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At least 1,063 records · Page 59Linked to original sources

PubMed1997

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC).

INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

Adult↗

PubMed2003

Cell death and tendinopathy.

Apoptosis and necrosis are presently recognized as the two major types of physiological and pathological cell death. Apoptosis is a tightly regulated cell deletion process that differs morphologically and biochemically from necrotic cell death. Tendinopathy is defined as a tendon injury that originates from intrinsic and extrinsic etiological factors. Excessive apoptosis has recently been described in degenerative tendon. The increased number of apoptotic tendon cells in degenerative tendon tissue could affect the rate of collagen synthesis and repair. Impaired or dysfunctional protein synthesis may lead to weaker tendon tissue and eventually increase the risk for tendon rupture. Clearly, there are many details to insert into this pathway, but there is hope that if the fine details of the pathway can be fleshed out, then strategies may be able to be developed to break the cycle at one or more points and prevent or treat tendinopathy more effectively.

Apoptosis↗

PubMed2002

Severe acute maternal morbidity and mortality in the Pretoria Academic Complex: changing patterns over 4 years.

OBJECTIVE: To compare the severe acute maternal morbidity (SAMM) and maternal mortality in the Pretoria Academic Complex for the year 2000 and the years 1997-1999. STUDY DESIGN: SAMM and maternal mortality was identified at daily audit meetings. The audit was performed from 1 January 2000 to 31 December 2000 and compared with the data obtained from the original 2-year audit [Br J Obstet Gynecol 105 (1998) 985]. The mortality index (MI) was defined as Maternal Death (MD) divided by SAMM and MD. This index is used to assess the standard of care in specific maternal conditions. Data was assessed using the Chi square test. RESULTS: SAMM and maternal mortality has significantly declined in all patients with a reduction in abortion complications as the main contributor (268/100,000 births versus 94/100,000 births P<0.006). There is a non-significant trend to increased morbidity and mortality in hypertension, hemorrhage and infections. CONCLUSIONS: The standard of care was constant. An audit of SAMM and maternal mortality allows for early detection of trends and early changes in health strategies.

Abortion, Induced↗

PubMed2003

Comparison of neonatal outcome including cerebral palsy between abruptio placentae and placenta previa.

OBJECTIVE: Our purpose was to evaluate the neonatal prognosis after abruptio placentae and placenta previa during pre-term gestation. STUDY DESIGN: A case-control study was performed using a logistic regression model. A poor outcome was defined as neonatal death occurring before hospital discharge or a diagnosis of cerebral palsy. RESULTS: A poor outcome was more frequent in cases of abruptio placentae (11/42, 26.2%) than in placenta previa (2/72, 2.8%) and pre-term labor (1/120, 0.8%). The difference was mainly due to the incidence of cerebral palsy. A significant association of abruptio placentae (odds ratio (OR) 61.0, 95% confidence interval (CI 3.4-1084), delivery at <31 weeks of gestation (OR 19.0, CI 2.8-128.8), and low Apgar score (<7) at 5min (OR 70.8, CI 16.5-304.9) with increased risk of poor outcome was found in the logistic regression model that controlled for confounding effects. In abruptio placentae, a low Apgar score (<7) at 5min (OR 19.8, CI 2.0-197.8) was associated with increased risk of poor outcome in the logistic regression model. CONCLUSION: From the standpoint of poor perinatal outcome including cerebral palsy, abruptio placentae was the most significant clinical entity in pre-term gestation.

Abruptio Placentae↗

PubMed2003

Prediction of adverse outcome associated with vaginal misoprostol for labor induction.

