Showing posts with label Sorafenib. Show all posts
Showing posts with label Sorafenib. Show all posts

Friday, January 19, 2018

First-Time Data for Merck’s KEYTRUDA® (pembrolizumab) in Patients with Previously Treated Advanced Hepatocellular Carcinoma (HCC) to be Presented at 2018 ASCO GI Symposium

First-Time Data for Merck’s KEYTRUDA® (pembrolizumab) in Patients with Previously Treated Advanced Hepatocellular Carcinoma (HCC) to be Presented at 2018 ASCO GI Symposium

KENILWORTH, N.J.--(BUSINESS WIRE)--Jan. 19, 2018-- Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced findings from the registrational phase 2 KEYNOTE-224 trial investigating the use of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced hepatocellular carcinoma (HCC), the most common type of liver cancer, who were previously treated with systemic therapy (sorafenib). Results showed an overall response rate (ORR) of 16.3 percent (95% CI, 9.8-24.9) (n=17/104) with KEYTRUDA as monotherapy. Data also include six-month overall survival (OS) and progression-free survival (PFS) rates. The findings will be presented at the 2018 American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium in San Francisco in an oral presentation on Friday, Jan. 19, from 1:10-1:15 p.m. PT (Location: Level 3 – Room 3014) (Abstract #209).

“There continues to be a significant need for new options in the treatment of advanced hepatocellular carcinoma,” said Andrew Zhu, M.D., Ph.D., lead investigator and director of liver cancer research at Massachusetts General Hospital Cancer Center. “The durable responses observed with KEYTRUDA monotherapy in this difficult-to-treat cancer are encouraging.”

“Merck is committed to understanding the clinical benefit of KEYTRUDA monotherapy across a range of gastrointestinal cancers, including advanced liver cancer,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “The findings from this study demonstrate the potential of KEYTRUDA in patients with advanced HCC following prior systemic therapy and support the advancement of our clinical development program in this cancer type.”

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 650 trials studying KEYTRUDA (pembrolizumab) across a wide variety of cancers and treatment settings, including multiple gastrointestinal disorders such as HCC and gastroesophageal cancer.

The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Data in Previously Treated Advanced HCC, KEYNOTE-224 (Abstract #209)

KEYNOTE-224 is a registrational, open-label phase 2 trial investigating KEYTRUDA monotherapy in patients with advanced HCC who had previously received systemic therapy with sorafenib. The primary endpoint is ORR; secondary endpoints include duration of response, disease control rate, time to progression, PFS and OS.

Findings presented at ASCO GI were based on data from 104 evaluable patients, previously treated with sorafenib, who received one or more doses of KEYTRUDA (200 mg intravenous infusion on day 1 of each 3-week cycle for up to 35 administrations). Data showed an ORR of 16.3 percent (95% CI, 9.8-24.9) (n=17/104) with a complete response rate of one percent (95% CI, 0.0-5.2) and a partial response rate of 15.4 percent (95% CI, 9.1-23.8). ORR was similar across subgroups with different etiology, including Hepatitis B and Hepatitis C positive patients. At the time of analysis, the median duration of response was 8.2 months (range: 2.3+ to 8.3+) with 94 percent of responses ongoing for six months or longer (calculated per Kaplan-Meier method). The disease control rate was 61.5 percent (95% CI, 51.5-70.9) (n=64/104). The median PFS was 4.8 months (95% CI, 3.4-6.6) with a six-month PFS rate of 43.1 percent. The median OS had not been reached at the time of analysis (95% CI, 9.4-not reached) with a six-month OS rate of 77.9 percent.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. The treatment-related adverse events (any grade occurring in 10% or more of patients) were fatigue (12.5%), increased aspartate aminotransferase (9.6%), diarrhea (9.6%) and pruritus (21.2%). Grade 3-5 treatment-related adverse events occurred in 26 (25%) patients and there was one treatment-related death. Immune-mediated adverse events occurred in 2.9 percent of patients. Seven patients discontinued treatment due to treatment-related adverse events.

About Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults. Worldwide, more than 782,000 new cases of liver cancer were diagnosed in 2012. In the U.S., the incidence of liver cancer has more than tripled since 1980 and it is estimated that 42,220 new cases will be diagnosed in this year. In Europe, around 63,500 new cases were diagnosed in 2012. Risk factors for liver cancer include gender, ethnicity, chronic viral hepatitis (Hep-B or Hep-C) infection, cirrhosis, heavy alcohol abuse and obesity. HCC – which is frequently diagnosed at an advanced stage – has one of the highest mortality rates of solid cancers, with a 5-year survival rate of less than 15 percent.

About KEYTRUDA ® (pembrolizumab) Injection 100mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
KEYTRUDA (pembrolizumab) Indications and Dosing

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Saturday, November 11, 2017

Reuters Health Information
Radiotherapy no better than sorafenib for inoperable liver cancer
Last Updated: 2017-11-10
By David Douglas
NEW YORK (Reuters Health) - Selective internal radiotherapy (SIRT) with yttrium-90 resin microspheres does not prolong survival compared to sorafenib in patients with advanced hepatocellular carcinoma not eligible for curative treatment, according to French researchers.

But lead author Dr. Valerie Vilgrain of Hopital Beaujon, in Clichy told Reuters Health by email, "We did observe a better tolerance a better quality of life and a higher tumor control."

The study, an open-label phase 3 trial conducted at 25 centers specializing in liver diseases, was published online October 26 in The Lancet Oncology. Participants had to be at least 18 years old and have a life expectancy greater than three months.

In all, 467 patients were randomly assigned to receive continuous oral sorafenib (400 mg twice daily) or SIRT with yttrium-90-loaded resin microspheres two to five weeks after randomization. Median follow-up was about 28 months.

In the intention-to-treat population, median overall survival with sorafenib (9.9 months) was not significantly greater than the 8.0 months seen with SIRT (P=0.18). In per-protocol analysis, OS was 9.9 months in both groups.

SOURCES: http://bit.ly/2zNoS8y and http://bit.ly/2hoUauS
Lancet Oncol 2017.

Saturday, September 9, 2017

Liver cancer patients can start with lower dose of chemotherapy and live just as long

Liver cancer patients can start with lower dose of chemotherapy and live just as long
September 08, 2017
Penn Medicine News
Penn study shows patients can benefit from fewer side effects and lower treatment costs.

Patients with the most common type of liver cancer who are taking the chemotherapy drug sorafenib can begin their treatment with a lower dose than is currently considered standard, and it will not affect how long they live when compared to patients who start on the full dose. That finding comes from a new study from the Abramson Cancer Center of the University of Pennsylvania, published in the Journal of Clinical Oncology, and it opens the door for patients with hepatocellular carcinoma to begin with a reduced dose of sorafenib, which helps to minimize the drug’s side effects while also saving money for patients, providers, and insurers.

A recent study found 85 percent of HCC patients taking the drug experienced adverse events. In 31 percent of patients on that study, the effects were severe enough to stop treatment. The standard dose sorafenib is 400mg, twice per day.

“Previous studies have started patients with half that dose, escalating only after the patients show they can handle it, but those studies have all been on a smaller scale,” said the study’s lead author Kim A. Reiss, MD, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania. “We wanted to see if we could reproduce those results using a much larger cohort of patients.”

Reiss and her team used a Veterans Health Administration database and identified almost 5,000 HCC patients who were treated with sorafenib between 2006 and 2015, but they couldn’t do a side-by-side analysis of those who received a reduced dose versus those who received the full amount.

“One of the challenges that we faced was that the sickest patients tended to get the reduced dose because of concerns over how much they could tolerate, so any attempt to evaluate these groups based on how long they lived was skewed,” Reiss said.

To solve that problem, researchers looked at patient information to match people from each group based on disease stage, overall health, and other factors. That left them with two groups, each with 1,675 patients.“Essentially, we used a computer model to simulate putting these patients into a randomized, controlled clinical trial,” said senior author David E. Kaplan, MD, MSc, an assistant professor of Gastroenterology and an associate professor of Medicine at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia.

The controlled data showed the reduced dose had no effect on overall survival. Patients starting at a lower dose had a median survival of 198 days, compared to 195 days for patients starting at the full dose.In addition, about 40 percent of patients receiving the reduced dose escalated the drug amount within the first two months, while almost 12 percent of standard dose patients had to reduce their level within the same time period.

“It’s important to remember that the reduced dose patients will ramp up as they show they can handle it, while the full dose patients may have to ramp down because of these toxicities, so the dosage levels will converge in the middle,” Reiss said. “All of the patients get the treatment they need, but the reduced dose approach helps keep cost and toxicities down.”

The cost saving was significant. The study found the reduced dose patients took an average of about 100 fewer pills over the course of their treatment. That translated to an average savings of about $3,000 per patient. Reiss noted those numbers are based on VA prices, which tend to be lower than other centers, meaning the real savings for many patients could be even larger.

The researchers note that some doctors are already making use of this practice, which is why they were able to identify so many reduced dose patients for this study.
https://www.mdlinx.com/gastroenterology/top-medical-news/article/2017/09/08/7449400

Thursday, July 6, 2017

New At Healio - Nexavar beneficial in liver cancer regardless of prognostic factors

Nexavar beneficial in liver cancer regardless of prognostic factors

Nexavar treatment consistently showed benefit in hepatocellular carcinoma regardless of prognostic factors, according to results of a recently published study.

