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Biomedical subjects

J F Fowler

Publications and source records attributed to J F Fowler.

At least 55 records · Page 3Linked to original sources
PubMed1998

Methyldibromoglutaronitrile (Euxyl K400): a new and important sensitizer in the United States?

BACKGROUND: Methyldibromoglutaronitrile (MDGN) is a component of Euxyl K400, a preservative used in many skin care products in Europe. MDGN has been used in skin care products in the United States for the last 5 years. Contact allergy from MDGN has been reported from Europe. OBJECTIVE: The purpose of this study was to determine the frequency of MDGN as a sensitizer in patients undergoing routine patch testing. METHODS: We reviewed the results in 163 patients who underwent patch testing during a 4-month period to determine the number who had any reaction to MDGN at two different concentrations (0.2% and 0.5%). Tests were graded with the use of the North American Contact Dermatitis Group criteria (0 to 3+), and readings were performed at 48 and 96 hours (all positive reactions were evaluated at a follow-up visit or by telephone interview). RESULTS: In the 4-month period, 45 of the 163 patients showed some reaction (+/- to 3+) at one or more readings. Of these, the results for 23 patients were considered to be irritant false-positive reactions; for 3 patients, the results were classified as uncertain; and for 19 patients, the results were classified as allergic. Of these, the results for eight patients were of definite relevance; the results for five patients were of probable relevance, and the results for six patients were of doubtful relevance to the problem condition. Other positive patch tests to a variety of allergens were frequently seen in persons positive to MDGN. CONCLUSION: MDGN is a sensitizer in skin products and, with the increase of its use, should be considered in the patch test evaluation of patients with persistent dermatitis. Optimum patch test concentrations are yet to be determined.

Allergens↗
PubMed1998

Phase II trial of hyperfractionated accelerated radiation therapy for nonresectable non-small-cell lung cancer: results of Eastern Cooperative Oncology Group 4593.

PURPOSE: To assess the feasibility, toxicity, and efficacy of hyperfractionated accelerated radiation therapy (HART) for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty patients from six institutions with stage IIIA or IIIB NSCLC were enrolled between November 1993 and August 1995. Radiation therapy (total dose, 57.6 Gy in 36 fractions) was delivered over 15 days with the use of three daily fractions with a 4-hour interval between fractions and an 8-hour interval between on-cord fields. Patients were not treated on weekends. RESULTS: Twenty-eight patients (93%) completed radiation therapy. Treatment-related toxicities of grade 3 or greater included esophagitis in six patients and grade 3 skin reaction in three patients. The overall objective response rate was 54%, and the response rate within the radiation field was 64%. With a minimum follow-up of 19 months in surviving patients, the median survival and 1-year survival rate are 13 months and 57%, respectively. The median relapse-free survival and 1-year relapse-free survival rate are 7 months and 23%, respectively. No transverse myelitis or late toxicities of grade 4 or greater have been observed. CONCLUSION: HART, delivered to a total dose of 57.6 Gy over 15 total days, is practical and well tolerated. Survival appears similar to that seen with modern combined modality regimens. A phase III trial is under way.

Aged↗
PubMed1998

Allergy to cocamide DEA.

Three cases are reported of individuals allergic to cocamide DEA, also known as coconut diethanolamide. In two cases, multiple other cutaneous allergies were present. In both instances, cocamide DEA was present in several personal care products used by the patients. In the third case, occupational exposure was suspected. Cocamide DEA is an unusual allergen that may cause contact dermatitis in individuals who often have multiple other skin allergies.

Adult↗
PubMed1998

An economic evaluation of patch testing in the diagnosis and management of allergic contact dermatitis.

