Biomedical subjects
S A Spencer
Publications and source records attributed to S A Spencer.
RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck.
PURPOSE: Patients with recurrent squamous cell cancer of the head and neck (SCH&N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil. METHODS AND MATERIALS: The eligibility requirements included SCH&N presenting as a second primary or recurrence > or =6 months after definitive RT to > or =45 Gy, with > or =75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by > or =6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m2 of a 5-fluorouracil IV bolus given 30 min before each second daily fraction. RESULTS: Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p = 0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p = 0.083). CONCLUSION: Repeated RT with concurrent chemotherapy as given in this study is a feasible approach for selected, previously irradiated patients with SCH&N and may produce increased median and 1-year survival rates compared with systemic chemotherapy trials reported in the literature. A randomized study should be conducted to compare these two different approaches.
Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer.
PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m(2), followed by weekly infusions of 100 to 250 mg/m(2) for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).
Cheating at medical school. Anonymous letter should have been consigned to the bin.
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A fuzzy system for detecting distorted plethysmogram pulses in neonates and paediatric patients.
Pulse oximetry is a useful, quick, non-invasive and widely used technology for monitoring oxygen saturation (SaO2) for neonates and paediatric patients. However, pulse oximetry is fraught with artefacts, causing false alarms resulting from patient or probe movement. The shape of the plethysmogram is a useful visual indicator for determining the reliability of SaO2 numerical readings. If certain features could be defined that tag valid plethysmogram pulses, then automatic recognition of valid SaO2 values can be attained. We observed that the systolic upstroke time (t1), the diastolic time (t2) and heart rate (HR) extracted from the plethysmogram pulse constitute features which can be used for detecting normal and distorted plethysmogram pulses. Therefore, we developed a knowledge-based system using fuzzy logic for classifying plethysmogram pulses into two categories: valid and artefact. A total of 22,497 pulse waveforms were used to define the system parameters. These were obtained from 13 patients with heart rates ranging between 62 and 209 beats min-1. A further 1420 waveforms obtained from another four patients were used for testing the system, and visually classified into 833 (59%) valid and 587 (41%) distorted segments. The system was able to classify 679 (82%) valid segments and 543 (93%) distorted segments correctly. The calculations of the system's performance showed 82% sensitivity, 86% accuracy and 93% specificity. We, therefore, conclude that the algorithm used in this system can be implemented in its present from for real-time SaO2 monitoring in intensive care for detecting valid and distorted plethysmogram pulses.
A randomised controlled trial to compare methods of milk expression after preterm delivery.
OBJECTIVES: Primary: to compare sequential and simultaneous breast pumping on volume of milk expressed and its fat content. Secondary: to measure the effect of breast massage on milk volume and fat content. DESIGN: Sequential randomised controlled trial. SETTING: Neonatal intensive care unit, North Staffordshire Hospital NHS Trust. SUBJECTS: Data on 36 women were analysed; 19 women used simultaneous pumping and 17 used sequential pumping. INTERVENTIONS: Women were randomly allocated to use either simultaneous (both breasts simultaneously) or sequential (one breast then the other) milk expression. Stratification was used to ensure that the groups were balanced for parity and gestation. A crossover design was used for massage, with patients acting as their own controls. Women were randomly allocated to receive either massage or non-massage first. MAIN OUTCOME MEASURES: Volume of milk expressed per expression and its fat content (estimated by the creamatocrit method). RESULTS: Milk yield per expression was: sequential pumping with no massage, 51.32 g (95% confidence interval (CI) 56.57 to 46.07); sequential pumping with massage, 78.71 g (95% CI 85.19 to 72.24); simultaneous pumping with no massage, 87.69 g (95% CI 96.80 to 78.57); simultaneous pumping with massage, 125.08 g (95% CI 140.43 to 109.74). The fat concentration in the milk was not affected by the increase in volume achieved by the interventions. CONCLUSIONS: The results are unequivocal and show that simultaneous pumping is more effective at producing milk than sequential pumping and that breast massage has an additive effect, improving milk production in both groups. As frequent and efficient milk removal is essential for continued production of milk, mothers of preterm infants wishing to express milk for their sick babies should be taught these techniques.
Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers.