“Although analyses of potential predictive factors for sorafenib benefit have been attempted with data from single-arm, observational studies, the lack of a placebo arm in these trials has prevented proper differentiation between prognostic and predictive markers,” Jordi Bruix, MD, from the BLCL Hospital Clinic Barcelona, Spain, and colleagues wrote. “Our analysis showed a consistent OS benefit with sorafenib treatment compared with placebo irrespective of patient baseline characteristics, subgroup or prognostic factors for survival.”

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Saturday, April 22, 2017

SIRT is better tolerated than sorafenib, but doesn't increase overall survival in HCC

Meeting Updates
Updates On This Blog

SIRT is better tolerated than sorafenib, but doesn't increase overall survival in HCC
           
ILC 2017: Selective internal radiation therapy (SIRT) also resulted in tumor response rates of 19 percent versus 11.6 percent in the sorafenib group

April 22, 2017, Amsterdam, The Netherlands: Results of the SARAH trial presented today demonstrate that SIRT resulted in median overall survival (OS) of 8.0 months compared to 9.9 months with sorafenib (p=0.179), in patients with locally advanced and inoperable hepatocellular carcinoma (HCC). The trial, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, further demonstrated that the cumulative incidence of radiologic progression in the liver as the first event was significantly lower in the SIRT group compared to the sorafenib group (p=0.014), and the response rate was significantly higher in the SIRT group compared to the sorafenib group (19.0% vs 11.6%, p=0.042). Both the side-effect profile and quality of life scores were significantly better over time in the SIRT group compared to the sorafenib group (p=0.005).

Liver cancer, or HCC, is the second most common cause of cancer-related deaths worldwide.1,2 HCC represents more than 90% of primary liver cancers and is a major global health problem.3 The prognosis for patients with advanced liver cancer is poor,2 and the multikinase inhibitor, sorafenib, is the only approved first-line systemic treatment.3 If patients are not tolerant or have contraindications for sorafenib therapy, there is currently no standard of care and patients lack effective treatment options.3 SIRT with yttrium-90 (Y-90) resin microspheres has shown promising anti-tumour results with a safe profile; further trials are needed to establish this treatment as a viable option for patients.3

"Patients with advanced or inoperable hepatocellular carcinoma have a poor prognosis, often with underlying cirrhosis, and the treatment option currently available, sorafenib, has a high level of toxicity. As cohort studies have demonstrated the efficacy of SIRT with Y-90 resin microspheres, we set out to compare the efficacy of this treatment versus the current standard of care," said Prof Valérie Vilgrain, Hôpital Beaujon Service de Radiologie, Paris, France, and lead author of the study.

"While SIRT demonstrated significantly reduced side effects, better quality of life, higher response rates and more effectively controlled tumour progression in the liver, the overall survival of patients was not higher than in the sorafenib group. Nonetheless, this study provides evidence that SIRT may be a better-tolerated alternative for managing this complex and difficult-to-treat disease, deserving further evaluation."

The SARAH trial was a randomised, controlled, open-label, multicentre investigator initiated Phase 3 trial. Patients with locally advanced or inoperable HCC, who did not respond to other treatments or had two failed rounds of transarterial chemoembolisation, were randomised to SIRT with Y-90 resin microspheres, or oral sorafenib 400 mg twice daily. The primary endpoint of the study was OS and secondary endpoints included progression-free survival (PFS), time to radiological progression at any site and in the liver as the first event, tumour response, quality of life, and safety and toxicity.

There were 459 patients from 25 French clinical centres included in the study, 237 of whom received SIRT. Median PFS was 4.1 months and 3.7 months in the SIRT and sorafenib groups, respectively (p=0.765). Cumulative incidence of radiological progression at any site did not differ in either group (p=0.256). Overall, there were 1,297 and 2,837 treatment-related adverse events (AEs) including 230 and 411 grade ?3, in the SIRT and sorafenib groups, respectively. The number of patients with at least one treatment-related adverse event was 173 (76.5%) and 203 (94.0%), (p<0.001), including 92 (40.7%) and 136 (63.0%) grade ?3 adverse events, (p<0.001), in the SIRT and sorafenib groups, respectively. Quality of life, assessed using the Global Health Status scale of the EORTC QLQ-C30 questionnaire, was significantly better in patients who received SIRT compared to the sorafenib group (p=0.005), an advantage that tended to increase with time (p=0.045).

"The SARAH trial is the first reported randomised controlled trial evaluating the survival benefit of SIRT in locally advanced HCC compared to sorafenib. SIRT was found to be safe, but regrettably the study failed meet the primary endpoint and SIRT did not show an overall survival superior to sorafenib. Further trials are needed to establish this treatment as a viable option for patients," said Prof Alejandro Forner, BCLC group, Liver Unit, Hospital Clinic Barcelona, Spain and EASL Governing Board Member.

Yttrium-90 resin microspheres
Y-90 resin microspheres are miniscule radioactive 'beads' that are used in SIRT. They contain the radioactive component yttrium-90. These microspheres are injected in huge quantities into the liver tumours, where they become stuck in the small blood vessels that are in and around the tumours. The microspheres then emit high doses of radiation, which enable doctors to deliver up to 40 times more radiation to the liver tumours than would be possible using standard radiation therapy, all while sparing surrounding healthy tissue.4

About The International Liver Congress™
This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2017 will take place from April 19 - 23, at the RAI Amsterdam, Amsterdam, The Netherlands.

About The European Association for the Study of the Liver (EASL)
Since its foundation in 1966, this not-for-profit organisation has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European Association with international influence, with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Onsite location reference
Session title: General session III and award ceremony II
Time, date and location of session: 10:00 - 12:00, Saturday 22 April, Hall 5
Presenter: Valérie Vilgrain, France
Abstract: SARAH: a randomised controlled trial comparing efficacy and safety of selective internal radiation therapy (with yttrium-90 microspheres) and sorafenib in patients with locally advanced hepatocellular carcinoma (GS012), 10:00 - 10:15

Author disclosures
Speaker fees: Guerbet, SIRTEX, Supersonic, Toshiba. SIRTEX: Funding of SARAH trial. Guerbet: Study Investigator.

References
1 World Health Organization. Cancer. Available from: http://www.who.int/mediacentre/factsheets/fs297/en/. Last accessed: April 2017.
2 World Health Organization. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Last accessed: April 2017.
3 EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943.
4 Sirtex Medical Liminted. About SIR-Spheres microspheres. Available from: http://www.sirtex.com/us/patients/about-sir-spheres-microspheres/. Last accessed: April 2017.

Friday, April 21, 2017

ILC 2017: Nivolumab produces durable responses with longterm survival in sorafenib-experienced patients with advanced liver cancer

ILC 2017: Nivolumab produces durable responses with longterm survival in sorafenib-experienced patients with advanced liver cancer 

New data shows that nivolumab demonstrates a manageable safety profile and promising long-term benefits in sorafenib-experienced patients with advanced HCC 

April 21, 2017, Amsterdam, The Netherlands: Results from the CheckMate 040 study presented today found that nivolumab, an immuno-oncology  drug which acts by modulating the immune system, produces durable responses with long-term survival rates, regardless of whether or not patients were infected with Hepatitis B or C. Interim results from the study, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, showed that the overall objective response rate (ORR) by blinded independent central review (BICR) was 14.5% and ORR by investigator assessment was 19.3% in sorafenibexperienced patients in the dose expansion phase of CheckMate 040. Responses by BICR were ongoing in 71.4% (15/21) of patients, and the 12-month overall survival rate in this cohort was 59.9%. The safety profile of nivolumab was manageable and consistent with that reported in other tumour types.

Liver cancer, or hepatocellular carcinoma (HCC), is the second most common cause of cancer-related deaths worldwide.1,2 The prognosis for patients with advanced liver cancer is poor,2 and the multikinase inhibitor, sorafenib, is the only approved systemic treatment.3 If the patient is not tolerant or has contraindications for sorafenib therapy, there is currently no standard of care and therefore patients lack effective treatment options.3 Nivolumab has already increased survival time in different types of cancers, and has become an important treatment option for certain types of kidney, blood, melanoma and non-small cell lung cancer.4 Preliminary results from the CheckMate 040 study presented earlier this year suggested that nivolumab could be an option for the treatment of liver cancer.5 Nivolumab is not yet licensed for HCC in the EU. 

“The durable responses and survival rates that were achieved with nivolumab are very welcome, especially as the side effects were manageable,” said Prof Bruno Sangro, Head of Liver Unit, Clinica Universidad de Navarra and CIBEREHD, and study author. “These data support the potential of nivolumab in the treatment and stabilisation of advanced liver cancer in those patients who have progressed on sorafenib, with or without chronic viral hepatitis.”

The CheckMate 040 study is a Phase 1/2, multi-cohort, open-label study of nivolumab conducted in patients with advanced liver cancer who were not suitable for surgery.6 The primary endpoint of the study was ORR by blinded, independent central review. All 145 patients previously treated with sorafenib in the dose-expansion portion of the study were given intravenous nivolumab 3 mg/kg every 2 weeks until the cancer progressed or side effects became intolerable. 

