Are patients with Hodgkin lymphoma and high-grade non-Hodgkin lymphoma in clinical therapy optimization protocols representative of these groups of patients in Germany?

BACKGROUND: Improvement of lymphoma therapy is largely driven by clinical therapy optimization protocols (TOPs). It is unclear, however, whether the patients treated in clinical TOP are representative for all patients. PATIENTS AND METHODS: TOP participants were compared with nonstudy patients in a population-based approach. The study included patients with Hodgkin lymphoma (HL) and high-grade non-Hodgkin lymphoma (hgNHL). Incident cases (N = 743) were ascertained in a large population-based epidemiologic survey. Each patient's status with respect to exclusion criteria of the pertinent TOP was abstracted from primary data sources. TOP participants were identified on the basis of the trial databases. Baseline characteristics and risk factor prevalence were compared between nonstudy and TOP patients. RESULTS: Eligible for the respective TOPs were 64.1% of all incident HL patients and 29.6% of all hgNHL patients in the population. Main exclusion criterion was age (HL: 15.2%; hgNHL: 27.4%). Only 71 HL patients (23.0%) and 11 hgNHL patients (3.4%) had actually been enrolled in the respective TOPs. CONCLUSIONS: TOP participants do not represent all patients with hgNHL and HL in the population. TOP inclusion criteria caused considerable selection among the participants. Further investigation is required to clarify possible limitations for the application of the outcomes observed in TOP patients for all patients with these diseases.

14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group.

PURPOSE: This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen given in 14-day intervals (BEACOPP-14) with granulocyte colony-stimulating factor (G-CSF) support in advanced Hodgkin's lymphoma. PATIENTS AND METHODS: From July 1997 until March 2000, 94 patients with Hodgkin's lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy. RESULTS: All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin's lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively. CONCLUSION: Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin's Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial.

BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin's disease (HD). PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Adsorption and interaction of ethylene on RuO2(110) surfaces.

Ethylene (C2H4) adsorbed on the stoichiometric and oxygen-rich RuO2(110) surfaces, exposing coordinatively unsaturated Ru-cus and O-cus atoms, is investigated by applying high-resolution electron energy-loss spectroscopy and thermal desorption spectroscopy in combination with isotope labeling experiments. On the stoichiometric RuO2(110) surface C2H4 adsorbs and desorbs molecularly. In contrast, on the oxygen-rich RuO2(110) surface ethylene adsorbs molecularly at 85 K and is completely oxidized through interaction with O-cus and O-bridge upon annealing to 500 K. The first couple of reactions are observed at 200 K taking place on Ru-cus: A change from pi- to sigma-bonding, formation of -C=O and -C-O groups, and dehydrogenation giving rise to H2O adsorbed at Ru-cus. Maximum reaction rate is reached for C2H4 chemisorbed at Ru-cus with O-cus neighbors on each side. A model for the first couple of reactions is sketched. For the final combustion, C2H4 reacts both with O-cus and O-bridge. Ethylene oxide is not detected under any circumstance.

A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation.

The control mechanisms involved in regeneration of murine intestinal crypts after perturbations are presently not well understood. The existence of some feedback signals from the cells on the villus to the cells in the crypt has been suggested. However, some recent experimental data point to the fact that regeneration in the crypt starts very early after perturbation, at a time when the villus cell population has hardly changed. In particular, this early cell proliferative activity is seen specifically at the bottom of the crypt, i.e. in the presumed stem cell zone and furthest from the villus. The objective of this study was to investigate whether a new concept of regulation operating solely at the stem cell level could explain the present mass of accumulated data on the post-irradiation recovery, which is an extensively studied perturbation from the experimental point of view. In order to check its validity, the new concept was formalized as a mathematical simulation model thus enabling comparison with experimental data. The model describes the cellular development from stem cells to the mature villus cells. As a basic feature it is assumed that the self-maintenance and the cell cycle activity of the stem cells are controlled by the number of these cells in an autoregulatory fashion. The essential features of the experimental data (i.e. the recovery with time and the consistency between different types of measurements) can be very well reproduced by simulations using a range of model parameters. Thus, we conclude that stem cell autoregulation is a valid concept which could replace the villus crypt feedback concept in explaining the early changes after irradiation when the damage primarily affects the crypt. The question of the detailed nature of the control process requires further investigation.