BACKGROUND: A previous retrospective study indicated that patch testing is cost-effective and well accepted by patients. OBJECTIVE: The objective of this observational prospective study was to show the cost-effectiveness of patch testing in patients suspected of allergic contact dermatitis (ACD) and to determine the order in which different severity groups rank in terms of cost-effectiveness. METHODS: This observational study was conducted in 567 patients from 10 investigator sites over a period of 1 year. All patients with a suspicion of contact allergy who exhibited at least moderate disease activity were included in the study and were stratified according to disease severity and whether or not they were patch tested. In each severity category, the cost-effectiveness of patch testing was evaluated. Patients who were ruled out for contact allergy by the first 6 months after admission were excluded. A validated dermatology-specific quality of life instrument was administered to all the patients at entrance into the study and at 6 and 12 months after that. The cost-effectiveness analysis is shown using a decision analysis model. RESULTS: Patch testing was performed on 22% of patients with mild disease, 41% of patients with moderate disease, and 50% of patients with severe disease. As a result of changes made in their lifestyle, 66% in the patch-tested group and 51% in the non-patch-tested group reported 75% or more improvement in disease symptoms after 6 months. Early confirmation of diagnosis helped reduce the prediagnosis costs of treatment, which was mostly based on preliminary diagnosis. The greatest quality of life benefits from patch testing, relative to no patch testing, occurred in subjects with recurrent or chronic ACD. CONCLUSION: Patch testing is most cost-effective and reduces the cost of therapy in patients with severe ACD.

Chronic Disease↗
PubMed1997

The prediction of late rectal complications in patients treated with high dose-rate brachytherapy for carcinoma of the cervix.

PURPOSE: The aim of this work is to investigate an unusually high rate of late rectal complications in a group of 43 patients treated with concomitant irradiation and chemotherapy for carcinoma of the cervix between December 1988 and April 1991, with a view to identifying predictive factors. METHODS AND MATERIALS: The biologically effective dose received by each patient to the rectal reference point defined by the International Commission of Radiation Units and Measurements, Report 38, were calculated. Radiotherapy consisted of 46 Gy external beam irradiation plus three high dose-rate intracavitary treatments of 10 Gy each prescribed to point A. Cisplatin 30 mg/m2 was given weekly throughout the duration of the irradiation. The results have been compared to data from 119 patients treated with irradiation alone to assess the confounding effect of the cisplatin. RESULTS: The relationship between the biologically effective dose delivered to the rectal reference point and the development of late complications shows a strong dose-response with a threshold for complications occurring at approximately 125 Gy3 corresponding to a brachytherapy dose of approximately 8 Gy per fraction. This value is approximately the same biologically effective dose threshold as that found for external beam irradiation in the head and neck region. The data from the group of patients treated without cisplatin is comparable to the data from the first group of patients in the lower dose ranges; the higher doses were not used and thus are not available for comparison. CONCLUSION: Using the linear quadratic model applied to our clinical results, we have established a threshold for late rectal complications for patients treated with external beam irradiation and high dose-rate brachytherapy for carcinoma of the cervix. This threshold is consistent with similar data for external beam irradiation in the head and neck region.

Antineoplastic Agents↗
PubMed1997

Cell kinetic measurements in prostate cancer.

PURPOSE: Two approaches have been suggested for escalating the total dose in radiotherapy treatment of prostate cancer. One is conformal radiotherapy; the other is hyperfractionation using many small fractions. Both imply some possible prolongation in overall treatment time. To judge whether prolonged treatment schedules would be detrimental, it is necessary to know the proliferation rates in human prostate tumors, specifically, the potential doubling time (Tpot). There is a lack of data on this parameter in the literature. METHODS AND MATERIALS: Seven patients with adenocarcinoma of the prostate were studied. A tracer dose of 100 mg/m2 of IUdR was infused intravenously 4-12 h before biopies were taken. Biopsies were fixed in 70% ethanol, stored at 4 degrees C, and later prepared and stained by standard methods for flow cytometry, using the red fluorescence signal for DNA and the green fluorescence signal (fluorescein isothiocyanate) for 5-iodo-2'-deoxyuridine. The duration of DNA synthesis (Ts) was determined by the relative movement (RM) method, knowing the interval between tracer administration and biopsy. Tpot was calculated as the quotient of Ts by labeling index (LI). RESULTS: In two of the seven tumors the LI was too low (<0.6%) for a reliable estimate of RM to be made, so no determination of Tpot was possible for these tumors. The mean LI values in the other five tumors were 2.4%, 1.4%, 1.0%, 3.0%, and 0.9%. The durations of Ts were 13.2, 9.5, 10.0, 11.7, and 12.7 h, respectively. The resulting values of Tpot were 23, 28, 42, 16, and 61 days, respectively. CONCLUSION: The low labeling indices in prostate tumors, also reported by others, made estimation of Ts by RM impossible in about a third of these tumors. However, five tumors yielded long estimates for Tpot, implying that prolongation from 6 to about 8 weeks should not be detrimental.

