- Email: [email protected]
New hope reported for badly damaged eyes
“Rational” molecules enter early cancer trials
R
ationally designed molecules, developed by scientists doing basic molecular oncology research, are starting to enter phase 1 clinical trials. A recurring theme at the 11th Pezcoller Symposium (Rovereto, Italy; June 5–7) was that basic scientists and clinical investigators need to understand and learn from each other’s perspective, especially in the early phases of drug development. To acheive this, Enrico Mihich (Roswell Park Cancer Institute, Buffalo, NY, USA) would like to see more cancer-research centres where scientists mix with clinical researchers. Industry also appreciates the need for good communication, and at Novartis, which is active in molecular oncology, the solution is to have mulitdisciplinary teams, said Alex
Matter (Basel, Switzerland). The treatment of chronic myelogenous leukaemia (CML) is one instance where a molecule rationally designed in the laboratory is entering clinical trials. In CML, a balanced translocation in the long arms of chromosomes 9 and 22 results in the fusion protein BCRABL, a constitutively active tyrosine kinase. STI571 (developed by Novartis and previously called CGP57148) was synthesised from knowledge of the ATP-binding site of protein kinases and is a specific, potent, orally bioavailable inhibitor of the ABL and BCR-ABL tyrosine kinases. Nick Lydon (Kinetix, Medford, MA, USA) described a phase 1 trial of STI571 in patients with CML who were in the chronic phase of their illness and refractory
New hope reported for badly damaged eyes
J
apanese clinicians reported last week that transplantation of corneal epithelial stem cells can restore useful vision in some patients for whom standard corneal transplantation is not an option. Stratified corneal epithelium provides a smooth ocular surface. The most superficial cells of this surface are regularly replaced by cells derived from stem cells in the limbal area of the peripheral cornea. Standard corneal transplantation is an established treatment for some types of eye damage but cannot help if the stem cells have been destroyed —eg, in StevensJohnson syndrome, ocular pemphigoid, or after chemical and thermal injuries. In these cases, stem-cell depletion causes scarring, an opaque cornea, and functional blindness. Kazuo Tsubota (Keio University School of Medicine, Tokyo, Japan) and colleagues assessed the value of corneal epithelial stem-cell transplantation in 43 eyes of 39 patients with severe bilateral ocular-surface disorders and limbal dysfunction. Stem cells were obtained from cadavers. Before surgery, the patients had a mean visual acuity of 0·004—ie, vision limited to being able count the number of fingers held up by an
THE LANCET • Vol 353 • June 12, 1999
examiner. An average of 1163 days after transplantation, there was corneal epithelialisation in 22 of the eyes. In seven there was corneal stromal oedema but 15 had clear corneas. Mean visual acuity had improved to 0·02—ie, enough sight for navigation. Patients with clear corneas attained a visual acuity of 0·11. Where successful, treatment seemed to be long lasting. For example, 4 years after surgery, a 56-yearold woman with ocular pemphigoid still had a clear cornea and improved vision (N Engl J Med 1999; 340: 1697–703) This is not a new technique, says Steve Tuft (Moorfields Eye Hospital, London, UK), but the study is welcome because of its large number of patients. “Not many patients can benefit from corneal stem-cell transplants, so there is not a great deal of data to show just how effective it is”, says Tuft. But although the technique did increase sight in many of the patients, the immuosuppression needed after surgery could cause problems. Where only one eye is affected by trauma, “autografts will be the way forward”, adds Tufts, whose group is testing this approach.
to interferon treatment. At daily doses of 140–300 mg, 24 of 25 patients had a haematological response, which was complete in 11. Another approach moving from the laboratory to the clinic is that of dendritic-cell therapy. In vitro, dendritic cells loaded with tumour RNA can induce cytotoxic T lymphocytes that lyse the patient’s tumour cells. Eli Gilboa (Duke University Medical Center, Durham, NC, USA) has used microdissection of frozen tumour tissue followed by PCR to amplify tumour-specific mRNAs, which have been transfected into dendritic cells. Phase 1 studies have now started in patients with various solid tumours. David McNamee
News in brief Food-poisoning block Scientists from University College Cork, Ireland, speaking at the National Dairy Conference (Cork; June 3) announced that they have found a natural inhibitor effective against a range of food-poisoning bacteria. Lacticin 3147, discovered during research into the cheese-making process, can kill pathogens such as listeria in a range of dairy products. Coffee and gallstones Drinking coffee may decrease the risk of gallstone disease. An analysis of data collected on 46 000 men as part of the Health Professionals Follow-up Study indicates that after adjusting for other risk factors, men who drank 2–3 cups of regular coffee a day had a relative risk of developing gallstone disease of 0·60 (95% CI 0·42–0·92) compared with men who did not drink coffee. Drinking decaffeinated coffee did not reduce risk (JAMA 1999; 281: 2106–12). Subsyndromal depression 9·9% of people aged 60 years or older had subsyndromal depression in a new US study (J Am Geriatr Soc 1999; 47: 647–52). The authors write that “clinicians must remain mindful of so-called lesser mood conditions . . . recognizing both their substantial clinical impact and the dearth of empirical support for any specific treatment strategies”.