PURPOSE: Epidermal growth factor receptor (EGFr) is overexpressed in a majority of head and neck squamous cell carcinomas, and this overexpression is associated with a poor prognosis. Therefore, EGFr has become the target of investigations aimed at disabling the receptor to determine whether this process leads to improved tumor kill with conventional treatment. MATERIALS AND METHODS: C225 is an anti-EGFr monoclonal antibody that inhibits receptor activity by blocking the ligand binding site. A panel of human head and neck squamous cell carcinoma cell lines was used to study the combination of C225 and radiation. RESULTS: It was determined that the combination of C225 (5 microgram/mL) delivered simultaneously with radiation (3 Gy) resulted in a greater decrement in cellular proliferation than either treatment alone. This reduction in proliferation correlated with reduced EGFr tyrosine phosphorylation and a reduction in phosphorylated signal transducer and activator of transcription-3 (STAT-3) protein (known to protect cells from apoptosis). Also, the decrement in proliferation correlated with increased apoptotic events, thereby indirectly linking C225/radiation-induced regulation of STAT-3 protein to apoptosis. CONCLUSION: This preclinical work serves as important support for the ongoing clinical investigation of C225 and radiotherapy for patients with head and neck carcinomas. The initial results of these clinical studies have been promising.
A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.
PURPOSE: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. METHODS AND MATERIALS: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. RESULTS: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. CONCLUSIONS: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.
A prospective evaluation of the timing of postoperative radiotherapy for preventing heterotopic ossification following traumatic acetabular fractures.
PURPOSE: Preoperative and immediate postoperative irradiation of traumatic acetabular fractures (TAF), although known to reduce heterotopic ossification (HO), can cause significant organizational and logistic difficulties. We sought to determine an acceptable time interval between surgery and radiation without compromising control, as well as to update our large experience and to further validate our treatment philosophy. METHODS AND MATERIALS: Beginning in June 1995, we began a prospective study, irradiating 152 patients on postoperative days 1, 2, or 3. There were also 17 patients delayed further secondary to medical difficulties. RESULTS: All patients treated since June 1995 received 700 cGy/1 fx. Fifty-eight patients received radiation within 24 hours of surgery, 41 within 2 days, 53 within 3 days, 13 within 4 days, and 4 were delayed further. Delaying irradiation for up to 4 days postoperatively caused no statistical increase in HO (p = 0.625). Of 263 patients in our retrospective cohort, HO occurred in 5.3% of patients who received irradiation versus 60% of patients who did not. CONCLUSION: In our prospective study, we noted no perceptible increase in HO with up to a 3-day interval between surgery and radiotherapy. This allows a more structured treatment schedule and allows the patient more time to heal and recover. Updated results from our overall series continue to demonstrate that adjuvant radiation decreases the incidence and severity of HO after TAF.
A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer.
PURPOSE: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. METHODS: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. RESULTS: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. CONCLUSION: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.
Measurement of peripheral oxygen utilisation in neonates using near infrared spectroscopy: comparison between arterial and venous occlusion methods.
The aim of this study was to develop an arterial occlusion method and compare it with the venous occlusion method for measurement of peripheral oxygen utilisation in neonates using near infrared spectroscopy (NIRS). Twenty healthy neonates were studied. Arterial occlusion was produced by inflating a neonatal blood pressure cuff to 100 mmHg for 30-40 s and oxygen utilisation (VO(2)) was calculated using the HbO(2) decrement slope following occlusion. Venous occlusion was produced by inflating the cuff to 30 mmHg for 15-20 s and VO(2) was calculated by: VO(2)=HbTx4x(SaO(2)-SvO(2)), where SaO(2) is the arterial oxygen saturation measured by pulse oximetry and SvO(2) is the venous oxygen saturation measured by NIRS. Each baby had a minimum of three arterial and three venous occlusions. Criteria were developed for acceptance/rejection of an occlusion. Using the arterial method, the mean VO(2) was 1.12 mM cm(-1) O(2)/min (S.D.=0.25), (95% CI=1.00-1.24 mM cm(-1) O(2)/min). The coefficient of variation was 6.6+/-4.1%. Using the venous method, the mean VO(2) was 1.60 mM cm(-1) O(2)/min (S.D.=0.48), (95% CI=1. 38-1.82 mM cm(-1) O(2)/min). The coefficient of variation was 12. 6+/-5.7%. The correlation between the two methods was weak (r=0.28 and r(2) was 0.08). The mean difference between the two methods was 0. 47 mM cm(-1) O(2)/min (S.D.=0.51). The limits of agreement were -0. 53 to 1.47 mM cm(-1) O(2)/min. The arterial method gives more consistent results.