A dynamic model of proliferation and differentiation in the intestinal crypt based on a hypothetical intraepithelial growth factor.

A widely accepted model of the temporal and spatial organization of proliferation and differentiation in intestinal epithelial is based on a cellular pedigree with all cells descending from a few active stem cells and undergoing a sequence of transitory divisions until the non-proliferating maturing cell stages develop. Model simulations have shown that such a pedigree concept can explain a large variety of data. However, so far there is neither a direct experimental proof for the existence of an intrinsic age structure in the transitory proliferative cell stages nor for the distinction between stem and transitory cells. It is our objective to suggest an alternative model which is based on evidence for intercellular communications such as might be mediated through gap junctions. We consider the diffusion of a hypothetical intraepithelial growth factor in a chain of cells which are connected via gap junctions. Individual cells can divide if a critical growth factor concentration is exceeded. Simulation studies show that the model is consistent with many observed features of the small intestinal crypt in steady state and after perturbation.

Combined positive/negative selection for highly effective purging of PBPC grafts: towards clinical application in patients with B-CLL.

Autologous PBPC transplantation is a potentially curative treatment for patients with chronic lymphocytic leukemia (CLL). As the autografts are frequently contaminated with large numbers of tumor cells, we have studied double purging of PBPC using immunomagnetic CD34+ cell selection (Isolex 300i) followed by negative depletion with anti-CD19/20/23/37-labeled immunomagnetic beads. In four small-scale experiments using PBPC from patients with CLL or leukemic low-grade lymphoma, double purging resulted in CD34+ enrichment from 0.9-4.4% to 95.8-99.4%. Lymphoma cells were always undetectable by FACS and PCR (CDR3 or t(14;18)) after negative depletion. Next, seven heavily contaminated full grafts from five patients with CLL or lymphoplasmocytoid immunocytoma were subjected to the double purging procedure, resulting in a CD34+ enrichment from 1.6% (0.7-5.6) to 98.5% (96-99.8). The CD34+ yield after double purging was 1.3-6.3 x 10(6)/kg, according to a median recovery of 32%. The overall reduction of lymphoma cells was 5.6 (>4.6-6) log. Although CLL cells were completely absent after purging in five cases as assessed by FACS, all grafts remained PCR positive. The first two patients have been reinfused with double selected products after myeloablative radiochemotherapy and showed prompt and uneventful hematopoietic engraftment. We conclude that without significant loss of CD34+ cells, negative depletion adds 2 log of CLL cell depletion to CD34+ selection, resulting in an overall purging efficacy of more than 5 log. This combination of positive and negative selection can be successfully applied even to heavily contaminated PBPC grafts.

Influence of altered gravity on the cytochemical localization of cytochrome oxidase activity in central and peripheral gravisensory systems in developing cichlid fish.

Cichlid fish larvae were reared from hatching to active free swimming under different gravity conditions: natural environment, increased acceleration in a centrifuge, simulated weightlessness in a clinostat and near weightlessness during space flight. Cytochrome oxidase activity was analyzed semiquantitatively on the ultrastructural level as a marker of regional neuronal activity in a primary, vestibular brainstem nucleus and in gravity receptive epithelia in the inner ear. Our results show, that gravity seems to be positively correlated with cytochrome oxidase activity in the magnocellular nucleus of developing fish brain. In the inner ear the energy metabolism is decreased under microgravity concerning utricle but not saccule. Hypergravity has no effect on cytochrome oxidase activity in sensory inner ear epithelia.

Can factors influencing in-patient treatment in Hodgkin's disease be identified?--Retrospective analysis of HD6 patients of the GHSG.