Of the 145 patients who had previously received sorafenib, 132 (91.0%) had progression of their cancer and 12 (8.3%) were intolerant of the therapy. The median follow up was 12.9 months in this interim analysis of the dose expansion phase. The median duration of response (DOR) was not yet reached, and 8/21 responders had a DOR of greater than 12 months. The overall median overall survival (OS) was 16.7 months, and it was not reached in those with chronic viral hepatitis B and C. Responses to nivolumab occurred regardless of programmed death-1 (PD-1) ligand expression on tumour cells. Overall, grade 3/4 treatmentrelated adverse events occurred in 16.6% of patients. 

Nivolumab is a programmed-death-1 (PD-1) immune checkpoint inhibitor that is designed to use the body’s own immune system to help restore the anti-cancer immune response.5 It restores T-cell-mediated anti-tumour activity so that the T cells recognise and attack cancer cells.5 

“The reported median survival of 16.7 months in patients previously treated with sorafenib is promising and it encourages the evaluation of nivolumab in patients affected with hepatocellular carcinoma,” said Prof Alejandro Forner, BCLC group, Liver Unit, Hospital Clinic Barcelona, Spain and member of the EASL Governing Board.

MedPage Today
Opdivo Offers Encouraging Outcomes in Liver Cancer
CheckMate study reports 16.7-month median survival
by
Contributing Writer, MedPage Today
AMSTERDAM -- One in five advanced liver cancer patients treated with nivolumab (Opdivo) showed some tumor regression and improvement in overall survival (OS), researchers said here.

Monday, February 20, 2017

Sorafenib benefit dependent on hepatitis status in patients with HCC

February 19, 2017
Sorafenib improved OS among patients with hepatocellular carcinoma who were hepatitis C positive but hepatitis B negative, suggesting that the beneficial effects of sorafenib may be based on hepatitis status, according to results of a meta-analysis.

Of Interest
MicroRNA-125a-5p is a downstream effector of sorafenib in its antiproliferative activity toward human hepatocellular carcinoma cells.
Article ID: 669739
Released: 17-Feb-2017 3:05 PM EST
Source Newsroom: Sbarro Health Research Organization (SHRO)

Sorafenib is a multikinase inhibitor with specific activity against Raf kinase and several receptor tyrosine kinases. The addition of sorafenib to hepatocellular carcinoma cells increased cellular expression of miR-125a. Upregulation of this miRNA inhibited cell proliferation and induced cell cycle arrest by targeting c-Raf, part of the ERK pathway that is involved in cell proliferation and sirtuin-7, (SIRT-7) a NAD(+)-dependent deacetylase that inhibits transcriptional activation of the cell cycle inhibitor p21. Therefore, sorafenib inhibits Raf activity and upregulates miR125 that, in turn, targets c-Raf and SIRT7; this dual inhibition of Raf activity and expression together with p21-dependent cycle arrest coherently combine to explain the antiproliferative activity of the drug.

Newswise — Treatment options for liver cancer are often limited and almost exclusively involve transplantation if possible, or local chemoembolization and radiofrequency ablation. Medical treatments for more advanced stages have been explored during recent decades, but only the drug sorafenib, a small molecule multi-kinase inhibitor, has shown promising results and been approved for use by international medical agencies. Unfortunately, only 25% of patients respond to sorafenib treatment, so researchers have endeavored to understand its mechanism of action and discover a way to boost its effectiveness.

A recent study, published in the journal Journal of Cellular Physiology, describes further scientific insight into the involvement of a small non coding RNA, miR-125a, in the anti-cancer effects of sorafenib in the treatment of liver cancer, or hepatocellular carcinoma. These results are interesting as miRNAs have multiple available intracellular targets and could contribute to the amplification of the effects of sorafenib.

The link between small kinase inhibitors such as sorafenib, and the existing molecular pathways that govern cell proliferation such as miR-125a, may be useful to potentiate the anticancer activity of sorafenib. Clinical applications of this knowledge might seek to identify and increase the number of liver cancer patients that respond positively to the drug.

The study includes work done by Prof. Michele Caraglia and Aniello Russo, of the University of Campania “L. Vanvitelli” in Naples, and Caserta, Italy, in collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia.

“Sorafenib is still the only drug indicated in the treatment of hepatocellular carcinoma, which highlights the difficulty in the medical treatment of liver cancer,” says Prof. Antonio Giordano. “Sorafenib is effective because it acts upon multiple intracellular targets and interferes with both cancer proliferation and tumor blood supply. However, its activity is limited to only 25% of patients that are sensitive to its effects. This strongly pushes the researchers to define the mechanism of action of the drug,” Giordano concludes.

“MicroRNAs can act as either cancer-fighting tumor suppressors, or as cancer-causing oncogenes,” says Professor Michele Caraglia. "We have found that the expression of miR-125a is strongly involved in the mechanism of action of sorafenib and its ability to regulate cancer cell proliferation. These findings suggest the possible use in the future of miR125a in combination with sorafenib in order to potentiate the anti-cancer activity of the drug,” Caraglia concludes.

The study results open a new scenario of intervention in the treatment of hepatocellular carcinoma in which small molecules such as sorafenib can be used in association to nucleic acids such as miR-125a. The latter could be administered to patients systemically encapsulated in novel drug delivery options such as nanocarriers. Researchers plan to further study the in vivo efficacy of these strategies to increase treatment options for this difficult form of cancer.

Citations
Potenza N, Mosca N, Zappavigna S, Castiello F, Panella M, Ferri C, Vanacore D, Giordano A, Stiuso P, Caraglia M, Russo A. MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells. J Cell Physiol. 2016 Dec 16. doi: 10.1002/jcp.25744.

Saturday, January 7, 2017

Meta-analysis/Effect of sorafenib for advanced liver cancer dependent on patients’ hepatitis status

Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials

The following article summary is provided by HealthDay News, abstract and discussion is available below or view the original report published in the Journal of Clinical Oncology.

Summary

Sorafenib Effect on HCC Survival Depends on Hepatitis Status
For patients with advanced unresectable hepatocellular carcinoma, the effect of sorafenib on overall survival is dependent on patients' hepatitis status, according to a meta-analysis published online Jan. 3 in the Journal of Clinical Oncology.

Richard Jackson, from the Liverpool Cancer Trials Unit in the United Kingdom, and colleagues undertook an individual patient data meta-analysis of three prospective randomized trials in which sorafenib was the control arm. Data were included for 1,643 patients with advanced unresectable hepatocellular carcinoma who received sorafenib.

The researchers found that patients who were both hepatitis B virus (HBV) negative and hepatitis C virus (HCV) positive had improved OS for sorafenib (log [hazard ratio], −0.27). In this subgroup, the median unadjusted survival was 12.6 and 10.2 months for sorafenib and other treatments, respectively. Other patient subgroups defined by HBV and HCV did not have improvement in OS. Consistent results were seen across all trials.

"There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status," the authors write. "There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib."

One author disclosed financial ties to the pharmaceutical industry; Bristol-Myers Squibb, Pfizer, and AbbVie gave access to data from studies in which they acted as sponsor.

Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials
Richard Jackson, Eftychia-Eirini Psarelli, Sarah Berhane, Harun Khan, and Philip Johnson

Abstract
Purpose
Following the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib has become the standard of care for patients with advanced unresectable hepatocellular carcinoma, but the relation between survival advantage and disease etiology remains unclear. To address this, we undertook an individual patient data meta-analysis of three large prospective randomized trials in which sorafenib was the control arm.

Methods
Of a total of 3,256 patients, 1,643 (50%) who received sorafenib were available. The primary end point was overall survival (OS). A Bayesian hierarchical approach for individual patient data meta-analyses was applied using a piecewise exponential model. Results are presented in terms of hazard ratios comparing sorafenib with alternative therapies according to hepatitis C virus (HCV) or hepatitis B virus (HBV) status.

Results
Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to −0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for “other” treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran’s Q statistic.

Conclusion
There is consistent evidence that the effect of sorafenib on OS is dependent on patients’ hepatitis status. There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib. There was no evidence of any improvement in OS attributable to sorafenib for patients positive for HBV and negative for HCV.

We have carried out an IPD meta-analysis of three phase III RCTs that demonstrates that the effect of sorafenib compared with other treatments for patients with aHCC cannot be considered independent of a patient’s HBV and HCV status. For patients who were HBV positive and HCV negative, there was no evidence of any positive effect on OS due to sorafenib, with the HR in this subgroup favoring the comparator, although this was not statistically significant. This patient group comprises 51% of all patients included in the analysis. There was, however, a significant positive effect of sorafenib in the group of patients who were HCV positive and HBV negative (n = 628; 22%). For all remaining patients, there was a trend supporting the use of sorafenib, but this was not statistically significant.

Our analysis extends the previous aggregate meta-analysis, which, although lacking the ability of IPD analyses to investigate treatment effects within patient subgroups, did involve additional trials to ours (the SHARP4 and Asia-Pacific region5 studies) and concluded that sorafenib might provide more survival benefits to patients positive for HCV. IPD meta-analyses are the gold standard and allow us to analyze trial data that may be more mature than the published results, ensure consistency of analytical techniques across the data sources, and further allow for the inspection of subgroup effects and treatment interactions, which would not be possible using an aggregate meta-analytical approach. Still, the results reported here represent secondary analyses of trial subgroup effects and the evidence provided is not as strong as a RCT, which specifically would look at the effect of sorafenib within each hepatitis subgroup.

