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Breast tumor recurrence after lumpectomy
127
otes
Anthracyclines and myocardial impairment in chiidren The anthracyclines, especially doxorubicin, are among the most useful anti-cancer agents used in the treatmeut of childhood and adult malignancies. Unfortunately, cardiomyopathy is a serious dose-limiting side effect. Cardiac failure is observed in approximately 30% of patients who have received more than 550 mg/m* of doxorubicin. This complication is observed more often in patients who have received smaller doses and in some cases have been off all therapy for months to years. There is a need to detect those patients who are particularly sensitive to this cardiotoxic effect of anthracyclines prior to their development of cardiac failure. A non-invasive exercise method was used to look for impairment of myocardial function in apparently normal children who had received moderate doses of anthracyclines for cancer treatment. Nineteen children who had received anthracyclines (mean total dose 230 mgf m2) and IO who had received other cytotoxic drugs but not anth~cyclines were selected for the study. All children were in remission. They underwent measurement of heart rate, blood pressure and left ventricular dimensions by echoc~diography before and after exercise on a bicycle for a maximum of 10 minutes. All the subjects shnwed normal fractional shortening at rest but the increase in fractional shortening on exercise was significantly lower in the children who had received anthracyclines than in those who had not (3% versus 23% P c 0.05). This difference remained significant after adjustment for age, diagnosis and other drug exposure. Thus, many children who have received anthracyclines may have suffered subclinical myocardial damage and post-exercise echocardiography appears to be a useful non-invasive method for detecting such damage. Long-term cardiological follow-up of patients who have received anthracyclines in even moderate doses is indicated. Chemotherapy protocols should be reviewed to limit anthracycline exposure where this is consistent with a favourable treatment outcome and the role of cardiopratectants such as dexrazoxane (ICRF157) needs to be further explored. PJ Smith (1) University of Queensland Medical School, Brisbane Q 4006, Australia Cyclosporin in severe refractory atopic dermatitis A small number of patients with atopic dermatitis remain severely affected well into adult life and require
treatment with systemic steroids, azathioprine or photochemotherapy. We have conducted the first doubleblind, placebo-con~olled, crossover study to assess the efficacy and safety of cyclosporin in a group of 33 adult patients with severe refractory atopic dermatitis. 5ach patient was randomly allocated to receive either cyclosporin, in a dose of 5 mg/kg/day for 8 weeks followed immediately by placebo for 8 weeks or vice versa. Systemic steroids, cytotoxic drugs or photochemotherapy were stopped two weeks before the study. Patients were assessed every two weeks by rn~su~ng both activity and extent of disease using clinical scoring systems. Patients in both treatment sequences showed a rapid and highly significant improvement in both disease activity and extent of disease scores on cyciosporin. Once cyclosporin was stopped, relapse was rapid but the mean scores were not higher than their respective baseline values. There were 20 reports of adverse events by patients whilst on cyclosporin and 8 whilst on placebo. There main side-effects from cyclosporin were nausea, abdominal discomfort and paraesthesia, but none of these events warranted withdrawal from the study. Although the mean bilirubin level increased significantly by 3.1 pmobl during cyclosporin therapy, this was not thought to be clinically relevant and none of the patients had concomitant or persistent increases in other liver enzymes. None of the patients developed hypertension and although the parameters for assessing renal function tended to worsen during cyclosporin therapy, the changes did not reach clinical or statistical significance. This study confirms the efficacy of cyclosporin therapy in atopic dermatitis and shows that the drug can be safely used as a short-term treatment in patients with severe disease. JM Sowden(2) Queen’s MedicalC~ntn?. UniversityHospital,Nottingham MC7 2UH, UK Breast tumor recurrence after lumpectomy in a study started in 1976, almost 2 000 women were randomly assigned to either total mastectomy, lumPeCfollowed by breast tomy alone, or lumpectomy irradiation. After 9 years of fotlow-up. there was no significant difference in distant disease-free survival (DDFS) or survival (S) among the three gmu-ps despite the fact that 43% of the women treated by 1umpectomY alone and 12% of those who underwent 1umPectomY
_I-
(1) Lurxet (199i) 337, 816
(2) The Lancer (1991) 338, 137