OBJECTIVE: To identify predictors of adverse outcome in pregnant women at term receiving 50 microg of intravaginal misoprostol for labor induction. STUDY DESIGN: A prospective observational study was conducted of 720 pregnant women at term with an unfavorable cervix and a medical or obstetric indication for labor induction. All patients received 50 microg of intravaginal misoprostol every 4h up to three doses. The primary outcome measure was "adverse outcome" defined as: neonatal death, fetal acidemia and emergent cesarean delivery performed for non-reassuring fetal heart rate tracings. A stepwise logistic regression analysis was used to identify predictors of adverse outcome. RESULTS: Tachysystole (frequent uterine contractions) (odds ratio (OR), 3.7; 95% confidence interval (CI), 1.2-10.8) and fetal tachycardia (OR, 4.8; 95% CI, 1.4-16.2) were determined as significant predictors of adverse outcome. The specificity of the model was 94.2%, whereas the sensitivity was 20.4%. CONCLUSION: In the absence of tachysystole and fetal tachycardia, an uneventful delivery might be expected for women receiving 50 microg of intravaginal misoprostol.

Administration, Intravaginal↗

PubMed2001

The exercise test that indicates a low risk of events. Differences in prognostic significance between patients with chronic stable angina and patients with unstable angina.

OBJECTIVES: The objective of this prospective study was to determine the differences in the prognostic significance of an exercise test (ET) that indicates a low risk of events (low-risk exercise test [LRET]) between patients with unstable angina (UA) and those with chronic stable angina (CSA). BACKGROUND: It is not known whether the prognostic significance of an LRET is influenced by the disease; that is the reason for performing exercise testing. METHODS: All patients not presenting with high-risk criteria were submitted to a prognostic ET. The ET was performed by patients with CSA and patients with primary UA stabilized with medical therapy. Medical therapy was planned for all patients. A combined end point was defined as cardiac death, nonfatal acute myocardial infarction or hospital admission for UA. Multivariate analysis was performed to determine the independent predictors of events. RESULTS: Low-risk criteria were fulfilled by 105 patients with UA and 86 patients with CSA. The mean follow-up time was 347 +/- 229 days. The event rate was higher in the UA group than in the CSA group (28% vs. 9%, p = 0.001). The CSA group showed worse ET results. Performance of ET by patients with UA was the principal predictor of events (odds ratio 4.2, p = 0.0005). CONCLUSIONS: Among patients who underwent an LRET, those with UA had a rate of events significantly higher than that of patients with CSA, despite the worse results of ET in patients with CSA.

Aged↗

PubMed2003

Coronary stent implantation is superior to balloon angioplasty for chronic coronary occlusions: six-year clinical follow-up of the GISSOC trial.

OBJECTIVES: We investigated whether the benefits of stent implantation over balloon percutaneous transluminal coronary angioplasty (PTCA) for treatment of chronic total coronary occlusions (CTO) are maintained in the long term. BACKGROUND: Several randomized trials have shown that in CTO, stent implantation confers clinical and angiographic mid-term outcomes superior to those observed after PTCA. However, limited information on the long-term results of either technique is available. METHODS: Six-year clinical follow-up of patients enrolled in the Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche (GISSOC) trial was performed by direct visit or telephone interview. Major adverse cardiac events (MACE), defined as cardiac death, myocardial infarction, target lesion revascularization (TLR), and anginal status, were recorded. RESULTS: Freedom from MACE at six years was 76.1% in the stent group, compared with 60.4% in the PTCA group (p = 0.0555). This difference was due mainly to TLR-free survival rates (85.1% vs. 65.5% for the stent and PTCA groups, respectively; p = 0.0165). Eleven patients underwent TLR after the nine-month follow-up visit (stent group: n = 5; PTCA group: n = 6); however, in most cases, restenosis of the study occlusion was evident at nine-month angiography. CONCLUSIONS: This study represents the longest reported clinical follow-up of patients after percutaneous recanalization of CTO and demonstrates that the superiority of stent implantation over balloon PTCA is maintained in the long term. Stent and PTCA results appear to remain stable after nine-month angiographic follow-up. Stent implantation in CTO that can be recanalized percutaneously is therefore a valuable long-term therapeutic option.