Glucose sensor with improved haemocompatibilty.
A new biocompatible copolymer has been synthesised and used in an electrochemical enzyme-based glucose sensor. The copolymer incorporates three segments including a monomer with an electrically neutral phosphorylcholine head group that is able to reject protein adsorption and two segments that increase the affinity to polyurethane substrate. Peel and solution circulation tests showed that this material has high attachment to polyurethane. With the new copolymer as the outermost layer and the polyurethane as the diffusion-limiting membrane, the sensor showed extended linearity up to 50 mM glucose and stable output in bovine serum for 70 h. During in vivo tests, the sensor exhibited a steady current signal and a rapid transient response when the glucose concentration was raised. These results imply that the haemocompatibility of the glucose sensor coated with the new copolymer has been improved, which is crucial for a sensor used for clinical real-time monitoring. The material may also be suitable for application to other implantable devices.
Photoplethysmography: a futuristic view for neonatal care.
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Concomitant chemotherapy and reirradiation as management for recurrent cancer of the head and neck.
Thirty-five patients with inoperable recurrent head and neck cancer previously treated with definitive irradiation were treated with reirradiation and concomitant chemotherapy. Patient records were retrospectively reviewed to assess toxicity, response, and survival. Patients received one of three regimens: 1) 40 Gy total (2 Gy daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 2 g hydroxyurea orally daily for 5 days; 2) 48 Gy total (1.2 Gy twice daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 1.5 g hydroxyurea orally daily for 5 days; 3) 60 Gy total (1.5 Gy twice daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 1.5 g hydroxyurea orally daily for 5 days. For all regimens, treatment was given only on weeks 1, 3, 5, and 7. Acute toxicity was mainly hematologic and was less severe with the lower hydroxyurea dose. Acute mucosal and skin toxicity was acceptable for all regimens. Late toxicity was noted in 4 of 17 patients who survived 12 months or more. Late effects were Radiation Therapy Oncology Group grade 3 or less. Fifteen of 35 patients achieved a complete response, and 11 of 35 patients achieved a partial response. The median survival rate was 10.5 months. There was no significant difference in responses or median survival between the groups. Reirradiation of head and neck cancer with 5-fluorouracil and hydroxyurea offers acceptable acute toxicity and minimal late effects. The clinical response rates and median survival are encouraging. Further investigation is warranted.
Phase I/IIa study of concurrent paclitaxel and cisplatin with radiation therapy in locally advanced non-small cell lung cancer: analysis of early and late pulmonary morbidity.
Recent efforts to improve survival outcome in patients with locally advanced non-small cell lung cancer have focused on the use of chemoradiotherapy regimens containing vinblastine/cisplatin or etoposide/cisplatin. However, the overall treatment outcome with these regimens remains poor, emphasizing the need for new therapeutic options. Based on the activity of paclitaxel in advanced non-small cell lung cancer, its additive cytotoxicity with cisplatin, and the radiation-sensitizing effect of both agents, a phase I/IIa study was designed to examine the feasibility of paclitaxel/cisplatin concurrently with conventional thoracic irradiation in patients with locally advanced tumors. One major concern regarding combined modality therapy has been the enhancement of pulmonary toxicity. This report describes the incidence and severity of pulmonary toxicities observed in this trial according to the Radiation Therapy Oncology Group scoring criteria. A literature-based review was performed in an attempt to determine the impact of paclitaxel-based versus non-paclitaxel-based chemoradiotherapy regimens on the early and late pulmonary morbidity. Twenty-four evaluable patients died and 14 (37%) are still alive without evidence of disease. The 1- and 2-year survival rates are 62% and 40%, respectively, with a median survival of 17 months. Pulmonary toxicity >/=grade 2 was more frequently manifested as late toxicity in approximately 70% of the patients. In most, prompt symptomatic and radiologic improvement was observed with the early administration of corticosteroids. There were three late grade 5 toxicities characterized by diffuse (bilateral) rapidly progressive interstitial infiltrates. Protracted lymphocytopenia was noted in the great majority of patients, and its role in the pathogenesis of this complication remains to be determined. There were minor changes in pulmonary function parameters, except in the forced vital capacity and diffusion capacity to carbon monoxide. In a univariate analysis, no relationship was noted between paclitaxel dose level, degree of lymphocytopenia, changes in pulmonary function indices, and incidence of pulmonary toxicity. However, there was a significant dose-volume relationship (using conventional dose-volume histograms) with late pulmonary toxicity at radiation doses between 15 Gy and 30 Gy. Based on a literature review, paclitaxel-based chemotherapy regimens seem to be associated with a slightly higher risk of pulmonary toxicity; however, comparison of such toxicity between trials has many limitations that require that the conclusion reached be viewed with caution.