The subgroup analysis of the SHARP trial showed that patients positive for HCV had a superior median OS of 14 months compared with 7.4 months in the placebo-treated group, and this benefit was also seen in terms of time to tumor progression (7.6 v 2.8 months) and disease control rate (44.2% v 29.6%).6 As noted by Bruix et al,6 the SHARP trial was not randomized relative to etiology and, therefore, the resulting subgroups were at risk for imbalance. Nonetheless, inspection of the data provided in this subgroup analysis shows that there were a significant number of patients within the HCV-positive subgroup (n = 167; 86 receiving sorafenib and 81 receiving placebo), and that the treated and the placebo groups were, in fact, well balanced with respect to region, age, sex, Child-Pugh class, macrovascular invasion/extrahepatic spread, ECOG PS, and disease stage. These observations, combined with the present detailed IPD meta-analysis and the previous aggregated meta-analysis, support the contention that the impact of sorafenib is largely confined to the patients who are HCV positive. Because the overall benefit of sorafenib in the SHARP study was only 2.8 months compared with placebo, and we found little significant overall effect of sorafenib in the analyses presented here, there is insufficient evidence to support the absolute benefit of sorafenib outside patients positive for HCV. We considered the possibility that ethnicity might be a confounding factor (because HCV and HBV are more prevalent in Western and Eastern populations, respectively), but our analysis did not support this contention. Treatment before trial entry, which may be less intense in Western (and, hence, HCV-positive) populations may also be a confounding factor, but we had insufficient data to exclude this possibility.

There is evidence of genetic diversity22-25 in HCC that can be linked to specific etiologic factors22,26 and may permit identification of specific targets for therapy. The reasons for differential response to sorafenib according to etiology remain unclear. Although some in vitro data have suggested that sorafenib inhibits HCV viral replication directly, this has not been borne out in the clinical setting.7,27 There is evidence of Wnt-pathway dysregulation in about 50% of HCC cases. Of the two major activating classes (CTNNB1 and Wnt-TGFβ), the former appears to be related to HCV infection and activity is modulated by sorafenib in a xenograft model.13,24,28 HCV has also been shown to upregulate C-RAF,29 a known sorafenib target, and Braconi et al30 have shown that HCV proteins can modulate the expression of microRNAs and thereby influence the sensitivity of HCC cells to sorafenib.

Irrespective of the mechanism, our data suggest that in future trials in aHCC, particularly where sorafenib is the control arm, there should be stratification according to etiology. Etiologic differences have already been considered as factors in the interpretation of clinical trials. In the trial of adjuvant sorafenib after surgical resection or local ablation (STORM), although the overall results of the trial were negative, there was a trend for longer time to recurrence in the HCV-related cases.31

Following a proposal from the International Committee of Medical Journal Editors32, it is likely that individual patient data will become accessible to investigators unrelated to the original trial. Thus, as a condition of consideration for publication, it is proposed that authors will be required to include a description of the data-sharing plan in the submitted manuscript. Although the editors considered that “sharing data will increase confidence and trust in the conclusions drawn from clinical trials,”32(p468) our study shows how the benefits of access to completed trial data are not necessarily confined to reanalysis of the original hypothesis tested by the trial. Here, by a meta-analysis, we arrive at an answer to a question that was not considered when the trials were conceived and could not have been answered by any of the trials individually. It also illustrates the clinical benefit arising when enlightened pharmaceutical companies are prepared to share their data with an academic unit, even when the primary question does not relate to their products.

Continue reading online....

Friday, July 29, 2016

Dr. Yasmin Thanavala on targeted therapy for liver cancer


Roswell Park Findings Will Help Clinicians Select Best Therapy for Patients with Advanced Liver Cancer

Newswise — BUFFALO, NY - New research from Roswell Park Cancer Institute offers clinicians treating patients with advanced liver cancer a way of determining which patients may benefit most from the targeted therapy sorafenib.

“Our study is the first to demonstrate the potent immunotherapeutic benefits of sorafenib and to suggest that this targeted treatment may extend survival among a subset of patients with liver cancer,” says the paper’s senior author, Yasmin Thanavala, PhD, Professor in the Department of Immunology and Member of the Tumor Immunology and Immunotherapy program at Roswell Park. “The drug has significant antiangiogenic properties, and also appears to beneficially impact the suppressed immune system of patients with advanced liver cancer.”

Looking at blood samples from patients with advanced liver cancer, researchers evaluated the frequency and expression levels of several immunosuppressive cells and molecules before and after treatment with sorafenib. The team found a statistically significant reduction of the checkpoint molecule PD-1 and levels of its expression on important immune cells known as “helper,” “killer” and regulatory T cells, and that this response was strongly linked to the patients’ overall survival. They also observed a beneficial increase in the ratio of T effector cells to T regulatory cells following treatment with sorafenib. The findings suggest that sorafenib reduces the number of immune-suppressing cells in patients who respond to therapy, and that the combination of this targeted agent with immune-based therapies may improve treatment outcomes in patients with liver cancer.

“These results indicate that patients with an increased number of cells expressing the checkpoint molecule PD-1 before treatment are more responsive to sorafenib therapy. These increased numbers in pretreatment blood samples may be a biomarker indicating which patients will respond better to therapy and may help to predict overall patient survival,” adds Dr. Thanavala.

This research has been highlighted in a press release from the journal JCI Insight.

Editor’s note: See a video interview with Dr. Yasmin Thanavala, lead author of the study, at https://youtu.be/X3H_avWi-Ko

Tuesday, May 7, 2013

TACE, sorafenib improve survival among patients with infiltrative HCC



TACE, sorafenib improve survival among patients with infiltrative HCC
May 7, 2013
Patients with infiltrative hepatocellular carcinoma experienced prolonged survival when treated with transarterial chemoembolization or sorafenib in a recent retrospective cohort study.
Researchers evaluated data from 155 patients with infiltrative hepatocellular carcinoma (iHCC) seen at the University of California, San Francisco Medical Center between 2002 and 2010. Participants had a median age of 60 years, MELD score of 13, maximum tumor diameter of 11.3 cm and alpha-fetoprotein level of 347 ng/mL.
Full Story »

Boceprevir/peginterferon/ribavirin effective, safe in chronic HCV patients with compensated cirrhosis
May 6, 2013
Patients with chronic hepatitis C and compensated cirrhosis experienced higher rates of sustained virologic response with the addition of boceprevir to therapy with pegylated interferon and ribavirin in a study presented at the International Liver Congress in Amsterdam.
Full Story »

Wednesday, December 5, 2012

Survival Rates at 1 Year Were Higher in TACE-vs Sorafenib-Treated Patients With Hepatocellular Carcinoma: Presented at ASCO Quality Care

Source - DGDispatch 

Survival Rates at 1 Year Were Higher in TACE-vs Sorafenib-Treated Patients With Hepatocellular Carcinoma: Presented at ASCO Quality Care

By Cathy Yarbrough

SAN DIEGO -- December 4, 2012 -- Patients with hepatocellular carcinoma (HCC) in the European Union and United States who were treated with arterial chemotherapy infusion and chemoembolization of the liver (TACE) had statistically significant higher 1-year survival rates than patients whose first-line therapy was sorafenib, according to a study presented here at the American Society of Clinical Oncology (ASCO)'s inaugural 2012 Quality Care Symposium.

In Asia, however, 1-year survival did not differ between TACE- and sorafenib-treated patients, said Glen I. Misek, Abbott Laboratories, Abbott Park, Illinois, on November 30.

Misek and colleagues analysed a global database of 4,000 patients with HCC to understand differences in overall survival (OS) and progression-free survival that could be the result of patient demographics such as ethnicity and comorbidities such as hepatitis B or C and alcohol-induced cirrhosis. Effectiveness of treatments according to the stage of disease was also examined.

HCC is the sixth leading cancer, with a global incidence of >700,000 individuals. Although new drugs against HCC are now available, prognosis is poor in that the 5-year survival is only 11%, Misek said.

The researchers determined that 5-year survival rates were comparable across geographic regions. However, 1-year survival of patients with HCC was significantly lower in China and Korea than in the United States and the European Union. China and Korea's lower survival may reflect the region's different treatment practices.

A surprising result of the analysis, according to Misek, was that concomitant conditions of hepatitis and cirrhosis did not affect differences in 1-year survival regardless of sorafenib use. Compared with Asian patients, US and EU patients tended to have more concomitant comorbidities such as hypertension, diabetes, asthma, kidney disease, and depression/anxiety.

An expected finding was that 1-year survival rates of patients with HCC stages III and IV, versus stage I/II, were significantly reduced. Similarly, according to Child-Pugh (CP) classifications, the survival rates of patients with CP-C (most advanced) were significantly lower than patients with CP-A.

Misek said that because sorafenib therapy did not affect OS of patients with stage IV HCC, the disease's impact may be more effectively reduced by increased screening and detection and treatment of patients at high risk of the disease than by expanding the use of the drug in patients with late-stage disease.