and breast irradiation experienced an ipsilateral breast tumor recurrence (IBTR). This observation provided jnsti~cation for the use oi‘ breast conservation Oumpectomy) in the trea%ment of breast cancer and led to the conclusion that there is no causai relation between an IBTR and distant disease. Despite these findings, many physicians have been hesitant about performing a lumpectomy. They fear that if patients develop an TBTR at some interval of time following lum~tomy, they would be at increased risk for distant me&stases because the unremoved tumor at the time of the primary operation would grow and disseminate cancer cells during the period before recrpnition of the IBTR. The report indiLates that, with the sagnosis of an IBTR after lumpectomy, a patient is indeed at increased risk for distant disease (3.41 times greater) than she was before the IBTR was recognized, akhough this increased risk is not because of dissemirated tumor cells that could have been avoided had a m~tectomy been perFormed. An IBTR is a marker of a risk for distant disease present at the time of primary tumor removal, and that risk woufd have been the same even if radical surgery had been carried out initially. Thus. mastectomy or breast i~di~tio~ after lumpectomy eliminates or reduces the opportunity For identification of a marker of risk for distant disease (an IBTR) but does not reduce the development of distant disease. The relation of an IBTR to distant metastatic disease is analogous to that OF a woman without breast cat:er who learns on a pa~jcuI~ day that her sister has been diagnosed with the disease. On that day, the ‘hormal” sister becomes at greater risk for developing breast cancer thsn she was the day before, even though her increased risk existed prior to her sister’s diagnosis of breast cancer. Thus, although mastectomy or breast irradiation following tumpectomy prevents expression of the marker (IBTR), neither lowers the risk of distant disease. Similarly, even if the sister with breast cancer had been treated with an effective-preventive agent which precluded her ever having developed the disease, her normal sibling would still be at increased risk for breast cancer. The findings further justify lumpectomy and suggest that, because of the greater risk for distant disease, systemic therapy should be considered when an IBTR is diagnosed. B Fisixerf 1f Un~~e~ity~~~ttsbur~h, Pittsburgh,PA 15261,USA Caronnry artery disease: sex differenres
Even though coronary artery disease is the main cause of death among women, previous studies have suggested that physicians are less likely to take an aggressive approach in managing coronary artery disease in women than in men. To further define this issue, phys~~ja~ management practices were analyzed for the 1842 men
and 389 women who were randomized into the postheart attack Survival and Ventricular Enlargement {SAVE: :&I. The patient sample was drawn from 112 participating hospitals in the Ltnited States and Canada, Before their qualifying heart attack, women were as likely as men to have cardiac chest pain and receive drug ~eatment for this pain. However, despite patient complaints cnnsistent with greater functional disability from cardiai: chest pain in women, significantly fewer women had previously undergone diagnostic cardiac catheterizatinil (15.4% of wc,men and 27.‘Y& of men), or coronary bypass surgsry (5.9% of women and 12.7% of men). The lower rate of diagnostic cardiac catheterization in women wes even a contributing factor to the exclusion of otherwise eligible women from enrolement in the SAVE trial. Despite having chest pain following their heart attack, women were stitl half as likely as men to undergo caMtiae catherization, disqualifying them from randomization. We conclude that physicians utilize a less aggressive management approach to coronary disease in women than men, despite greater cardiac disability in women. RM Steingart(2) Winthrop-University Hospital Mineola,LongIsland,New York, NY 11501,USA
Phosphorylatlon of phospholipase-y 1, profilin and tyw sine The bi.rding
of epidermal growth facgor (EGF) to its receptor on the surface of cell membranes triggers a cascade of events inside the cell, leading to cell growth and division. The connections between individual events triggered by EGF are not well uladerstood. One approach to studying these complex events is to break them dawn into the minimal necessary coitection of purified components (such as proteins and lipids) to recreate a regulated signal-response pathway irr vitro. In doing this, we were able to provide a link between 2 major cellular responses to EGF, namely phosphoinositide turnover and cytoskeletal reorganizations We &owed that profilin (a small soluble protein) prevents the hydrolysis of phospha~idyl~nosjtol 4,s bisphosphate (PIP2 a key phospholipid involved in cell signailing~ until phospholipase C-y becomes phosphorylated on ryrosine by the activated ~GF-~ceptor. Profilin interacts with actin an PIP2. It binds to actin monomers and inhibits polymerization but accelerates the exchange of nucleotide {ATP or ADP) on actin monomers. It dissociates from actin when bound to PIP2, and prevents PIPz hydrolysis by unphosphorylated PLC-)? Thus, these two seemingly unrelated events may share a common regulatory protein and thus be intimately connected. Understanding the regulation of normal cellular‘ events helps US to observe an abnormal or transfo~ed \;eff znd ask questions concerning the molecular level based on
