Influence of Interferon Gamma +874 T>A (rs2430561) Polymorphism on Renal Allograft Rejection: A Meta-analysis

BackgroundReported associations of the interferon gamma (IFNG) +874T/A (rs2430561) polymorphism with post-kidney transplantation allograft rejection (AR) have been inconsistent, prompting a meta-analysis to obtain more precise estimates.MethodsEighteen articles (22 studies) were included in the meta-analysis. Operating on the hypothesis that IFNG rs2430561 either increases or reduces AR risk, we used a genetic model-free approach to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Subgrouping was based on ethnicity (white, Middle Eastern, black, and mixed) and rejection type (ACR: acute rejection and CHR: chronic rejection). Quality of the associative effects was assessed with sensitivity treatment and test for publication bias.ResultsThe overall analysis in the dominant model indicated increased risk (OR = 1.26; P^a = .02) was validated in the ACR subgroup (OR = 1.29; P^a = .01), which contrasted with the CHR subgroup, with a nonsignificant effect indicating reduced risk (OR = 0.83; P^a = .68). Only the black subgroup showed significant increased risk (OR = 2.87; P^a = .04), but the association was tenuous on account of low sample size (n = 2) and imprecise effect (95% CI, 1.07-7.73).ConclusionsIncreased risk associations (overall and ACR) of IFNG rs2430561 with AR is significant, robust, statistically powered, and lacking bias. Contrasting ACR (1.3-fold increased risk) and CHR (7% protective) effects may be clinically relevant in the genetics of renal transplantation.     

Opinion and Evidence in Respiratory Medicine

Respiratory Medicine is a vast and evolving area for researchers, primary care physicians and specialists. To help keep you up-to-date with the latest advances worldwide on all aspects of drug therapy and management of respiratory disorders, this section of the journal brings you information selected from the drug therapy reporting service Inpharma Weekly ¹. The following reports are selected from the latest issues, summarizing the most important research and development news, clinical studies, treatment guidelines, pharmacoeconomic and adverse reaction news, and expert opinion pieces published across a broad range of literature sources.     

Posterior fossa hemorrhage in the newborn — diagnosis and management

Two cases of posterior fossa hemorrhage in full-term newborns are presented. Because of possible sonographic misinterpretations computer tomographic (CT) scans are advocated for a reliable diagnosis. Regarding the management of the primary hemorrhage as well as the posthemorrhagic hydrocephalus a conservative approach is recommended.     

Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease

The cell cycle inhibitor p16(INK4A) (also known as cyclin-dependent kinase inhibitor 2A) is expressed in vivo in many tissues with age. The exposure of certain chronic stresses can trigger p16(INK4A) expression and a senescence-like phenotype. We studied whether p16(INK4A) expression is induced in glomerular disease (GD). We performed p16(INK4A) immunostaining on 35 biopsies with GD, 12 tubulointerstitial nephritis (TIN), and 19 normal live donor kidneys at transplantation. Based on values for 42 normal kidneys, we calculated expected nuclear p16(INK4A) expression for age and compared the observed values in diseased kidneys to those expected for age. In GD, p16(INK4A) expression was strikingly increased in glomerular and interstitial cell nuclei compared to normals and TIN, and could not be attributed to age (P<0.05). By multivariate analyses, GD was independently associated with increased nuclear p16(INK4a) expression in glomeruli (P<0.001) and interstitium (P=0.01). The p16(INK4A) expression in glomerular and interstitial cell nuclei, and tubular cytoplasm was higher in kidneys with proteinuria and with atrophy/fibrosis (P<0.05). Older age was associated with increased nuclear p16(INK4a) expression in tubules (P=0.01), and interstitial inflammation was associated with increased nuclear p16(INK4a) expression in interstitial cells (P=0.001). The p16(INK4a) staining in tubular cytoplasm was increased in both GD and TIN compared to normals (P<0.001), and was not related to age (P>0.05). Thus, kidneys with GD display increased expression of senescence marker p16(INK4A) in glomerular and interstitial cell nuclei compared to kidneys with normal aging or TIN. The findings suggest a role for somatic cell senescence mechanisms in progression of GD.     

Posaconazole: SCH 56592

Posaconazole [SCH 56592, SPRIAFIL, Noxafil] is an orally active triazole derivative that is in phase III trials with the Schering-Plough Research Institute (SPRI) in the US for the treatment of serious opportunistic fungal infections, including aspergillosis, candidiasis, coccidioidomycosis and fusariosis. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. Preclinical studies have also been conducted in Italy for the potential treatment of Cryptococcus neoformans infection (cryptococcosis).     

Opinion and Evidence in Respiratory Medicine

Respiratory Medicine is a vast and evolving area for researchers, primary care physicians and specialists. To help keep you up-to-date with the latest advances worldwide on all aspects of drug therapy and management of respiratory disorders, this section of the journal brings you information selected from the drug therapy reporting service Inpharma Weekly ¹. The following reports are selected from the latest issues, summarizing the most important research and development news, clinical studies, treatment guidelines, pharmacoeconomic and adverse reaction news, and expert opinion pieces published across a broad range of literature sources.     