Because brief sorafenib therapy regimens may improve a patient's quality of life and reduce healthcare costs, Misek concluded that prospective indicators to identify patients who could benefit from minimal treatment regimens are needed.

Stratification of groups by type of drug treatment including sorafenib use did not measurably affect OS within geographies.

[Presentation title: Effectiveness of HCC Treatments in Real-World Experience. Abstract 61]



Monday, July 23, 2012

Combination of Tarceva, Nexavar fails to meet main goal of Phase III liver cancer study

July 23, 2012
Combination of Tarceva, Nexavar fails to meet main goal of Phase III liver cancer study
Last Updated:July 23, 2012 07:36

Bayer, Onyx Pharmaceuticals and Astellas announced Monday that a late-stage trial investigating the combination of Tarceva (erlotinib) and Nexavar (sorafenib) failed to meet the main goal of a late-stage trial in patients with unresectable hepatocellular carcinoma (HCC). "The data from SEARCH showed that the addition of Tarceva to Nexavar did not provide additional benefit to patients with unresectable HCC," remarked Dimitris Voliotis, vice president of global clinical development oncology at Bayer.

The SEARCH study randomised 720 patients with advanced liver cancer to receive treatment with Nexavar twice daily, either in combination with Tarceva once daily or placebo. Results demonstrated that the addition of Tarceva to Nexavar did not improve overall survival compared to Nexavar alone. The companies noted that data from the trial will be presented at a future medical meeting.

Nexavar, which is being jointly developed by Bayer and Onyx, is approved in the US and other countries for the treatment of patients with unresectable HCC and for the treatment of patients with advanced renal cell carcinoma. Tarceva is used to treat lung cancer and is co-marketed by Astellas and Roche's Genentech unit.

Analysts at Cheuvreux said the study results were a small negative for Bayer, but they left peak sales forecasts for Nexavar unchanged at 971 million euros ($1.2 billion) in 2019. Meanwhile, a spokesman for Roche noted while the company provided financial support as well as Tarceva for the trial, it did not have a development plan for the drug in liver cancer, either alone or as part of a combination.

Reference Articles
Bayer says Nexavar-Tarceva trial unsuccessful - (CNBC)
Bayer Says Phase III Tarceva-Nexavar Study Fails - (FinanzNachrichten)
Bayer Says Phase III Tarceva-Nexavar Study Fails - (NASDAQ)
Addition of Tarceva (erlotinib) to Nexavar (sorafenib) did not Provide Additional Benefit to Patients with Unresectable Liver Cancer Versus Nexavar alone in Phase 3 Trial - (PR Newswire)

Source - http://www.firstwordplus.com/Fws.do?src=corp_site&articleid=3BC42477F6134983B32824385309019C

Friday, May 25, 2012

Sorafenib benefits select HCC patients with cirrhosis

NEW YORK (Reuters Health) – Single-agent sorafenib improves outcomes for select patients with advanced hepatocellular carcinoma (HCC) and underlying Child-Pugh B liver cirrhosis, researchers from Hong Kong report in the April 19th online issue of Cancer.

“I would only recommend prescribing sorafenib to patients with score 7 instead of 8-9, as most benefits are seen in score 7 patients,” Dr. Thomas Yau from Queen Mary Hospital, Hong Kong, China told Reuters Health in an email.

Although sorafenib is FDA-approved as first-line treatment for advanced HCC, its efficacy and tolerability remain largely unknown for patients with suboptimal liver function.

Dr. Yau and colleagues explored that question in a retrospective study of three groups of patients with advanced HCC: 108 with Child-Pugh A cirrhosis (CPA), 37 with Child-Pugh B disease and a score of 7 (CPB7), and 27 with scores of Child-Pugh B and scores of 8-9 (CPB8-9).
Patients in Child-Pugh class A have well compensated disease. Child-Pugh B indicates significant functional compromise. (Child-Pugh class C patients, not included here, have decompensated liver disease.)

The overall clinical benefit rates (complete response + partial response + stable disease) did not differ significantly between patients with CPA, CPB7, or CPB8-9 (23.3%, 32.4%, and 14.8%; p=0.23).
Median progression-free survival was also similar — 3.2 months for CPA, 3.2 months for CPB7, and 2.3 months for CPB8-9 — but median overall survival was significantly greater for CPA and CPB7 than for CPB8-9 (6.1 and 5.4 vs 2.7 months; p=0.02).

Rates of most nonhematological and hematological adverse events were comparable in the three groups. There were, however, significantly more GI bleeding events and hepatic encephalopathy in CPB patients than CPA patients.

More CPB than CPA patients had drug termination due to adverse events, primarily related to more cirrhotic complications in CPB (15.6%) than CPA (5.6%) patients during sorafenib treatment.
“Therefore,” the researchers suggest, “when sorafenib is routinely used to treat advanced HCC patients with CPB cirrhosis, more vigilant surveillance and follow-up is advisable.”

“The on-going GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib) study will certainly provide us more information about the efficacy and safety of sorafenib use in patients with Child Pugh B cirrhosis,” Dr. Yau said. “We are planning to explore the potential benefits and safety of using sorafenib in other advanced HCC subgroups, such as patients with ECOG 3/4.”

The study was supported by the University of Hong Kong hepatocellular carcinoma research fund.


Friday, November 11, 2011

AASLD-JX594/TG6006 Trial Showing Statistically Significant Survival Benefit in Patients with Advanced Liver Cancer

TRANSGENE : and Jennerex Announce Final Data at AASLD From JX594/TG6006 Randomized Phase 2 Clinical Trial Showing Statistically Significant Survival Benefit in Patients with Advanced Liver Cancer


Median survival of 13.8 months (high dose) vs. 6.7 months (low dose)


Transgene (Paris:TNG) (Euronext Paris: FR0005175080) and Jennerex, Inc. announce final data from a randomized dose-ranging Phase 2 clinical trial of JX594/TG6006 in patients with advanced liver cancer showing a statistically significant benefit in overall survival for the high JX594/TG6006 dose group versus the low dose group. The final data from the HEP007 trial demonstrated that the risk of death for patients who received JX594/TG6006 at the high dose was markedly reduced (by nearly 60 percent; hazard ratio = 0.41) when compared to patients randomized to a low dose control (one-tenth of the high dose). The median overall survival for high and low dose groups was 13.8 months versus 6.7 months, respectively (p = 0.029 for superiority of the high dose). The percent of patients alive at one year was 66 percent versus 23 percent in high- and low-dose groups, respectively (Kaplan-Meier estimate). JX594/TG6006 was well-tolerated with patients experiencing transient flu-like symptoms that generally resolved within 24 hours. Clinical investigators enrolled 30 patients at sites in the United States, Canada and South Korea.


The data were presented by Tony Reid, M.D., Ph.D., professor of medicine, hematology/oncology, director of clinical investigation, and the tumor growth, invasion and metastasis program, Moores UCSD Cancer Center at the University of California, San Diego. Dr. Reid presented during the late-breaking oral session at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, California. The abstract (#LB-1) was entitled "A Randomized, Controlled Phase 2 Clinical Trial of JX594, a Targeted Multi-Mechanistic Oncolytic Poxvirus, in Patients with Advanced Hepatocellular Carcinoma: Final Data."


A randomized, placebo-controlled Phase 2b clinical trial of JX594/TG6006 in patients with hepatocellular carcinoma (HCC) having failed sorafenib (Nexavar®) treatment was recently initiated. This trial (TRAVERSE), conducted globally with Jennerex's partners, is evaluating survival in advanced HCC patients who have either progressed or exhibited intolerance after treatment with sorafenib, the current standard of care.


"These data showing an improvement in overall survival are very encouraging--particularly when coupled with the favorable tolerability profile of JX594/TG6006 experienced in this and prior clinical trials. Another therapeutic option to treat patients with HCC, the third leading cause of cancer death globally, is urgently needed" stated Dr. Reid, a clinical investigator on the HEP007 clinical trial.


"The strength of these data--showing a statistically significant benefit in overall survival--gives us great confidence in the potential of JX594/TG6006 to benefit patients with liver and other types of cancer world-wide" stated David H. Kirn, M.D., President and Chief Medical Officer of Jennerex. He added: "Based on these clinical data, and clinical data we have previously published, we are accelerating the development of JX594/TG6006. Together with our partners, we are initiating a more expansive late-stage TRAVERSE clinical trial of JX594/TG6006 in HCC, and we are moving into Phase 1/2 trials in additional cancer types, including ras mutant and Erbitux-refractory colorectal cancer."


"The clinical data presented by Jennerex at AASLD once again validates our commitment to JX594/TG6006 and demonstrates that the product could really change the treatment paradigm in liver cancer. Should these findings be confirmed in late stage clinical trials, and notably in the TRAVERSE study, then the chances of JX594/TG6006 coming to the market will be very high" stated Philippe Archinard, Chairman and CEO of Transgene.


Other Recent Clinical Data for JX594/TG6006 in Liver Cancer:
In a second Phase II trial which sequentially combined intravenous and intratumoral administration of JX594/TG6006 and sorafenib treatment, interim data from 15 patients, including a subgroup of 10 who have failed previous treatment with sorafenib, demonstrated tumor responses by Choi criteria (a measure of tumor necrosis) in both injected and non-injected tumors in 8 of 11 evaluable patients. Tumor responses were maintained for up to 15 months post JX594/TG6006 treatment initiation. Significant tumor necrosis following JX594/TG6006 and sorafenib was observed in 6 of 7 evaluable sorafenib resistant patients (86 percent).