Adult↗

PubMed1997

Long-term prognostic significance of dobutamine echocardiography in patients with suspected coronary artery disease: results of a 5-year follow-up study.

OBJECTIVES: This study sought to assess the long-term prognostic utility of dobutamine stress echocardiography in predicting fatal and nonfatal cardiac events. BACKGROUND: Although dobutamine stress echocardiography has improved sensitivity and specificity for detection of coronary artery disease, little is known of its predictive value for long-term cardiac events. Therefore, we followed up 120 consecutive patients who underwent dobutamine echocardiography for suspected coronary disease from March 1989 to August 1991. METHODS: All patients presenting for coronary angiography for chest pain were eligible for recruitment. Follow-up was 100% complete at 5 years (range 3.0 to 6.1). Cardiac events were defined as cardiac death or nonfatal myocardial infarction or the need for coronary revascularization (coronary angioplasty or bypass surgery). RESULTS: Positive (n = 78) and negative (n = 42) dobutamine test groups differed in their rates of coronary artery bypass graft surgery (37.2% vs. 9.5%, p < 0.001, respectively) and mortality. Of 26 total deaths, 22 occurred in the group with positive dobutamine test results (28% vs. 9.5%, p < 0.018); all 7 cardiac deaths occurred in this group as well (9% vs. 0%, p < 0.045). By multivariate regression analysis, positive results on dobutamine echocardiography remained independently predictive of future cardiac death after left ventricular ejection fraction and other clinical variables were accounted for. CONCLUSIONS: A positive finding on dobutamine echocardiography is an independent predictor of long-term cardiac mortality, whereas a negative finding confers a significantly reduced likelihood of cardiac death as much as 5 years from initial testing. We conclude that dobutamine stress echocardiography can be used to predict which patients with suspected coronary artery disease are at low risk for cardiac death and do not require concurrent nuclear or invasive testing.

Aged↗

PubMed1999

Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908).

BACKGROUND: Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs. METHODS: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy. RESULTS: AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; P <.05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation. CONCLUSIONS: Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs.

Animals↗

PubMed1999

Thoracic radiation therapy before autologous bone marrow transplantation in relapsed or refractory Hodgkin's disease. PMH Lymphoma Group, and the Toronto Autologous BMT Group.

The aim of this study was to assess the relationship between radiation therapy (RT) and treatment-related mortality in patients receiving high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT) for recurrent/refractory Hodgkin's disease (HD). Between December 1986 and December 1992, 59 patients previously treated at the Princess Margaret Hospital underwent HDCT (etoposide 60 mg/kg, melphalan 160 mg/m2) and ABMT, performed for refractory (13 patients) or relapsed (46 patients) HD. RT was incorporated in the salvage treatment with the intent to achieve complete control of disease prior to ABMT. RT was given before ABMT in 33 patients, and after ABMT in 4 patients. Treatment-related (TR) mortality was defined as any death occurring within 100 days of ABMT. Autopsies were performed for all patients with TR deaths. With a median follow-up of 4.6 years (range 1.2-7.4 years), the actuarial overall survival was 41% +/- 14% at 5 years. We observed 37 deaths, and 10 of these were TR deaths. Among the 24 patients who received thoracic RT before ABMT, there were 8 TR deaths, 3 of these solely attributable to radiation pneumonitis. The remaining 5 TR deaths all had respiratory failure with complicating sepsis as a major medical problem. The interval from RT to ABMT was shorter for 8 patients dying of TR death (mean 37 days; range 0-103 days), than for the 16 survivors (mean 105 days; range 0-263 days) (P = 0.026). Among 9 patients with ABMT within 50 days of thoracic RT, 6 had TR death. In contrast, among the 35 patients without thoracic RT (26 no RT, 9 non-thoracic RT), there were only 2 TR deaths. The 4 patients treated with mantle RT post-ABMT had no serious pulmonary complications. The use of thoracic RT before HDCT and ABMT was associated with a high post-transplant mortality rate. It was most evident in patients who received thoracic RT within 50 days prior to ABMT, or when the target volume included large volume of lung. We recommend that the use of post-transplant RT be investigated to decrease TR mortality.