otes
Anthracyclines and myocardial impairment in chiidren The anthracyclines, especially doxorubicin, are among the most useful anti-cancer agents used in the treatmeut of childhood and adult malignancies. Unfortunately, cardiomyopathy is a serious dose-limiting side effect. Cardiac failure is observed in approximately 30% of patients who have received more than 550 mg/m* of doxorubicin. This complication is observed more often in patients who have received smaller doses and in some cases have been off all therapy for months to years. There is a need to detect those patients who are particularly sensitive to this cardiotoxic effect of anthracyclines prior to their development of cardiac failure. A non-invasive exercise method was used to look for impairment of myocardial function in apparently normal children who had received moderate doses of anthracyclines for cancer treatment. Nineteen children who had received anthracyclines (mean total dose 230 mgf m2) and IO who had received other cytotoxic drugs but not anth~cyclines were selected for the study. All children were in remission. They underwent measurement of heart rate, blood pressure and left ventricular dimensions by echoc~diography before and after exercise on a bicycle for a maximum of 10 minutes. All the subjects shnwed normal fractional shortening at rest but the increase in fractional shortening on exercise was significantly lower in the children who had received anthracyclines than in those who had not (3% versus 23% P c 0.05). This difference remained significant after adjustment for age, diagnosis and other drug exposure. Thus, many children who have received anthracyclines may have suffered subclinical myocardial damage and post-exercise echocardiography appears to be a useful non-invasive method for detecting such damage. Long-term cardiological follow-up of patients who have received anthracyclines in even moderate doses is indicated. Chemotherapy protocols should be reviewed to limit anthracycline exposure where this is consistent with a favourable treatment outcome and the role of cardiopratectants such as dexrazoxane (ICRF157) needs to be further explored. PJ Smith (1) University of Queensland Medical School, Brisbane Q 4006, Australia Cyclosporin in severe refractory atopic dermatitis A small number of patients with atopic dermatitis remain severely affected well into adult life and require
treatment with systemic steroids, azathioprine or photochemotherapy. We have conducted the first doubleblind, placebo-con~olled, crossover study to assess the efficacy and safety of cyclosporin in a group of 33 adult patients with severe refractory atopic dermatitis. 5ach patient was randomly allocated to receive either cyclosporin, in a dose of 5 mg/kg/day for 8 weeks followed immediately by placebo for 8 weeks or vice versa. Systemic steroids, cytotoxic drugs or photochemotherapy were stopped two weeks before the study. Patients were assessed every two weeks by rn~su~ng both activity and extent of disease using clinical scoring systems. Patients in both treatment sequences showed a rapid and highly significant improvement in both disease activity and extent of disease scores on cyciosporin. Once cyclosporin was stopped, relapse was rapid but the mean scores were not higher than their respective baseline values. There were 20 reports of adverse events by patients whilst on cyclosporin and 8 whilst on placebo. There main side-effects from cyclosporin were nausea, abdominal discomfort and paraesthesia, but none of these events warranted withdrawal from the study. Although the mean bilirubin level increased significantly by 3.1 pmobl during cyclosporin therapy, this was not thought to be clinically relevant and none of the patients had concomitant or persistent increases in other liver enzymes. None of the patients developed hypertension and although the parameters for assessing renal function tended to worsen during cyclosporin therapy, the changes did not reach clinical or statistical significance. This study confirms the efficacy of cyclosporin therapy in atopic dermatitis and shows that the drug can be safely used as a short-term treatment in patients with severe disease. JM Sowden(2) Queen’s MedicalC~ntn?. UniversityHospital,Nottingham MC7 2UH, UK Breast tumor recurrence after lumpectomy in a study started in 1976, almost 2 000 women were randomly assigned to either total mastectomy, lumPeCfollowed by breast tomy alone, or lumpectomy irradiation. After 9 years of fotlow-up. there was no significant difference in distant disease-free survival (DDFS) or survival (S) among the three gmu-ps despite the fact that 43% of the women treated by 1umpectomY alone and 12% of those who underwent 1umPectomY
_I-
(1) Lurxet (199i) 337, 816
(2) The Lancer (1991) 338, 137