Adenocarcinoma↗
PubMed1997

Biological effect of pulsed dose rate brachytherapy with stepping sources if short half-times of repair are present in tissues.

PURPOSE: To explore the possible increase of radiation effect in tissues irradiated by pulsed brachytherapy (PDR) for local tissue dose rates between those "averaged over the whole pulse" and the instantaneous high dose rates close to the dwell positions. Increased effect is more likely for tissues with short half-times of repair of the order of a few minutes, similar to pulse durations. METHODS AND MATERIALS: Calculations were done assuming the linear quadratic formula for radiation damage, in which only the dose-squared term is subject to exponential repair. The situation with two components of T1,2 is addressed. A constant overall time of 140 h and a constant total dose of 70 Gy were assumed throughout, the continuous low dose rate of 0.5 Gy/h (CLDR) providing the unitary standard effects for each PDR condition. Effects of dose rates ranging from 4 Gy/h to 120 Gy/h (HDR at 2 Gy/min) were studied, covering the gap in an earlier publication. Four schedules were examined: doses per pulse of 0.5, 1, 1.5, and 2 Gy given at repetiton frequencies of 1, 2, 3, and 4 h, respectively, each with a range of assumed half-times of repair of 4 min to 1.5 h. Results are presented for late-responding tissues, the differences from CLDR being two or three times greater than for early-responding tissues and most tumors. RESULTS: Curves are presented relating the ratio of increased biological effect (proportional to log cell kill) calculated for PDR relative to CLDR. Ratios as high as 1.5 can be found for large doses per pulse (2 Gy) if the half-time of repair in tissues is as short as a few minutes. The major influences on effect are dose per pulse, half-time of repair in tissue, and--when T1/2 is short--the instantaneous dose rate. Maximum ratios of PDR/CLDR occur when the dose rate is such that pulse duration is approximately equal to T1/2. As dose rate in the pulse is increased, a plateau of effect is reached, for most T1/2s, above 10 to 20 Gy/h, which is therefore radiobiologically equivalent to the highest HDR. A stepping source of 1 curie carries a sphere of "HDR" of radius 20 mm with it in its track through tissue. High ratios of PDR/LDR effect can be avoided by keeping dose per pulse below 1 Gy. CONCLUSIONS: Therefore, about 75% of the total dose is delivered at HDR in a PDR implant of moderate volume, reducing to 40% as the source decays from 1 to 0.3 curies. Even so, restricting the dose per pulse to 0.5 or 0.6 Gy should avoid ratios of increased effect larger than about 10%. It appears likely that PDR delivered by stepping source might behave more like HDR than LDR, especially for tissues with a substantial component of repair of very short T1/2.

Brachytherapy↗
PubMed1997

Biologically effective doses in medium dose rate brachytherapy of cancer of the cervix.