Patients receiving chemotherapy for Hodgkin's disease can potentially be treated in the out-patient department. In spite of this the proportion of patients receiving the chemotherapy on in-patient departments is 54% per chemotherapy cycle in average in the HD6 trial for advanced Hodgkin's disease of the German Hodgkin Study Group (GHSG). The aim of this retrospective analysis is to identify the set of parameters which influence the decision of in- or out-patient treatment for the patients in the HD6 trial. Parameters tested in the univariate analysis are the patient characteristics, the type of chemotherapy, toxicity and the type of treatment institution. The significant parameters are included in a logistic regression model. From this multivariate analysis the type of treatment institution turned out to be the most important factor in the decision of treatment setting. Restricting the analysis to university clinics, the treatment setting of the first two cycles is more influencial than patient dependent parameters.

Cost of illness of malignant lymphoma in Germany.

Cancer causes a high economic burden. The purpose of this study is to determine and compare the direct, indirect and societal costs of illness for Hodgkin's Disease (HD), Non-Hodgkin's Lymphoma (NHL), Plasmocytoma and Chronic Lymphatic Lymphoma (CLL). We used a database of 1.9 million individuals enrolled in a statutory sickness fund in Germany to identify 4,172 patients treated for malignant lymphoma in 2000. Direct, indirect and societal costs were calculated using a case-control design and the human capital approach. Direct cost (in Euro) for patients with HD was 3604, for NHL patients 6,149, for Plasmocytoma 8,400, and for CLL patients 3,226. Total indirect cost for HD was 69 million, for NHL patients 404 million, for Plasmocytoma 144 million, and for CLL patients 52 million. Totalling 1.7 billion Euro in economic cost for Germany in 2000, with 44,000 productive years lost, malignant lymphomas are a relatively costly disease group. As life expectancy increases, costs for malignant lymphoma are likely to rise due to the high prevalence among the elderly. Further research employing disaggregated, incidence-based cost is needed.

Effects of development and altered gravity conditions on cytochrome oxidase activity in a vestibular nucleus of the larval teleost brain: a quantitative electronmicroscopical study.

The mitochondrial enzyme, cytochrome oxidase, was localized cytochemically in the nucleus magnocellularis, a primary relay nucleus of vestibular information within the area octavolateralis in the fish brain. Larvae of the cichlid fish Oreochromis mossambicus were analyzed at different developmental stages (4, 10, and 35 days post-hatching) and after long-term exposure (8 days) to increased gravity (2-4 g). Quantification of highly reactive, moderately reactive, and nonreactive mitochondria reveals differences in the cytochrome oxidase activity of various cellular structures, for example, perikarya of neurons, presynaptic terminals, and myelinated and nonmyelinated cell profiles. Cytochrome oxidase activity in the mitochondria of neuronal perikarya increases during development which parallels the differentiation of the area octavolateralis. This possibly reflects the increasing energy demand during maturation and innervation of the magnocellular nucleus. Hyper-g-exposure of the larvae for 8 days (centrifuge) caused a further augmentation of cytochrome oxidase activity in the perikarya within the nucleus magnocellularis. This may reflect an increased oxidative metabolism resulting from the need for compensation of altered inputs from gravity-sensitive epithelia in the inner ear. Another possibility is that acceleration within a centrifuge causes physiological stress for the animals and, therefore, influences the cytochrome oxidase activity in neurons.

Imaging of thick sections of nervous tissue with energy-filtering transmission electron microscopy.

Electron microscopy of nervous tissue requires on the one hand nanometre resolution for the analysis of fine structures of nerve cell contacts, for instance synaptic vesicles, synaptic membranes and associated organelles. On the other hand, the visualization of the three-dimensional organization of nervous tissue on the level of dendrites and neurites is essential for the understanding of neuronal integration and also for a stereological evaluation of quantitative parameters such as size and shape of synaptic contact zones, number and distribution of synaptic vesicles, organization of cytoskeleton and distribution of organelles like mitochondria and endoplasmic reticulum. Therefore, it is necessary to have access to the fine structure and to the spatial organization within one sample. Energy-filtering transmission electron microscopy (EFTEM) enables the imaging of sections up to 1 micron thickness with a high resolution because the chromatic error due to inelastic scattering is avoided by selecting electrons within a restricted energy-loss range for imaging. The contrast depends strongly upon the section thickness, the selected energy range and the composition of the sample, so that optimum imaging conditions can be found for each object. Different staining protocols enable either a high global contrast or a selective staining of peculiar tissue properties. The three-dimensional organization can be visualized with stereopairs or with extended tilt series, which shows that characteristic structures as the synaptic junctions are detectable only within a narrow range of orientations to the electron beam. This is especially important for quantitative approaches with stereological tools which profit generally from the fact that a wide range of section thickness is available with EFTEM. EFTEM is therefore a powerful tool for the imaging of thick sections of biological materials with attractive possibilities of contrast tuning and advantages for stereological quantifications. The main benefit is the rapid and effective visualization of the three-dimensional organization of cells and tissues.