and breast irradiation experienced an ipsilateral breast tumor recurrence (IBTR). This observation provided jnsti~cation for the use oi‘ breast conservation Oumpectomy) in the trea%ment of breast cancer and led to the conclusion that there is no causai relation between an IBTR and distant disease. Despite these findings, many physicians have been hesitant about performing a lumpectomy. They fear that if patients develop an TBTR at some interval of time following lum~tomy, they would be at increased risk for distant me&stases because the unremoved tumor at the time of the primary operation would grow and disseminate cancer cells during the period before recrpnition of the IBTR. The report indiLates that, with the sagnosis of an IBTR after lumpectomy, a patient is indeed at increased risk for distant disease (3.41 times greater) than she was before the IBTR was recognized, akhough this increased risk is not because of dissemirated tumor cells that could have been avoided had a m~tectomy been perFormed. An IBTR is a marker of a risk for distant disease present at the time of primary tumor removal, and that risk woufd have been the same even if radical surgery had been carried out initially. Thus. mastectomy or breast i~di~tio~ after lumpectomy eliminates or reduces the opportunity For identification of a marker of risk for distant disease (an IBTR) but does not reduce the development of distant disease. The relation of an IBTR to distant metastatic disease is analogous to that OF a woman without breast cat:er who learns on a pa~jcuI~ day that her sister has been diagnosed with the disease. On that day, the ‘hormal” sister becomes at greater risk for developing breast cancer thsn she was the day before, even though her increased risk existed prior to her sister’s diagnosis of breast cancer. Thus, although mastectomy or breast irradiation following tumpectomy prevents expression of the marker (IBTR), neither lowers the risk of distant disease. Similarly, even if the sister with breast cancer had been treated with an effective-preventive agent which precluded her ever having developed the disease, her normal sibling would still be at increased risk for breast cancer. The findings further justify lumpectomy and suggest that, because of the greater risk for distant disease, systemic therapy should be considered when an IBTR is diagnosed. B Fisixerf 1f Un~~e~ity~~~ttsbur~h, Pittsburgh,PA 15261,USA Caronnry artery disease: sex differenres
Even though coronary artery disease is the main cause of death among women, previous studies have suggested that physicians are less likely to take an aggressive approach in managing coronary artery disease in women than in men. To further define this issue, phys~~ja~ management practices were analyzed for the 1842 men
and 389 women who were randomized into the postheart attack Survival and Ventricular Enlargement {SAVE: :&I. The patient sample was drawn from 112 participating hospitals in the Ltnited States and Canada, Before their qualifying heart attack, women were as likely as men to have cardiac chest pain and receive drug ~eatment for this pain. However, despite patient complaints cnnsistent with greater functional disability from cardiai: chest pain in women, significantly fewer women had previously undergone diagnostic cardiac catheterizatinil (15.4% of wc,men and 27.‘Y& of men), or coronary bypass surgsry (5.9% of women and 12.7% of men). The lower rate of diagnostic cardiac catheterization in women wes even a contributing factor to the exclusion of otherwise eligible women from enrolement in the SAVE trial. Despite having chest pain following their heart attack, women were stitl half as likely as men to undergo caMtiae catherization, disqualifying them from randomization. We conclude that physicians utilize a less aggressive management approach to coronary disease in women than men, despite greater cardiac disability in women. RM Steingart(2) Winthrop-University Hospital Mineola,LongIsland,New York, NY 11501,USA
Phosphorylatlon of phospholipase-y 1, profilin and tyw sine The bi.rding
of epidermal growth facgor (EGF) to its receptor on the surface of cell membranes triggers a cascade of events inside the cell, leading to cell growth and division. The connections between individual events triggered by EGF are not well uladerstood. One approach to studying these complex events is to break them dawn into the minimal necessary coitection of purified components (such as proteins and lipids) to recreate a regulated signal-response pathway irr vitro. In doing this, we were able to provide a link between 2 major cellular responses to EGF, namely phosphoinositide turnover and cytoskeletal reorganizations We &owed that profilin (a small soluble protein) prevents the hydrolysis of phospha~idyl~nosjtol 4,s bisphosphate (PIP2 a key phospholipid involved in cell signailing~ until phospholipase C-y becomes phosphorylated on ryrosine by the activated ~GF-~ceptor. Profilin interacts with actin an PIP2. It binds to actin monomers and inhibits polymerization but accelerates the exchange of nucleotide {ATP or ADP) on actin monomers. It dissociates from actin when bound to PIP2, and prevents PIPz hydrolysis by unphosphorylated PLC-)? Thus, these two seemingly unrelated events may share a common regulatory protein and thus be intimately connected. Understanding the regulation of normal cellular‘ events helps US to observe an abnormal or transfo~ed \;eff znd ask questions concerning the molecular level based on