The amount of dose reduction on changing from low dose rate (LDR) brachytherapy to medium dose rate (MDR) or high dose rate (HDR) afterloading has been the subject of much debate. The magnitude of reduction depends, together with other possible factors, on two radiobiological parameters: the alpha/beta ratio and the half-time of repair of the relevant tissues. In an attempt to extract these radiobiological parameters for the late rectal complications observed in our previously published clinical results four different schedules using MDR and one using LDR are analyzed. The percentage incidence of complications was a function of increasing biologically effective dose (BED), but would yield nonsense scattergrams if plotted against raw total dose. In addition, for three other published MDR series, three LDR series, and two HDR series, the incidence of rectal complications is plotted against BED to examine the predictive potential of using BED as the surrogate of total dose. Our own results were published in 1996, consisting of 102 patients treated at the LDR of 0.44 Gy/hr and 88 patients treated by four different schedules using an MDR of 1.6-1.7 Gy/hr. Follow-up is at least 3 years in all schedules. The linear quadratic formula including the "g" dose rate factor was used to analyze them, assuming exponential repair of the repairable beta term. First, multivariate and profile likelihood analyses were carried out to obtain estimates of alpha/beta and T1/2 for rectal late responding tissues. Then graphs of incidence of rectal complications vs. BED were constructed, assuming alpha/beta = 3 Gy and T1/2 = 1.5 hr, values which had not been contradicted by the multivariate analysis. Graphs were drawn both for "all grades including mild reactions" (grades 1 + 2 + 3) and for "serious" complications (grade 3 in our system). In addition, other published cervical brachytherapy series were reviewed, with calculation of their BEDs if not published by the authors. It was necessary to review and compare their grading systems, so that "mild and moderate" (grades 1 and 2) could be contrasted with "serious" (grades 3 and 4 or 5 in various systems). Comparisons were made with other published results, including three LDR, three MDR, and two HDR series spanning from 1982 to 1997. The BEDs at which the incidence of rectal complications rose above the arbitrary level of 10% were compared for all three ranges of dose rate. The multivariate analysis gave estimates of alpha/beta and T1/2 which were not significantly different from 3 Gy and 1.5 hr, respectively, so these values were used to compute the BEDs for the subsequent comparisons. It was found that the graphs of incidence of rectal complications for "all grades including mild" agreed rather better between all series than might have been expected, within a provisional (10%) threshold BED of range 100-123 Gy3 (60-74 Gy given as 2 Gy fractionated external beam or as LDR). The dose-response curves diverged above these values, as expected until common grading systems such as SOMA/ LENT become more widely used. For "serious" complications the 10% incidence occurred at a median BED of 140 Gy3 (84 Gy given as 2 Gy fractionated external beam or as LDR), range 124-155 Gy3. The use of BED (or extrapolated response dose), assuming alpha/beta = 3 Gy and T1/2 = 1.5 hr, instead of total dose, enabled incidence of late rectal complications in cervical brachytherapy with LDR, MDR, and HDR to be plotted in a reasonably consistent way. This does not mean that those parameter values have been definitively determined, but they appear to be provisional values that may be of use in comparing the expected effects of new schedules until better values are obtained from greater use of common grading systems.

Brachytherapy↗
PubMed1997

Dose reduction factors when increasing dose rate in LDR or MDR brachytherapy of carcinoma of the cervix.

BACKGROUND: The detailed summary of results from Bristol where 270 patients with carcinoma of the cervix were treated with either 75 cGy/h from manually loaded caesium or 150 cGy/h by remote afterloading (Newman, G. Increased morbidity following the introduction of remote afterloading, with increased dose rate, for cancer of the cervix. Radiother. Oncol. 39: 97-103, 1996) can be analysed to study the radiobiological factors that could have contributed to the different outcomes reported. The increases in grade 3 late complications from 4 to 22%, and in grade 2 + 3 from 12 to 32%, in spite of a reduction of 20% in dose, imply a rather large difference in biological effect between the two systems, which might or might not be due to dose rate differences. PURPOSE: The possibility that a significant part of the effect might have been due to the dose rate is investigated, with particular attention to what values of radiobiological parameters might explain it, or can be excluded. A similar set of clinical data from Tilsburg (Rodrigus, P., de Winter, K., Venselaar, J. and Leers, W.H. Evaluation of late morbidity in patients with carcinoma of the uterine cervix following a dose rate change. Radiother. Oncol. 42: 137-141, 1997), where dose rate was doubled from 54 to 107 cGy/h with a dose reduction of 20%, is also considered. METHODS: Linear quadratic modelling is employed to calculate Biologically Effective Doses (or ERDs) corresponding to the clinical protocols used. Repair of sublethal radiation damage at a range of half-times is assumed, both for mono- and bi-exponential components. When the LDR is doubled it is called MDR in the present study. RESULTS: The maximum ratios calculated for the BEDs of 16 Gy at MDR to 20 Gy at LDR were 1.06-1.15, assuming alpha/beta = 4-2 Gy, the latter being an unlikely extreme for rectal or urinary complications. These maxima occurred over a narrow range of t1/2 values from 1.5 to 2.5 h. If t1/2 were as long as 4-7 h or as short as 0.5-0.75 h, the biological effects would have been equal. The theoretically ideal dose reduction factors, calculated using the t1/2 values derived from the clinical data, are in the range of 24-29% instead of 20%. CONCLUSIONS: Somewhat greater dose reduction factors for late complications were suggested by this analysis than the 20% that has been commonly used when the dose rate is increased, both from the Bristol and Tilsburg data. The Bristol data showed no loss of therapeutic ratio on changing from manual to remote afterloading. Due to the close-to-optimum choice of the dose reduction factor which was actually used, some values for the half-time of repair of late complications in gynaecological brachytherapy could be estimated and used to calculate the theoretical dose reduction factors.