Molecular cloning and characterization of human and murine DNase II.
We have cloned and sequenced novel cDNAs that encode human and murine DNase II, the acidic deoxyribonuclease. Sequence analysis predicts that huDNase II contains an N-terminal signal sequence and that mature DNase II has 344 residues with a calculated molecular mass of 38 032 Da. DNase II is a novel enzyme with no homologies to proteins of known function. Surprisingly, C. elegans appears to possess a family of DNase II homologs. Unlike DNase I-like enzymes that have tissue-specific expression patterns, huDNase II is ubiquituously expressed at low levels. When huDNase II is expressed in human 293 cells, we observe secretion of a novel 42-44 kDa glycoprotein; approximately 20-30% of recombinant human DNase II activity is secreted in this system. The secreted enzyme possesses DNA hydrolytic activity and shares biochemical properties with purified DNase II obtained from other species. We also show that the mechanism by which DNase II cuts DNA is similar to DNase I in that the enzyme produces nicks rather than double-strand cuts.
Cloning and characterization of an actin-resistant DNase I-like endonuclease secreted by macrophages.
We have cloned human and murine DNase I-like cDNAs, termed LS-DNase, which are expressed at high levels in liver and spleen tissues. LS-DNase expression is highly specific to macrophage populations within these and other tissues. Mature LS-DNase from both species is a secreted, non-glycosylated protein containing 285 residues, with a calculated molecular mass of 33 kDa and a basic isoelectric point. Human and murine LS-DNase are highly conserved and share 83% identity. Sequence analysis reveals that LS-DNase shares 46% amino acid sequence identity with DNase I. However, several residues identified as important for interaction of human DNase I with actin are not conserved in both human and murine LS-DNase. Consistent with this observation, recombinant human LS-DNase possesses a DNA hydrolytic activity which, unlike DNase I, is not inhibited by G-actin. The existence of a family of DNase I-like molecules that have tissue-specific expression patterns and the possible role of a macrophage specific DNase are discussed.
Fatty acid balance studies in preterm infants fed formula milk containing long-chain polyunsaturated fatty acids (LCP) II.
A milk formula (Prematil-LCP) containing long-chain polyunsaturated fatty acids (LCP) and with a fatty acid profile closely resembling breast milk has recently been introduced for preterm infants. A double-blind randomized controlled trial was performed comparing fatty acid absorption from Prematil-LCP (n=10) and standard Prematil (n=10). Formula-fed preterm infants underwent 3 d fat balances (once full enteral feeds were established) along with a parallel human milk fed group (n=11). Plasma samples were taken on the last day. Median total fat excretion (absorption, %) was 2.34g kg(-1) (82.0), 2.64g kg(-1) (82.9) and 1.65g kg(-1) (87.8) with Prematil, Prematil-LCP and human milk feeding, respectively. This reflected differences in the excretion and absorption of long-chain saturated fatty acids. All groups excreted detectable LCP. LCP disappearance was higher in infants fed human milk than in those fed Prematil-LCP, particularly for n-6 LCP (p < 0.01). Nevertheless, excreted LCP equated to < 30% dietary intake, with Prematil-LCP feeding. Plasma lipid fatty acid composition reflected differences in dietary LCP intake.