Correlation of altered gravity and cytochrome oxidase activity in the developing fish brain.

The mitochondrial enzyme, cytochrome oxidase, was localized cytochemically in the nucleus magnocellularis, a primary relay nucleus of vestibular information within the area octavolateralis in the fish brain. Cichlid fish larvae were analyzed after long-term exposure (9 days) to altered gravity situations: increased acceleration in a centrifuge (3 g) and near weightlessness during space flight. Controls (1 g) were reared under identical conditions in the centrifuge but without rotation on earth or with an acceleration resulting in gravity of 1 g in space shuttle. Quantification of highly reactive mitochondria reveals a correlation of gravity and cytochrome oxidase activity: low enzyme activity in respect to 1 g controls under near weightlessness conditions and an increased activity after hyper-g exposure in a centrifuge. This gravity effect on the energy metabolism of vestibular nuclei of developing cichild fish seems to reflect adaptational processes in response to gravity stimulation.

Is the international prognostic score for advanced stage Hodgkin's disease applicable to early stage patients? German Hodgkin Lymphoma Study Group.

BACKGROUND: The seven-factor International Prognostic Score (IPS) has been developed and verified for patients with advanced stage Hodgkin's disease (HD). This report aims to assess the predictive power of the IPS for early stage HD patients. PATIENTS AND METHODS: Data on patient characteristics, therapy and follow-up were available for 1424 adult patients in clinical stages I-IIIA treated for primary HD in two German Hodgkin's Lymphoma Study Group (GHSG) trials (1988-1994). Patients with risk factors or in stage IIIA received chemo radiotherapy (CMT; trial HD5); others received extended field radiotherapy (RT) alone (HD4). The IPS could be calculated for 712 HD5 and 249 HD4 patients (70%). The prognostic value of the IPS and its component factors was assessed using Cox proportional hazards regression. A search was made for additional factors which could add predictive power to the IPS. RESULTS: The IPS identified 40% of the unfavourable early stage patients with an 8% lower disease-free survival at six years (hazard ratio 1.66, P = 0.0018). The factor 'low albumin' was the only score component giving a significant individual contribution. Allowing for the IPS, extranodal involvement, particularly in stages IIB-IIIA, was associated with worse prognosis, but no further significantly prognostic factors were revealed. The IPS identified a similar hazard ratio in HD4, although here the effect was not significant. CONCLUSIONS: The IPS for advanced HD has modest predictive ability in unfavourable early stage patients. Modification of the IPS for use with early stages may improve its prognostic power.

The crypt cycle in mouse small intestinal epithelium.

We have used a mutation-induced marker system in the intestine of mice heterozygous at the Dlb-1 locus, which determines the expression of binding sites for the lectin Dolichos biflorus agglutinin, and the frequency of clustering of mutated crypts with time as a means of investigating the frequency of the crypt fission process and the crypt cycle. Whole-mount preparations from heterozygous Dlb-1b/Dlb-1a mice were stained with a peroxidase conjugate of Dolichos biflorus agglutinin. Mutations at the Dlb-1b locus in crypt stem cells result in loss of DBA-Px binding in these cells and subsequently their progeny, which eventually results in a rare isolated single, unstained crypt. The subsequent development of pairs, triplets and clusters of negative staining crypts has been assumed to be the result of crypt fission. The frequency of these fission events has been measured in control untreated mice. These negative crypts are the result of spontaneous mutations. We have also looked at mutated crypts after treatment with N-nitroso-N-ethylurea or N-methyl-N'-nitro-N-nitrosoguanidine of young adult mice, which elevates the number of mutations. Our results suggest that the crypt cycle in control animals is very long, 187 +/- 44 weeks (3.6 years, i.e. essentially the life of a laboratory mouse). This implies that about a third of the crypts may divide once in the life of a mouse. After sufficient time for conversion of mixed crypts to monophenotypic crypts after mutagen treatment several clusters of negative crypts were seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Ocular drug safety and HMG-CoA-reductase inhibitors.