Brachytherapy↗
PubMed1997

Predicting realistic RBE values for clinically relevant radiotherapy schedules.

To consider the therapeutic potential of radiation effect modifiers it is necessary to balance the modification of the injury in tumours with that in different types of normal tissue. It is especially important to ensure that the effects that have been demonstrated in preclinical experiments are both qualitatively and quantitatively relevant for the radiation doses that will be used in clinical schedules. Most radiobiology studies are initially performed with large single doses or a few large fractions, and from those results predictions have sometimes been made of the potential clinical benefit from a radiation modifier. In the clinic they will be used with many repeated small fractions of about 2 Gy over a period of several weeks. The effects will be quantitatively different in these two dose ranges for a variety of reasons. No modifiers of radiation effect are truly dose-modifying over the whole dose spectrum. They all have a differential effect on the type of damage inflicted at high and low dose levels, i.e. those described by the linear and quadratic terms in the LQ model. This means that every modifier has a dose or dose per fraction dependence on the magnitude of the sensitization or protection. The details of that dose dependence will vary with the alpha/beta ratio of the tissue under consideration. Furthermore all tissues and tumours contain a mixture of cells, with different proliferative, redox and other characteristics that influence their sensitivity to radiation and their susceptibility to the radiomodifier. The influence of different subsets of cells changes as a fractionated treatment progresses and the sensitive cells are eradicated, leaving more resistant survivors. The overall response to a fractionated schedule then depends critically on whether there is re-assortment of cells from the resistant phase into more sensitive or modifiable phases before the next fraction in the series. In addition, the magnitude of dose modification depends totally on the standard curve against which the comparison is made. The reference standard is different in preclinical laboratory studies and in conventional clinical experience. Those differences must be considered when moving from the laboratory to the clinic and back again. The effect of these different factors is considered using the linear quadratic model to dissect the components. Examples are provided to demonstrate the clinical relevance.

Animals↗
PubMed1997

Allergy to cocamidopropyl betaine may be due to amidoamine: a patch test and product use test study.

Cocamidopropyl betaine (CAPB) is an amphoteric surfactant commonly used in personal care products and surface cleaners. Patch testing with commercially-available CAPB has yielded occasional reactions indicative of allergic contact dermatitis. To determine if subjects with previous positive patch tests would react in provocative use tests of products containing CAPB, and to study various contaminants in commercial CAPB supplies for allergenicity in these subjects, 10 subjects previously positive to CAPB on patch testing used a hair shampoo, hand soap, and body wash containing CAPB for 1-6 weeks or until a reaction developed. Later, they were patch tested to 2 different purity grades of CAPB and 3 possible manufacturing contaminants (dimethylaminopropylamine, amidoamine, and sodium monochloroacetate). 7 of the 10 subjects developed dermatitis from 1 or more CAPB-containing products at some point during the study. 9 of the 10 use-test subjects were then patch tested, and 6 of these subjects showed a reaction to amidoamine (0.1% aq.). None reacted to dimethylaminopropylamine (0.1% pet.). 1 subject reacted to CAPB but not to amidoamine. In the follow-up patch testing with CAPB that was free of amidoamine, there were no positive reactions. Most subjects who were patch-test-positive showed a reaction when using CAPB-containing skin and hair care products. The chemical amidoamine, which is used in the synthesis of CAPB and which is a known contaminant of CAPB preparations, is likely to be the actual sensitizer in most cases rather than CAPB itself. The results do not rule out the possibility that CAPB itself may be an allergen in rare cases.

Acetates↗
PubMed1997

ARCON--current status: summary of a workshop on preclinical and clinical studies.

