially true for patients receiving combination treatment before the reduction of the 5-FU dosage. By reducing 5-FU dosage during weekly therapy, severe diarrhea could be clearly reduced. Conclusions: In patients with advanced colorectal cancer, combination treatment with folinic acid and the reduced form of 5-FU 500 mg/m2 weekly is well tolerated and significantly prolongs relapse-free and, in subgroups, even overall survival as compared to an intensive 5-FU monotherapy regimen.

The purpose of this study was to systematically review the process for topic selection by health technology assessment (HTA) agencies around the world to provide the knowledge base for the improvement of topic selection frameworks in HTA agencies. A systematic search was conducted in PubMed and EMBASE to identify papers up to February 2019. Gray literature was identified by screening the Web sites of HTA agencies on the nonprofit member list of the International Network of Agencies for Health Technology Assessment (INAHTA). Data were extracted for each HTA agency and synthesized, with issues including general contextual information about each agency and the process of topic selection. Out of forty-nine nonprofit members of INAHTA, a total of seventeen HTA agencies with a framework for topic selection were identified from twenty-two included papers/documents. Multiple criteria were used for topic selection in all frameworks and agencies undertook multiple steps, which could include the specification of criteria for topic selection, identification of topics, short listing of potential topics, scoping of potential topics, scoring and ranking of potential topics, and deliberation and decision on final topics for HTA. Shortcomings were found in relation to methods of scoring and ranking as well as lack of monitoring and the evaluation of the process. Our study provides insights into the current practice of topic selection in HTA agencies. Multiple criteria decision analysis methodology appears highly relevant to these processes. A consensus approach for the development of methods of topic selection would be valuable for the HTA community.

Background and Purpose- We performed a systematic review and meta-analysis to explore the efficacy and safety of cilostazol as a mono or combination (plus aspirin or clopidogrel) treatments compared to conventional single antiplatelet therapy (SAPT, mainly aspirin) for secondary stroke prevention. Methods- Randomized controlled trial studies were searched across multiple comprehensive databases (MEDLINE, EMBASE, and Cochrane) for review. The primary outcome was recurrent stroke comprising ischemic and hemorrhagic stroke. Secondary outcomes included ischemic stroke, hemorrhagic stroke, myocardial infarction, and composite outcomes. We performed an updated systematic review and meta-analysis of the identified reports, including 2 recently published randomized controlled trials. In addition, network meta-analysis was performed to compare the relative effects of mono versus combination cilostazol treatments. Results- Ten studies were included in this review, 5 of which were assigned to the cilostazol mono group (n=5429) and the other 5 to the combination group (n=2456). The relative risks of recurrent stroke, ischemic stroke, and composite outcomes with cilostazol mono as well as combination treatments were significantly lower than with SAPT without any significant heterogeneity. An indirect comparison of these 3 outcomes revealed the cilostazol combination approach to be superior. The cilostazol mono treatment diminished hemorrhagic stroke more significantly than SAPT and the cilostazol combination did not increase hemorrhagic stroke compared to SAPT. The outcomes from the 2 cilostazol regimens were comparable to SAPT in the case of myocardial infarction. Conclusions- Cilostazol is a more effective and safer treatment option than SAPT approaches using mainly aspirin. Cilostazol regimens can also be modified to clinical situations as this drug reduces recurrent and ischemic stroke more efficiently as a combination therapy but is more beneficial for hemorrhagic stroke as a monotherapy.

VSV Oncolysis in Combination With the BCL-2 Inhibitor Obatoclax Overcomes Apoptosis Resistance in Chronic Lymphocytic Leukemia

PurposeCombined oral anticoagulant (OAC) and antiplatelet (AP) therapy is generally discouraged in atrial fibrillation (AF) outside of acute coronary syndromes or stenting because of increased bleeding. We evaluated its frequency...