Adolescent↗

PubMedDate not supplied

Exercise equilibrium radionuclide angiography predicts long-term cardiac prognosis in patients with abdominal aortic aneurysm being considered for surgery.

BACKGROUND: Patients with an abdominal aortic aneurysm (AAA) have a high prevalence of coronary disease and are at risk for cardiac events. This may offset the prognostic benefit of surgical repair. We investigated whether preoperative exercise equilibrium radionuclide angiography (ERNA) could be used to identify patients at high risk for cardiac events after successful AAA repair. METHODS: Between 1990 and 1995, 173 patients with an AAA were referred for supine bicycle exercise ERNA preoperatively. Follow-up information was obtained from a questionnaire sent to each patient's family physician. Cardiac events were defined as cardiac death or nonfatal myocardial infarction. RESULTS: A total of 139 patients were able to exercise and did not die or suffer myocardial infarction perioperatively. The median follow-up period was 3.8 years. Diabetes mellitus, an exercise ejection fraction (EF) below 0.50, and a fall in EF with exercise were univariable predictors of cardiac risk during the follow-up period (P < .05). On multivariable analysis, diabetes mellitus (risk ratio [RR], 6.9; 95% CI 1.5 to 32.0) and an EF fall (RR, 4.1; 95% CI 1.5 to 11.4) emerged as the most important predictors. CONCLUSIONS: Exercise ERNA predicts long-term cardiac events in patients being considered for elective AAA repair. Such predictive information may influence the decision to operate, for example, on small unthreatening aneurysms, or lead to invasive cardiological management to minimize risk.

Aged↗

PubMedDate not supplied

Impact on exercise single-photon emission computed tomographic thallium imaging on patient management and outcome.

BACKGROUND: Stress perfusion imaging is useful in risk stratification of patients with known or suspected coronary artery disease. In the current era of managed health care, there is a need to provide data on patient outcome. METHODS AND RESULTS: This study examined the impact of exercise single-photon emission computed tomographic (SPECT) thallium imaging on patient management (the subsequent need for coronary angiography and revascularization) and outcome (the occurrence of hard cardiac events defined as cardiac death or nonfatal acute myocardial infarction) in 2700 patients who were being evaluated for diagnostic purposes. None of the patients had previous coronary angiography, coronary revascularization, or Q-wave myocardial infarction. The SPECT images were normal in 2027 patients (group 1) and abnormal in 673 patients (group 2). Within 6 months after thallium imaging 53 patients in group 1 (3%) and 242 patients in group 2 (36%) underwent coronary angiography (p = 0.0001). The patients who underwent coronary angiography had higher pretest probability of coronary disease (group 1) or more perfusion defects (group 2) than patients who did not (p = 0.0001 each). Coronary revascularization within 3 months of coronary angiography was performed in 1 of the 53 patients (2%) in group 1 and in 87 of 242 patients (30%) in group 2 (p = 0.0001). Among the remaining patients who had coronary angiography but were medically treated there were no hard cardiac events in group 1 but there were 15 events in group 2 (p = 0.02). CONCLUSIONS: The results of exercise SPECT thallium imaging are important in patient management and outcome. Coronary angiography, coronary revascularization and events are rare in patients with normal exercise SPECT thallium images.

Adult↗

PubMed2002

The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy.

We have reported previously that despite treatment with angiotensin-converting enzyme inhibitors and beta blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor-alpha (TNF-alpha) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF-alpha, on clinical status, left ventricular function, and circulating plasma levels of TNF-alpha, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF-alpha determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P = 0.009 between groups). A combined end-point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow-up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P = 0.03). Treatment with pentoxifylline (P = 0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.