150 patients suffering from primary hypercholesterolemia were divided into three different groups receiving (1) lovastatin, (2) simvastatin, or (3) fenofibrate as controls. The aim of the study was to detect possible drug-induced ocular side effects, especially in the lens. The study period was 2 years. Ophthalmological examination and Scheimpflug photography were performed at the beginning and every 6 months. Increases or decreases in the visual acuity were distributed very similarly in the three groups. Definite evidence of side effects was not found, nor was there evidence of deleterious effects on refraction. The intraocular pressure revealed intraindividual fluctuations without clinical significance. Many changes were observed in the lens, all were minimal, including those of the extreme lens periphery which had no effect on visual acuity. The present study shows the great value of Scheimpflug photography with densitometric image analyses because of its objectivity when compared with other methods. Our observations provide good evidence that lovastatin and simvastatin have no undesirable toxic effects on the lens and other ocular tissues, compared with fenofibrate.

The differentiation and lineage development of goblet cells in the murine small intestinal crypt: experimental and modelling studies.

The objective of this study was to provide a new insight into the origin and lineage development of mucus-producing cells in the small intestinal crypt. For this, new experimental data were obtained from both crypt sections and whole mounts. Model simulation studies were undertaken to investigate which rules are most likely to govern the dynamic cellular development and goblet cell pedigree. We have measured the frequency of mucus-secreting goblet cells (using alcian blue and periodic acid Schiff's stains) at each cell position in the ileal murine crypt. These measurements, made on sections, overestimate the number of goblet cells because of the size and centripetal position of the stained cytoplasm. The correction factor for this overscoring has been measured to be 0.25 by two independent methods. The data suggest that there are about 12 functional goblet cells per crypt many of which retain an ability to divide. We have also determined the labelling index of the crypt goblet cells at each cell position. Spatially, goblet cells exhibit a small degree of clustering in the crypt and show a good mixture with columnar cells. We have adapted our earlier dynamic matrix-based computer stimulation model to take into account goblet cell differentiation. The modelling suggested the following conclusions: firstly, goblet cells do not have their own stem cells but share a common stem cell with the columnar cells; secondly, the goblet lineage differentiates from the transit population two to three generations before the end of the lineage; and thirdly, the decision to switch on goblet properties is stochastic at a specific step in the development of columnar cells.

Scoring mitotic activity in longitudinal sections of crypts of the small intestine.

Various counts have been made of the number of mitotic figures in whole crypts and sections of crypts of the small intestine of the mouse. Samples were analysed from animals killed at different times of the day and at different times after administration of vincristine. Measurements have been made of the size of mitotic and interphase nuclei and of the radial position of mitotic figures. The correction factor, f, which is required to take into account the enhancement of mitotic counts in sections as a consequence of their centripetal position has been investigated. The results indicate the following: (1) transverse sections of the crypt differ from longitudinal sections if they involve cutting the intestine before fixation which may result in a relaxation of the crypt and its widening by 25%; (2) columnar cell nuclei have a shape that resembles a sphere flattened so that the average diameter is 20% greater in crypt transverse sections; (3) mitotic nuclei tend to be about half-way between the crypt edge and the central axis of the crypt; (4) between about four and seven times more mitotic figures have their mitotic axis parallel to the long axis of the crypt; (5) about one-third of all mitotic figures in a crypt are seen in a longitudinal section of the crypt. If this is related to the number of cells in the crypt as a whole and in a section, a correction factor fD for the mitotic index of 0.59 is obtained; (6) the correction factor fT derived from the shape and position of the mitotic figures measured in 3 microns longitudinal sections is 0.53; (7) relating cell cycle and mitotic accumulation data using a computer-based model of the crypt also permits a correction factor fmod to be estimated. This gives a value of 0.66. When sectioned material is used to calculate a mitotic index the most appropriate correction factor is fD; for mouse small intestine it is 0.59.