Hepatocellular Carcinoma: A Global Unmet Need:
Hepatocellular carcinoma is the fifth most common cancer worldwide and the third leading cause of cancer death, with over 600,000 new cases diagnosed annually resulting in more than 90 percent mortality. The annual incidence rate in the U.S., Europe, Japan and China are estimated to be 20,000, 55,000, 40,000 and 350,000 patients, respectively. Currently, there is only one approved agent for HCC, a drug called sorafenib (Nexavar®), which is associated with moderate efficacy (tumor response rate of ~2%) and a side effect profile that results in treatment discontinuation in one fourth to one third of patients.



JX594/TG6006: A Multi-Mechanistic Approach To Targeting Cancer:
JX594/TG6006 is a proprietary, engineered oncolytic virus that is designed to selectively target and destroy cancer cells. JX594/TG6006 is designed to attack cancer through three diverse mechanisms of action: 1) the lysis of cancer cells through viral replication, 2) the shutdown of the blood supply to tumors through vascular targeting and destruction, and 3) the stimulation of the body's immune response against cancer cells, i.e., active immunotherapy. Phase I and Phase II clinical trials in multiple cancer types to date have shown that JX594/TG6006, delivered either directly into tumors or systemically, induces tumor shrinkage and/or necrosis and is well-tolerated by patients (over 120 treated to date). Objective tumor responses have been demonstrated in a variety of cancers including liver, colon, kidney, lung cancer and melanoma. JX594/TG6006 has a favorable safety profile with predictable and generally mild side effects that typically include flu-like symptoms that resolve in 24 to 48 hours.


About Transgene:
Transgene, a member of the Institut Mérieux Group, is a publicly traded French biopharmaceutical company dedicated to the development of therapeutic vaccines and immunotherapeutic products in oncology and infectious diseases and has four compounds in Phase II clinical development: TG4010 and JX594/TG6006 having already completed initial Phase II trials, TG4001 and TG4040. Transgene has concluded strategic agreements for the development of two of its immunotherapy products: an option agreement with Novartis for the development of TG4010 to treat various cancers and an in-licensing agreement with US-based Jennerex, Inc. to develop and market JX594/TG6006, an oncolytic virus. Transgene has bio-manufacturing capacities for viral-based products. Additional information about Transgene is available at www.transgene.fr.


About Jennerex:
Jennerex, Inc. is a clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer. The Company's lead product JX594/TG6006 is currently in an international, randomized Phase IIb clinical trial (TRAVERSE) in patients with advanced primary liver cancer who have failed sorafenib therapy. In addition, JX594/TG6006 is being tested in the same patient population in combination with sorafenib. JX594/TG6006 is also in a Phase I clinical trial in patients with treatment-refractory colorectal cancer. Published studies designed to establish optimal dose levels and the safety profile of JX594/TG6006 have shown its ability to selectively target and cause destruction of a variety of common cancer types. JX594/TG6006 and other product candidates under development are designed to attack cancer tumors through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the ablation of the blood supply to tumors through vascular targeting and destruction and the stimulation of the body's immune response against the cancer. Jennerex is headquartered in San Francisco and has related research and development operations in Ottawa, Canada and Pusan, South Korea. For more information about Jennerex, please visit www.jennerex.com.


Disclaimer:
This press release contains certain forward-looking statements. Although the company believes its expectations are based on reasonable assumptions, these forward-looking statements are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those anticipated. In particular, the Company's ability to commercialize its first product depends on the continuing success of clinical studies, ongoing financing for further product developments and marketing launch, a positive response from the medical community regarding the product's costs and effectiveness. For a discussion of risks and uncertainties which could cause the company's actual results, financial condition, performance or achievements to differ from those contained in the forward-looking statements, please refer to the Risk Factors ("Facteurs de Risque") section of the Document de Reference prospectus, which is available on the AMF website (http://www.amf- france.org) or on Transgene's website (www.transgene.com). This press release and the information contained herein do not constitute an offer to sell or a solicitation of an offer to buy or subscribe to shares in Transgene in any country.
TransgenePhilippe Archinard, +33 (0)3 88 27 91 22Chairman & CEOorStéphane Boissel, +33 (0)3 88 27 91 02Executive Vice President & CFOorElisabetta Castelli, +33 (0)1 44 08 55 05Director IRorMC ServicesRaimund Gabriel, +49 89 210 228 30orShaun Brown, +44 207 148 5998

Monday, October 17, 2011

HCV News Ticker-Interferon Free RegimenTo Treat Hepatitis C ?

A fairy tale forest by edi - eduard sandu

Hello folks, hope everyone enjoyed a lovely fall weekend. Autumn for me is bittersweet, it's the season I completed treatment. I still remember walking in the woods with the leaves crunching underfoot, my mind racing with each step, knowing the virus was gone. In 2000 the regimen of drugs were unbearable, with less then a desirable chance of reaching SVR.

These days we dare to dream of an interferon free combination to treat hepatitis C. Could it happen? Enter; an all oral regimen, consisting of a few pills, a better cure rate, and less side effects. This month brought exciting news from Pharmasset on PSI-7977, if you missed the update you may want to read up @ The Haystack; Two HCV Meds are Better than One for Pharmasset .

According to the news this morning over at TheStreet Roche is hoping to achieve an all oral regimen of its own folks, by buying the pharmaceutical company Anadys, check it out.

SAN DIEGO (TheStreet) -- Roche is buying Anadys Pharmaeuticals for $230 million to bolster its pipeline of experimental hepatitis C drugs, the company said Monday.

By acquiring Anadys, Roche hopes to develop safer, convenient and all-oral treatments for hepatitis C that do not the use of injectable interferon -- a goal shared by all of the major drug makers pursuing new hepatitis C therapies. Continue reading

More from Adam Feuerstein, TheStreet Senior Columnist published @ Fidelity

Roche's All-Oral Hep C Therapy Could Be First, Not Best, to Reach Market

Roche's purchase of Anadys provides the third drug in what may be the first all-oral hepatits C regimen to start late-stage trials.
By Adam Feuerstein, TheStreet Senior Columnist

BOSTON (TheStreet (TST

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) -- Roche's (RHHVF


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)
purchase of Anadys likely provides the third drug in what might be the first (but not necessarily best) all-oral, interferon-free therapy for hepatitis C to begin phase III studies.


Being first to market with an all-oral Hep C therapy is important to Roche (RHHVF



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) because the company has a lot to lose by lagging behind. Roche (RHHVF


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)
sells Pegasys, the leading interferon used to treat hepatitis C today, with sales of 1.1 billion Swiss francs through the first nine months of the year. Roche (RHHVF


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executives aren't stupid; they look ahead a few years and see Pegasys sales going away, similar to the patent cliffs hitting other Big Pharma drug blockbusters.

If Roche (RHHVF



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) wants to maintain or grow its Hep C franchise, it has to figure out a way to develop an all-oral (interferon-free) therapy -- and fast.


One way of doing this is by acquiring or partnering Hep C drugs others consider to be weak or non-competitive on their own. That description fits Anadys' lead drug setrobuvir, which for $230 million, Roche (RHHVF



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) is acquiring at a relatively low price.


InterMune's (ITMN



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) danoprevir, which Roche (RHHVF ) acquired last year, is also seen as a weak Hep C drug.


Roche (RHHVF



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) could start relatively quickly a phase III study against Hep C that combines three oral drugs -- setrobuvir (from Anadys), RG7128 (partnered with Pharmasset (VRUS


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)
) and Merck's currently approved Hep C drug Victrelis, predicts Brian Skorney, biotech analyst at Brean Murray, Carret & Co. Roche (RHHVF ) and Merck have already announced plans to collaborate on Hep C.


Another potential Roche (RHHVF

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) all-oral regimen could include setrobuvir, RG7128 and danoprevir (acquired from InterMune (ITMN


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)
.


These Roche (RHHVF

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) triple combinations may require longer 24-week dosing (instead of faster 8 or 12 week dosing) and may not be as potent or effective as all-oral regimens being developed by Pharmasset (VRUS


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and others, but Roche (RHHVF


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may figure that being first is more important than being best, adds Skorney... Continue Reading


Also In The News This October Monday



Letters are in the mail to almost 7,000 people who had procedures at an Ottawa medical facility to warn them they may have been exposed to hepatitis B, hepatitis C and HIV.
Ottawa's chief medical officer Dr. Isra Levy announced Saturday that Ottawa Public Health has been investigating an unnamed non-hospital facility for the past several months because of "lapses in infection control" that may have led to some 6,800 people being exposed.


Many Children Suffer From Hepatitis C Without Diagnosis And Treatment
Many Children Suffer From Hepatitis C Without Diagnosis And Treatment. Many children with hepatitis C go undiagnosed and untreated, which can cord to unbending liver impair later in life, a new study warns. Researchers from the University of Miami Miller School of Medicine well-known that national data shows that between 0,2 percent and 0,4 percent continue reading..