The current status of the experimental and clinical studies of ARCON was presented. This is a new approach aimed at increasing the effectiveness of radiotherapy by acceleration in order to avoid tumour cell regeneration during therapy and using two forms of radiosensitizer of hypoxic cells. The background knowledge about human tumour proliferation and oxygenation was expertly reviewed. New experimental data were presented for various aspects of carbogen, Nicotinamide and a range of other potential sensitizers. These included mechanistic investigations, radiobiological studies of clinically relevant dose levels, tumour and normal tissue effects, pharmacology and blood flow measurements. Clinical data for both toxicity and initial estimates of the tumour response were presented. Extensive discussions about the side effects of Nicotinamide took place. The main conclusions from the preliminary clinical results were encouraging, especially in head and neck and bladder tumours. Two studies showed that local control is considerably increased compared with previous experience and with results from centres of excellence elsewhere. Several other clinicians reported optimism. So far, ARCON has not been taken into randomized clinical trials and the data are therefore still, of necessity, compared with historical controls or with general clinical experience.

Animals↗
PubMed1996

Fractionation in medium dose rate brachytherapy of cancer of the cervix.

PURPOSE: To establish an optimum fractionation for medium dose rate (MDR) brachytherapy from retrospective data of patients treated with different MDR schedules in comparison with a low dose rate (LDR) schedule. METHODS AND MATERIALS: The study population consists of consecutive Stage IB-IIA-IIB patients who received radiotherapy alone with full dose brachytherapy plus external beam pelvic and parametrial irradiation from 1986-1993. Patients also receiving surgery or chemotherapy were excluded. The LDR group (n = 102, median follow-up: 80 months) received a median dose to Point A of two 32.5 Gy fractions at 0.44 Gy/h plus 18 Gy of external whole pelvic irradiation. The MDR1 group (n = 30, median follow-up: 45 months) received a mean dose of two 32 Gy fractions at 1.68 Gy/h. An individual dose reduction of 12.5% was planned for this group according to the Manchester experience, but only a 4.8% dose reduction was achieved. The MDR2 group (n = 10, median follow-up: 36 months) received a dose of two 24 Gy fractions at 1.65 Gy/h. The MDR3 group (n = 10, median follow-up 33 months) received a mean dose of three 15.3 Gy fractions at 1.64 Gy/h. And finally, the MDR4 group (n = 38, median follow-up: 24 months) received six 7.7 Gy fractions from two pulses 6 h apart in each of three insertions at 1.61 Gy/h. The median external pelvic dose to MDR schedules was between 12 and 20 Gy. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) to tumor (Gy10) and rectum (Gy3), assuming T1/2 for repair = 1.5 h. RESULTS: The crude central recurrence rate was 6% for LDR (mean BED = 95.4 Gy10) and 10% for MDR4 (mean BED = 77.0 Gy10) (p = NS). The remaining MDR groups had no recurrences. Grade 2 and 3 rectal or bladder complications were 0% for LDR (rectal BED = 109 Gy3) 83% for MDR1 (BED = 206 Gy3), and 30% for MDR3 (BED = 127 Gy3). The MDR2 and MDR4 groups presented no complications (BED, 123 Gy3, and 105 Gy3, respectively). The LQ formula appears to correlate with late complications of the different MDR regimens. A BED above 125 Gy3 was associated with Grade 2 + 3 rectal complications. Adequate central tumor control may be compromised with a tumor BED below 90-95 Gy10. CONCLUSIONS: Medium dose rate brachytherapy at 1.6 Gy/h to Point A has a marked dose rate effect. Increased fractionation is the cost of overcoming the less favorable therapeutic ratio for MDR than for LDR. A larger (25%) reduction of brachytherapy dose than previously reported is also necessary. Our most recently developed schedule for Stage I-II patients is three insertions on three treatment days with six 8.0 Gy brachytherapy fractionations, two on each treatment day, following or preceding an external whole pelvis dose of 18 Gy, and followed by additional external parametrial dose.

Adult↗
PubMed1996

Application of the linear-quadratic model to myelotoxicity associated with radioimmunotherapy.