IntroductionOver the past decade there have been increasing interactions between health technology assessment (HTA) agencies through international networks at the policy level and European joint actions at the product level. A pilot project is underway to explore collaboration beyond Europe between HTA agencies in Australia, Canada, and the UK. This study the compared HTA recommendations of new active substances (NAS) appraised by Australia’s Pharmaceutical Benefits Advisory Committee (PBAC), Canada’s CADTH, and England’s National Institute for Health and Care Excellence (NICE).MethodsUsing publicly available data and established benchmarking methodology, we examined 45 NAS appraised by PBAC, CADTH, and NICE between 2017 and 2021. Analysis was performed to assess rollout time from regulatory to HTA recommendation, and to the first HTA recommendation.ResultsMost products were submitted to the Europe Medicine Agency first (89%). However, 71 percent of NAS in Australia and 69 percent in Canada were submitted to HTA in parallel with regulatory review, which shortened overall rollout time. The median HTA submission gap among the three agencies was 140 days in Australia, 102 days in Canada, and 8 days in England. PBAC had the highest number of negative recommendations (51%), followed by CADTH (18%), and NICE (5%). The congruence of HTA decisions was highest between CADTH and NICE (56%), compared with PBAC and CADTH (11%), and PBAC and NICE (20%)ConclusionsTo achieve a more collaborative HTA process it is necessary to understand the rollout time in these jurisdictions. This study identified submission gaps among the regulatory agencies, but there may be more synergy in the future as regulators in the three jurisdictions work collaboratively through the Access Consortium. Currently, the submission gap for the three HTA agencies was mostly within six months, making collaboration on joint assessment possible. We observed divergences in HTA recommendations due to the methodology and decision criteria applied by each agency. Therefore, collaboration on assessment should build on the clinical aspects, although HTA decisions should be grounded in the local context.

Predictors of change in low-density lipoprotein size during lipid-lowering treatment in type 2 diabetes

The aim of this study was to analyze the information needs of Spanish health technology assessment (HTA) agencies and units to facilitate access to the resources they require to substantiate their reports. A questionnaire was designed and distributed among HTA bodies to ascertain the actual situation of subscriptions to information resources and what information specialists from these bodies considered would be the ideal subscription situation. Their information needs were then studied, and the resources that best met these needs were put forward. Following this definition, a subscriptions policy was adopted with suppliers and publishers. The survey showed that HTA bodies share a minimum of core subscriptions that includes open sources (MEDLINE, DARE) and sources that the government subscribes to for the health community (ISI Web of Science, Cochrane Library Plus). There was no common approach to determining which databases to subscribe to (UpToDate, EMBASE, Ovid EBMR, CINAHL, or ECRI). After identifying the information needs, a list of resources was proposed that would best cover these needs and, of these, subscription to the following was proposed: Scopus, Ovid EBMR, Clinical Evidence, DynaMed, ECRI, and Hayes. There are differences in the way that HTA agencies and units access the different resources of biomedical information. Combined subscription to several resources for documentation services was suggested as a way of resolving these differences.

Interferon-alpha (IFN-alpha) induces sustained remission of chronic hepatitis C in approximately 25% of patients. In patients who are non-responders to the first course of therapy, retreatment with IFN-alpha is of limited efficacy. Ribavirin has also been used to treat chronic hepatitis C, but it induces only a transient response. In this study, we evaluated the efficacy of ribavirin and IFN-alpha combination therapy for IFN-alpha resistant chronic hepatitis C. Twenty-four IFN-alpha non-responders and 24 relapsers were randomized to receive either ribavirin (1000 mg per day) together with IFN-alpha (3-6 million units (MU) thrice weekly) or the same dose of IFN-alpha alone, for 6 months. Both at the end of treatment and 6 months later, normal transaminase levels were more common in the patients receiving combination therapy than in the group receiving IFN-alpha alone: 17 (70.8%) vs seven (29.2%) patients (P = 0.009) and six (25%) vs one (4.2%) patient (P = 0.034), respectively. At the end of treatment and 6 months later, serum HCV RNA was no longer detectable in eight (33.3%) and five (20.8%) patients in the combination therapy group and in six (25%) and one (4.2%) patient in the IFN-alpha therapy group, respectively. Three patients (12.5%) were withdrawn prematurely from combination therapy because of side-effects; ribavirin therapy was ceased or dosage reduced in six other patients (25%), again because of side-effects. In conclusion, this combination treatment was more effective than retreatment with IFN-alpha, alone, in inducing sustained biochemical remission of chronic hepatitis C that was resistant to a previous course of IFN-alpha. The combination treatment, however, was frequently associated with significant side-effects.