Adult↗

PubMed1972

Urban variation in infant mortality from birth injury and atelectasis in England and Wales in 1958-67.

Variations in mortality attributed to birth injury and atelectasis in the 10 years 1958-67 have been investigated for each county borough of England and Wales. It became evident that diagnostic difficulties in separating these two causes must have been such that for statistical purposes they should be combined in a single rate.Variables likely to affect the local rates such as the sex ratio of births, and rates of illegitimacy and immaturity as an ill-defined cause of death appeared to affect the mortality levels in certain towns but not sufficiently to account for the wide variations apparent in those levels. It is concluded that local surveys are necessary in the towns with highest rates to uncover differences in numbers of births in hospital, in obstetric techniques and in quality of medical care.

Asphyxia Neonatorum↗

PubMed2001

Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling.

In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IkappaBs. Activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor. The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-kappaB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45beta/myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-kappaB-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-kappaB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-alpha.

3T3 Cells↗

PubMed1996

Alternative pathways for the selection of antigen-specific peripheral T cells.

In the thymus, maturing lymphocytes receive activation signals mediated by the T-cell antigen receptor (TCR) that either promote clonal survival (positive selection) or induce apoptosis (negative selection). This balance between life and death is mirrored by the sensitivity of cortical thymocytes to apoptotic death induced by antibodies against the CD3 component of the TCR signal-transduction complex, bacterial superantigens that bind to the TCR beta-chain, and corticosteroids. In contrast, mature peripheral T cells are positively activated by anti-CD3 antibody or superantigens and are resistant to steroid-induced death. Here we show that in splenic germinal centres, T cells regain thymocyte-like sensitivity to TCR- and steroid-induced apoptosis and undergo antigen-driven positive and negative selection. T-cell responses elsewhere in the spleen are unaccompanied by programmed cell death. Our observations define a new differentiation pathway for peripheral T cells and suggest that germinal centres induce a lymphocyte phenotype necessary for the maintenance of self-tolerance.

Animals↗

PubMed1994

Lack of correlation between early intracellular calcium ion rises and the onset of apoptosis in thymocytes.

Apoptosis, a well-recognized process of cell death, is usually defined by chromatin condensation, plasma membrane blebbing, reduction in cell volume, and in many cell types the cleavage of DNA into nucleosomal multiples, and finally the formation of apoptotic bodies. We have characterized the time of onset and the range of concentrations at which the toxins gliotoxin and thapsigargin induce apoptosis in thymocytes. We also looked for early changes in cytosolic calcium ion concentration ([Ca2+]i). Three methods were used to detect apoptosis: cellular morphology, DNA fragmentation and a flow cytometric method using ethidium bromide. Calcium fluxes were measured using both flow cytometry and bulk cell fluorimetry. Gliotoxin concentrations of 50 nmol/L to 10 mumol/L induced significant numbers of cells to become apoptotic in a dose dependent manner. At these concentrations there was no observable increase in [Ca2+]i as determined by flow cytometry or in bulk cells. However, when thymocytes were treated with gliotoxin at concentrations greater than 500 mumol/L, rises in [Ca2+]i were apparent, but these cells died by necrosis. Thapsigargin induced low levels of apoptosis in thymocytes; the maximum effect observable after a 10 nmol/L treatment. Thapsigargin is known to inhibit the Ca(2+)-ATPase in the endoplasmic reticulum thereby causing a sustained increase in [Ca2+]i in thymocytes. The rise in [Ca2+]i observed was quantitatively similar when thymocytes were treated with thapsigargin concentrations ranging between 10 and 100 nmol/L. These results led us to investigate the effect of dexamethasone on [Ca2+]i. In these experiments thymocytes showed no rises in [Ca2+]i above the control over 85 min following treatment with 10 mumol/L dexamethasone.

Animals↗

PubMed2006

Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol.

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day x 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day x 5 days.

Adolescent↗