A Doctor For Legalization, But Against Medical Marijuana
By Lindsay Beyerstein

Skylandia, a doctor and guest blogger at the feminist Echnide of the Snakes, argues for marijuana legalization and against medical marijuana.

As a physician who practices evidence-based medicine, Skylandia is committed to prescribing based on research, not anecdotes. Yet, she faces a Catch-22: Since marijuana is a Schedule I drug, there there's a dearth of research on its safety and efficacy for most of the conditions that it is recommended for....continue reading..



FDA

By Lori Clapper, Editor
This year, the FDA says it has seen an improved quality of new drug submissions, having approved several scientific breakthroughs, including the first new treatment for Lupus in 50 years, two new therapies for Hepatitis C, and the first drug shown to be an effective treatment for Melanoma.

However, the agency is concerned with the low quantity of submissions. Investors spent nearly $95 billion for R&D in 2010 alone, and this money has not translated into a parallel increase in submissions. In fact, last year the agency received the lowest number of applications for novel drugs in nearly two decades. No single cause can be blamed for this slump in innovation, but the global economy, more complex science and products, and product safety and efficacy are all contributing factors. .. continue reading..

Research



Risk factors associated with symptomatic cholelithiasis in Taiwan: a population-based study
Shih-Chang Hung , Kuan-Fu Liao , Shih-Wei Lai , Chia-Ing Li and Wen-Chi Chen
BMC Gastroenterology 2011, 11:111doi:10.1186/1471-230X-11-111
Published:
17 October 2011

The risk factors for Gallstones were obesity, hyperlipidemia, hepatitis B infection, hepatitis C infection, and cirrhosis in both genders, and menopause in females.

Full Text Available Here

Abstract (provisional)
Background
Cholelithiasis has become a major health problem in Taiwan. The predominant type of gallstone found in Asian populations differs from that in the West, indicating possible differences in the etiology and risk factors for cholelithiasis. The aim of this study is to investigate the risk factors for cholelithiasis using data representative of the general population.

Methods
We performed a population-based, case-control study in which we analyzed medical data for 3725 patients newly diagnosed with cholelithiasis and 11175 gender- and age-matched controls with no history of cholelithiasis, using information obtained from the 2005 Registry for Beneficiaries of the National Health Insurance Research Database. Coexisting medical conditions were included in the analysis. Relative risks were estimated by adjusted odds ratio (OR) and 95% confidence interval (CI) using a multivariate logistic regression analysis.

Results
After controlling for the other covariates, multivariate logistic regression analysis identified the following as risk factors for cholelithiasis (in descending order of contribution): Among all patients - hepatitis C (OR=2.78), cirrhosis (OR=2.47), hepatitis B (OR=2.00), obesity (OR=1.89), and hyperlipidemia (OR=1.54); Among women - hepatitis C (OR=3.05), cirrhosis (OR=1.92), obesity (OR=1.91), menopause (OR=1.61), hepatitis B (OR=1.54), and hyperlipidemia (OR=1.49). Diabetes mellitus appeared to have a marked influence on the development of cholelithiasis but was not identified as a significant independent risk factor for cholelithiasis.

Conclusions
The risk factors for cholelithiasis were obesity, hyperlipidemia, hepatitis B infection, hepatitis C infection, and cirrhosis in both genders, and menopause in females. Despite differences in the predominate type of gallstone in Asian versus Western populations, we identified no unique risk factors among the population of Taiwan.
The complete article is available as a provisional PDF.


Journal of Hepatology

Volume 55, Issue 5 , Pages 957-959, November 2011

Targeting STAT3 in hepatocellular carcinoma: Sorafenib again…
  • Olivier Rosmorduc
  • Affiliations
    • Department of Hepatology, Hôpital Saint-Antoine, Paris, France
    • UPMC Univ Paris 06, F-75005 Paris, France
    • Centre de Recherche Saint-Antoine, INSERM UMR_S 938, F-75012 Paris, France
    • Corresponding Author InformationCorresponding author. Address: Department of Hepatology and INSERM UMR_S938, Hôpital Saint-Antoine, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, 184 rue du Faubourg St-Antoine, 75012 Paris, France. Tel.: +33 1 49282382; fax: +33 1 49282107.
  • Christèle Desbois-Mouthon
  • Affiliations
    • UPMC Univ Paris 06, F-75005 Paris, France
    • Centre de Recherche Saint-Antoine, INSERM UMR_S 938, F-75012 Paris, France

published online 28 June 2011.

See Article, pages 1041–1048

Article Outline
Sorafenib is the first drug of proved clinical efficacy on hepatocellular carcinoma (HCC) as it provides a modest but significant increase in survival rate in patients with advanced HCC [1]. Initially developed as a Raf-1 kinase inhibitor, sorafenib also targets other Raf kinase isoforms (wild-type B-Raf and oncogenic B-Raf V600) and receptor tyrosine kinases such as vascular endothelial growth factor receptors (VEGFR-2 and -3), platelet-derived growth factor-β (PDGFR-β), Flt-3, and c-Kit. More recently, the BCR/ABL kinase has been also identified as a sorafenib target [2]. The broad spectrum of actions of sorafenib against kinases involved in neovascularisation and tumor progression is supposed to contribute to its potent activity towards tumor angiogenesis and tumor growth in a variety of tumors including HCC [3]. Accordingly, in vitro and in vivo studies have shown that sorafenib promotes antiproliferative and proapoptotic effects in tumor cells as well as in endothelial cells. However, it appears that the molecular mechanisms underlying the direct effects of sorafenib in these cells are not completely understood and they probably involve additional pathways.

Consistent with its inhibitory activity towards Raf kinases, sorafenib impairs the ERK signaling pathway in diverse tumor cell types and this effect has been linked to the antiproliferative action of sorafenib. However, there are also substantial data showing that sorafenib antiproliferative activity does not fully correlate with the inhibition of ERK phosphorylation and with the downregulation of cyclin D1. This discrepancy was observed in different tumor cell types including HCC cells [4], [5], [6]. Regarding apoptosis, sorafenib treatment is frequently associated with the downregulation of the anti-apoptotic Bcl-2 family member Mcl-1 and survivin. Several studies have shown that Mcl-1 and survivin downregulation occurs through a MEK/ERK-independent mechanism [7], [8], [9]. As compelling data continue to accumulate, it now appears that STAT3 inhibition may be responsible for the ERK-independent effects of sorafenib.

STAT3 (for Signal Transducer and Activator of Transcription 3) represents a key transducer in signaling pathways involved in the injury-inflammation-regeneration response associated with chronic liver diseases and human HCC development [10]. STAT3 is inactive in non-stimulated cells but is rapidly activated by various cytokines and growth factors such as interleukin-6 (IL-6), epidermal growth factor (EGF) family members or hepatocyte growth factor and acts as a nuclear transcription factor. STAT3 activation requires Tyr705 phosphorylation by different kinases such as Janus kinases, Src, EGFR, or MEK kinase 1, which results in STAT3 dimerization, nuclear translocation, DNA binding, and gene transcription. STAT3-stimulated genes promote angiogenesis, proliferation, and survival and include genes coding for cyclin D1, Mcl-1 and survivin. STAT3 activation also turns on strong negative feedback loops involving tyrosine phosphatases (SHP1 and SHP2) and suppressors of cytokine signaling (SOCS). By reducing the levels of phospho-STAT3, phosphatases block STAT3 dimerization and transcriptional activity, thus insuring that STAT3 activation is a transient event in normal cells.

STAT3 is constitutively activated (i.e. phosphorylated) in most cancers, including 60% of HCC as a result of inflammation, oxidative stress, growth factor stimulation, epigenetic silencing of SOCS, and low expression levels of phosphatases [10]. IL-6 and STAT3 are required for tumorigenesis in the mouse liver. IL-6- or STAT3-deficient mice exhibit a marked reduction of diethylnitrosamine (DEN)-induced liver carcinogenesis in comparison to wild-type mice [11], [12]. SHP2 ablation enhances DEN-induced HCC development which is abolished by concurrent deletion of SHP2 and STAT3 in hepatocytes [13].

It has been recently observed that sorafenib inhibits Tyr705 STAT3 phosphorylation in a variety of tumor cells including medulloblastoma [5], cholangiocarcinoma [14], and HCC [15]. The inhibition of STAT3 signaling and the subsequent downregulation of Mcl-1 play a prominent role in sorafenib-induction of apoptosis in these cells. The mechanism whereby sorafenib prevents STAT3 activation has been addressed by Gores’s laboratory in cholangiocarcinoma cells [14]. Their study showed that sorafenib promotes Tyr705 STAT3 dephosphorylation by stimulating phosphatase SHP2 activity since the knockdown of SHP2 using siRNA technology abrogated sorafenib-stimulated Tyr705 STAT3 dephosphorylation. As the Raf kinase inhibitor ZM336372 also resulted in Tyr705 STAT3 dephosphorylation, this result led the authors to conclude that sorafenib promotes Tyr705 STAT3 dephosphorylation by inhibiting Raf-1 kinase activity in cholangiocarcinoma.