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of >$US1 billion. Other analysts, at Merrill Lynch & Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.     

Cancer vaccine THERATOPE- Biomira

Biomira is developing a therapeutic cancer vaccine [THERATOPE] for treatment of breast and other cancers. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. THERATOPE consists of the mucin antigen, sialyl-Tn (STn), a carbohydrate located on the surface of breast, colorectal and ovarian cancer cells, conjugated to keyhole limpet haemocyanin (KLH). Merck KGaA has acquired a worldwide licence to THERATOPE for treatment of breast cancer. Under the terms of the licence, Biomira and Merck KGaA, via its US affiliate, EMD Pharmaceuticals, will jointly market the vaccine in the US. Merck KGaA holds exclusive marketing rights for the rest of the world, except in Canada (where Biomira retains rights), Israel and the Palestine Autonomy Area. Merck KGaA is now collaborating on phase III development for breast cancer. Biomira stands to receive $US150 million in licence, milestone payments and equity investments. The development costs will be shared between the two companies in North America but Merck KGaA will be solely responsible for these costs in countries outside the US. Previously, Chiron Corporation had purchased a licence to THERATOPE in 1997; however, Chiron terminated this agreement in June 2000. Under the terms of the termination, Biomira paid Chiron $US2.25 million to compensate the company for its investment in the development of THERATOPE. In addition, Biomira will make another payment of $US3.25 million to Chiron upon FDA approval of the vaccine. No further payments or royalties will be made. In the third quarter of 2002, an independent review of interim data from the trial was conducted. This was the fifth scheduled review of the data by the Independent Data Safety Monitoring Board (DSMB), all of which produced a positive response. Following the completion of the review, the DSMB stated that the trial should continue and that it had no safety concerns regarding this trial. Although the data, to which Biomira and Merck KgaA are blinded, did not meet the predetermined statistical significance for either endpoint at the time of the review, both companies have chosen to continue with the trial. Biomira has since announced that the p-value for the interim survival analysis was set at 0.01, while it is set at 0.03 for final survival analysis. The tighter criteria was set for the interim analysis to potentially give the companies the opportunity of applying for marketing approval earlier than expected. Final analysis of the trial will take place in mid-2003. If these analyses indicate therapeutic efficacy, Biomira will meet the FDA and Canadian regulatory officials to obtain marketing approval for the vaccine for breast cancer under the accelerated review guidelines. Assuming a best-case scenario, the vaccine could be filed for approval in 2004. The phase III trial was initiated following positive preliminary results achieved in a bridging study in patients with metastatic breast cancer in the US and UK. Biomira announced final results of the bridging study in May 1999. The results confirmed that antibody titres against the STn antigen were significantly higher in patients treated with the improved formulation of THERATOPE, compared with the corresponding titres of patients in the phase II trials of the old formulation of THERATOPE. In September 2002, the first patient was enrolled in a phase II THERATOPE trial, which is enrolling patients with metastatic breast cancer who are taking either an aromatase inhibitor or fulvestrant. Approximately 95 patients will be enrolled in the trial at up to 12 US sites. The study is primarily designed to evaluate THERATOPE's ability to induce an immune response in these patients. However, the safety and tolerability of the aromatase inhibitor plus THERATOPE, and the fulvestrant plus THERATOPE combinations will also be evaluated. The trial has not been designed to evaluate the efficacy of the two combinations. The US FDA has granted fast-track status tranted fast-track status to THERATOPE for development as an adjunct to first-line combination chemotherapy in responding patients with metastatic breast cancer. A phase II trial in patients with metastatic colorectal cancer has been completed in the US; positive preliminary results from this trial were released in May 2001. On 24 November 1999, Biomira announced that it had licensed two patents covering methods of preventing growth of cancer cells expressing a mucin-type glycoprotein. The patents have been issued in the US and are pending in Japan and Canada. When issued in Japan, the patents will provide additional protection for THERATOPE in that country. The patents were licensed from Dr Sen-itiroh Hakomori of the Biomembrane Institute in Seattle, with whom Biomira has also entered into a research collaboration. Biomira announced in April 2003 that following examination of its re-issue application by the US Patent and Trademark Office, its patent 5798090 was re-issued (RE 38046) with additional claims. These additional claims represent broader patent coverage. The additional coverage will last until 2015. Earlier, in February 2000, Biomira announced an expansion of equity line for up to $US100 million; a 3-fold rise that was done without any additional shares of Biomira stock being issued. In June 2002, Biomira stated that it believes the market size for THERATOPE in the US, Europe and Japan to be approximately 184000 patients for the indication of metastatic breast cancer, of which the US would be 100000, Europe 75000 and Japan 9000. For the indication of colorectal cancer, the total market population for THERATOPE is expected to be 183000 patients, of which the US has been estimated at 100000, Europe 75000 and Japan 9000.