Kathryn Senior
2045
R
ationally designed molecules, developed by scientists doing basic molecular oncology research, are starting to enter phase 1 clinical trials. A recurring theme at the 11th Pezcoller Symposium (Rovereto, Italy; June 5–7) was that basic scientists and clinical investigators need to understand and learn from each other’s perspective, especially in the early phases of drug development. To acheive this, Enrico Mihich (Roswell Park Cancer Institute, Buffalo, NY, USA) would like to see more cancer-research centres where scientists mix with clinical researchers. Industry also appreciates the need for good communication, and at Novartis, which is active in molecular oncology, the solution is to have mulitdisciplinary teams, said Alex
Matter (Basel, Switzerland). The treatment of chronic myelogenous leukaemia (CML) is one instance where a molecule rationally designed in the laboratory is entering clinical trials. In CML, a balanced translocation in the long arms of chromosomes 9 and 22 results in the fusion protein BCRABL, a constitutively active tyrosine kinase. STI571 (developed by Novartis and previously called CGP57148) was synthesised from knowledge of the ATP-binding site of protein kinases and is a specific, potent, orally bioavailable inhibitor of the ABL and BCR-ABL tyrosine kinases. Nick Lydon (Kinetix, Medford, MA, USA) described a phase 1 trial of STI571 in patients with CML who were in the chronic phase of their illness and refractory
New hope reported for badly damaged eyes
J
apanese clinicians reported last week that transplantation of corneal epithelial stem cells can restore useful vision in some patients for whom standard corneal transplantation is not an option. Stratified corneal epithelium provides a smooth ocular surface. The most superficial cells of this surface are regularly replaced by cells derived from stem cells in the limbal area of the peripheral cornea. Standard corneal transplantation is an established treatment for some types of eye damage but cannot help if the stem cells have been destroyed —eg, in StevensJohnson syndrome, ocular pemphigoid, or after chemical and thermal injuries. In these cases, stem-cell depletion causes scarring, an opaque cornea, and functional blindness. Kazuo Tsubota (Keio University School of Medicine, Tokyo, Japan) and colleagues assessed the value of corneal epithelial stem-cell transplantation in 43 eyes of 39 patients with severe bilateral ocular-surface disorders and limbal dysfunction. Stem cells were obtained from cadavers. Before surgery, the patients had a mean visual acuity of 0·004—ie, vision limited to being able count the number of fingers held up by an
THE LANCET • Vol 353 • June 12, 1999
examiner. An average of 1163 days after transplantation, there was corneal epithelialisation in 22 of the eyes. In seven there was corneal stromal oedema but 15 had clear corneas. Mean visual acuity had improved to 0·02—ie, enough sight for navigation. Patients with clear corneas attained a visual acuity of 0·11. Where successful, treatment seemed to be long lasting. For example, 4 years after surgery, a 56-yearold woman with ocular pemphigoid still had a clear cornea and improved vision (N Engl J Med 1999; 340: 1697–703) This is not a new technique, says Steve Tuft (Moorfields Eye Hospital, London, UK), but the study is welcome because of its large number of patients. “Not many patients can benefit from corneal stem-cell transplants, so there is not a great deal of data to show just how effective it is”, says Tuft. But although the technique did increase sight in many of the patients, the immuosuppression needed after surgery could cause problems. Where only one eye is affected by trauma, “autografts will be the way forward”, adds Tufts, whose group is testing this approach.
to interferon treatment. At daily doses of 140–300 mg, 24 of 25 patients had a haematological response, which was complete in 11. Another approach moving from the laboratory to the clinic is that of dendritic-cell therapy. In vitro, dendritic cells loaded with tumour RNA can induce cytotoxic T lymphocytes that lyse the patient’s tumour cells. Eli Gilboa (Duke University Medical Center, Durham, NC, USA) has used microdissection of frozen tumour tissue followed by PCR to amplify tumour-specific mRNAs, which have been transfected into dendritic cells. Phase 1 studies have now started in patients with various solid tumours. David McNamee
News in brief Food-poisoning block Scientists from University College Cork, Ireland, speaking at the National Dairy Conference (Cork; June 3) announced that they have found a natural inhibitor effective against a range of food-poisoning bacteria. Lacticin 3147, discovered during research into the cheese-making process, can kill pathogens such as listeria in a range of dairy products. Coffee and gallstones Drinking coffee may decrease the risk of gallstone disease. An analysis of data collected on 46 000 men as part of the Health Professionals Follow-up Study indicates that after adjusting for other risk factors, men who drank 2–3 cups of regular coffee a day had a relative risk of developing gallstone disease of 0·60 (95% CI 0·42–0·92) compared with men who did not drink coffee. Drinking decaffeinated coffee did not reduce risk (JAMA 1999; 281: 2106–12). Subsyndromal depression 9·9% of people aged 60 years or older had subsyndromal depression in a new US study (J Am Geriatr Soc 1999; 47: 647–52). The authors write that “clinicians must remain mindful of so-called lesser mood conditions . . . recognizing both their substantial clinical impact and the dearth of empirical support for any specific treatment strategies”.
Kathryn Senior
2045