In the present issue of the Journal of Hepatology [16], the study by Tai and colleagues provides new insights regarding the mechanism whereby sorafenib affects STAT3 activity in HCC cells. The authors have developed a series of sorafenib analogs whose characteristics are reported elsewhere [17]. Among them, SC-1 is a sorafenib derivative lacking inhibitory activity towards Raf-1 and VEGFR-2 kinases. Interestingly, SC-1 was as potent as sorafenib in the inhibition of cell viability and the induction of apoptosis in vitro in human HCC cell lines and endothelial cells. Antiproliferative and proapoptotic effects of SC-1 and sorafenib were both associated with a marked decrease of STAT3 phosphorylation and transcriptional activity and the downregulation of Mcl-1, cyclin D1, and survivin. The antitumoral effect of SC-1 was confirmed in vivo by using a subcutaneous xenograft model of HCC into nude mice and was comparable to that obtained with sorafenib. Based on these results, these authors propose that sorafenib mediates cell growth arrest and apoptosis through a Raf-1- and VEGFR2-independent mechanism in HCC and endothelial cells and that STAT3 dephosphorylation is a major signaling event involved in these effects. Further support for this contention was obtained with experiments showing that Raf-1 silencing with small interference RNA had no impact on SC-1 and sorafenib repression of Tyr705 STAT3 phosphorylation. Rather, the authors report that SC-1 and sorafenib potently stimulated in vitro and in vivo the activity of the phosphatase SHP1, probably through direct binding to the phosphatase. SHP1 activation was required for SC-1 and sorafenib induction of apoptosis and STAT3 dephosphorylation.

This study therefore highlights the major contribution of STAT3 in sorafenib-mediated antitumoral effects on HCC cells and demonstrates that Raf-1 and VEGFR2, the main classical targets of this drug, seem paradoxically to play a negligible role (Fig. 1). In addition, this study reinforces the necessity of testing inactive analogs -when available- to precise the main (and true) molecular mechanisms of antitumoral activity of new pharmacological compounds (as another example, LY303511, the “inactive analog” of the widely used phosphatidylinositide-3-kinase inhibitor LY294002, presents an antitumoral activity by itself [18]). This paper raises also important questions. It is still unclear whether SC-1 has no kinase inhibition activity or if it still maintains some inhibitory effects on other sorafenib targets such as Raf isoforms and PDGFR-β. The present study was largely conducted in vitro and the subcutaneous xenograft model has some limitations regarding the contribution of the immune system and the tumor microenvironment to HCC development. It is not excluded that SC-1 and sorafenib may present some different effects in vivo, in particular on tumor angiogenesis.

  • View full-size image.
  • Fig. 1.

    Role of STAT3 inibition in sorafenib-mediated antitumoral effects. In cancer cells, STAT3 can be activated by overactive receptor (such as IL-6R and EGFR) and constitutively active non-receptor tyrosine kinases (such as Src and ABL). After tyrosine phosphorylation on residue 705, STAT3 molecules dimerize and translocate to the nucleus, where they directly regulate the expression of genes involved in proliferation, survival, and angiogenesis. In HCC and endothelial cells, sorafenib is a very potent inhibitor of STAT3 phosphorylation which plays a major role in sorafenib-mediated antitumoral effects. This effect involves the direct activation of the tyrosine phosphatase SHP1 and is independent of Raf-1 and VEGF-R2 inhibition since it is mimicked by SC-1, a sorafenib analog devoided of inhibitory activity towards these two kinases.

This paper clearly reinforces the interest of STAT3 as a new potential therapeutic approach for HCC. Indeed, studies using STAT3 inhibitors show that STAT3 is not required for the survival of differentiated cells and may be therefore targeted in human cancers. Different STAT3 inhibitors have been designated to directly target STAT3 mainly by inhibiting its dimerization, DNA binding, or nuclear entry [19], [20]. However, of these inhibitors, a few show good activity in terms of inhibition of STAT3 biological functions and associated antitumor effects in murine models. The need remains therefore high for suitable and effective STAT3 inhibitors for clinical application in cancer. The ultimate and obvious question is how well (and how long) patients will respond to specific STAT3 inhibitors.

Conflict of interest

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

References


Largest Ever Genetic Study of Liver Function Could Point the Way to New Treatments
ScienceDaily (Oct. 16, 2011) — Researchers have identified a large number of areas in the human genetic code that are involved in regulating the way in which the liver functions, in a new study of over 61,000 people, published October 14 in the journal Nature Genetics.The work is an international collaboration led by Imperial College London and it identifies 42 genetic regions associated with liver function, 32 of which had not been linked to liver function before. The work should lead to a better understanding of precisely what goes wrong when the liver ceases to work normally. Ultimately, it could point the way to new treatments that can improve the function of the liver and help to prevent liver damage.

The liver is the body's largest internal organ and the British Liver Trust estimates that around two million people in the UK have a liver problem at any one time. The liver carries out hundreds of different tasks, including making proteins and blood clotting factors, and helping with digestion and energy release. It also purifies the blood of bacteria, and of the by-products of digestion, alcohol and drugs.

In the new genome-wide association study, the researchers compared the genetic makeup of over 61,000 people, in order to identify areas of the genetic code that were associated with liver function.

The team assessed the function of the volunteers' livers by looking at the concentrations of liver enzymes in their blood. People who have liver damage have high concentrations of these enzymes, which are associated with an increased risk of conditions such as cirrhosis, type 2 diabetes and cardiovascular disease.

Dr John Chambers, the lead author of the study from the School of Public Health at Imperial College London, said: "The liver is a central hub in the body and because it has so many diverse functions, it is linked to a large number of conditions. Our new study is a big step towards understanding the role that different genes play in keeping the liver working normally, and towards identifying targets for drugs that can help prevent the liver from functioning abnormally or becoming susceptible to disease."

The researchers identified 42 areas on the genetic code associated with liver function and they then went on to pinpoint 69 associated genes within these areas. Some of the genes are known to play a part in other functions in the body, including inflammation and immunity, and metabolising glucose and carbohydrates.

Professor Jaspal S Kooner, the senior author of the study from the National Heart and Lung Institute at Imperial College London, said: "This massive international research effort provides in-depth new knowledge about the genes regulating the liver. We are particularly excited about the genes whose precise role we don't yet know. Investigating these further should help us to fill in the gaps in our understanding about what happens when the liver ceases to function normally and how we might be able to tackle this."

Professor Paul Elliott, also a senior author of the study, from the School of Public Health at Imperial College London, said: "Liver problems affect a huge number of people and they can have a devastating effect on a person's quality of life. This study represents a vast discovery that opens up multiple new avenues for research."

The research was funded by the Imperial Comprehensive Biomedical Research Centre award from the National Institute for Health Research; the Medical Research Council; the Wellcome Trust; and other sources.


Measurement of health-related quality of life in patients with cirrhosis
The latest issue of the Alimentary Pharmacology & Therapeutics investigates computerised adaptive tests to measure health-related quality of life in patients with cirrhosis.
Cirrhotic patients have an impaired health-related quality of life, which is usually analysed using static paper-pencil questionnaires.

The Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive testing (CAT) are flexible, freely available, noncopyrighted, health-related quality of life instruments with US-based norms across 11 domains.
CAT presents 5 to 7 questions/domain depending on the patient’s response, from large validated question banks.

This provides brevity and precision equivalent to the entire question bank.
Dr Bajaj and colleagues from Virginia, USA evaluated PROMIS CAT tools against ‘legacy instruments’ for cirrhotics and their informal caregivers.

The team evaluated a total of 200 subjects, of which 100 cirrhotics and 100 caregivers were administered the PROMIS and legacy instruments [Sickness Impact Profile (SIP), Beck depression/anxiety inventories, Pittsburgh Sleep-Quality Index (PSQI) and Epworth Sleepiness scale (ESS)] concurrently.

Both legacy and PROMIS results for patients were compared with caregivers and US norms.
The research team also compared compensated and decompensated patients.
Preference for SIP or PROMIS was inquired of a selected group.
Test – retest reliability was assessed in another group of 20 patients.
The team found that patients had significant impairment on all PROMIS domains apart from anger and anxiety compared with caregivers and US norms.

Decompensated patients had significantly worse sleep, pain, social and physical function scores compared with compensated ones, similar to legacy instruments.

The research team observed a statistically significant correlation between PROMIS and their corresponding legacy instruments.

The team found that 71% preferred PROMIS over SIP.
PROMIS tools had significant test – retest reliability when administered 12 days apart.
Dr Bajaj's team commented, "PROMIS computerised adaptive testing tools had significant concurrent and discriminant validity, test – retest reliability and subject preference for assessing health-related quality of life in cirrhotic patients."
Aliment Pharmacol Ther 2011: 34(9): 1123–1132
17 October 2011


Healthy You

Many Pills, Many Not Taken
(The Wall Street Journal, New York)
"When it comes to medicine, as many as half of Americans don't stick to their regimens. They fail to fill about 20% to 30% of prescriptions written by doctors, don't take drugs as directed, and don't refill medications when they run out. Now, health-care providers have new strategies to increase medication adherence, as concerns rise about health risks and the high costs of treating noncompliant patients who have chronic illnesses. Prescriptions that don't get picked up or refilled can be tracked using electronic medical records and prescribing technology. Clinical pharmacy specialists, case managers and other team members follow up with reminders, phone calls and counseling to get patients back on the wagon."