The purposes of this study were: (1) to use the linear-quadratic model to determine time-dependent biologically effective doses (BEDs) that were delivered to the bone marrow by multiple infusions of radiolabeled antibodies, and (2) to determine whether granulocyte and platelet counts correlate better with BED than administered radioactivity, which does not take stem cell repopulation, i.e., time, into consideration. Twenty patients with B-cell malignancies that had progressed despite intensive chemotherapy and who had a significant number of malignant cells in their bone marrow were treated with multiple 0.7-3.7 GBq/m2 (18-100 mCi/m2) intravenous infusions of Lym-1, a murine monoclonal antibody that binds to a tumour-associated antigen, labeled with iodine-131. Granulocyte and platelet counts were measured in order to assess bone marrow toxicity. BEDs were calculated according to the formula: BED=D(1+gD/(alpha/beta))-0.693(Tn-Tk)/alphaTp, where D represents the absorbed dose of radiation delivered to the red marrow by penetrating emissions of 131I throughout the whole body and nonpenetrating emissions of 131I in the blood and bone marrow, g is a factor that depends on the duration of irradiation relative to the repair half-life of human bone marrow, alpha is the coefficient of nonrepairable damage per Gy, beta is the coefficient of repairable damage per Gy2, Tn is the time required to reach the granulocyte or platelet count nadir after an 131I-Lym-1 infusion, Tk is the time at which bone marrow proliferation begins after the start of treatment and Tp is the doubling time of the bone marrow after the granulocyte or platelet count nadir has been reached. The cumulative 131I-Lym-1 radioactivity administered to each patient was calculated. Biologically effective doses from multiple 131I-Lym-1 infusions were summated in order to arrive at a total BED for each patient. There was a weak association between granulocyte and platelet counts and radioactivity (the correlation coefficients were -0.23 and -0.60, respectively). Likewise, there was a weak association between granulocyte and platelet counts and BED (the correlation coefficients were -0.27 and -0.40, respectively). The attempt to take bone marrow absorbed doses and overall treatment time into consideration with the linear-quadratic model did not produce a stronger association than was observed between peripheral blood counts and administered radioactivity. The association between granulocyte and platelet counts and BED may have been weakened by several factors, including variable bone marrow reserve at the start of 131I-Lym-1 therapy and the delivery of heterogeneous absorbed doses of radiation to the bone marrow.

Agranulocytosis↗
PubMed1996

Radiosensitisation in normal tissues with oxygen, carbogen or nicotinamide: therapeutic gain comparisons for fractionated x-ray schedules.

METHODS: Radiosensitisation with oxygen, carbogen or nicotinamide alone and oxygen or carbogen combined with nicotinamide was compared in early and late responding normal tissues in rodents. X-ray treatments were delivered as single doses or fractionated schedules of 2 fractions in 1 day, 2, 12 and 36 fractions in an overall time of 12 days and 10 fractions in 5 or 12 days. Acute skin reactions, survival of intestinal crypts, breathing rate, reduction in the packed red-cell volume and clearance of 51Cr-EDTA were used as assays of epidermal, gut, lung and renal damage. RESULTS: Relative to air-breathing mice, carbogen or oxygen produced a small, and not always significant, increase in sensitivity (enhancement ratios < or = 1.15) in gut, lung and kidneys; however, in skin a dose enhancement of 1.2-1.3 was observed. The effect of nicotinamide in air, carbogen or oxygen was studied only in lung and gut. The drug produced variable but generally significant increases in radiosensitisation ( < or = 1.26) in all three gases. Relative to treatments in air, enhancement ratios for nicotinamide alone were usually slightly higher than those observed when either carbogen or oxygen were administered without the drug. With all three modifiers (i.e. oxygen, carbogen, nicotinamide alone or for the drug-gas combinations) there was no significant change in the enhancement ratios observed as the number of radiation dose fractions was varied. CONCLUSIONS: Comparisons with fractionated X-ray studies done previously in rodent tumours indicate that a therapeutic benefit, relative to lung, gut and renal damage, would be observed with oxygen or carbogen alone but not with nicotinamide alone. The greatest gain would be achieved with the combination of carbogen and nicotinamide, with which a benefit was observed even relative to epidermal damage. These results indicate that some decrease in normal tissue tolerance could be observed when using these modifiers in clinical radiotherapy and, although small, the appropriate dose reductions should be considered; caution should be exercised especially when carbogen and nicotinamide are used in conjunction with the more radical accelerated schedules.

Animals↗