Biomedical subjects
Publications and source records attributed to B Glimelius.
Computed tomography (CT) was performed on 204 patients with rectal carcinoma in an attempt to determine the tumour stage preoperatively. In 154 patients CT and histopathology could be compared. Correct staging was achieved in 60 to 70 per cent of the patients, but considerable over- and understaging limit the use of CT in preoperative staging of rectal carcinoma.
During the last few years several factors have contributed to an increasing change in the medical treatment of advanced colorectal cancer. Among them are the more general acceptance of the impact of chemotherapy on quality of life and survival in first as well as in second-line treatment, the introduction of new drugs and the definition of novel endpoints which can roughly be defined as "patient benefit". For this reason the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) felt it was appropriate to organize a workshop with experts from different countries and national groups to discuss in depth several aspects concerning the treatment of patients with advanced colorectal cancer.
In a series of 328 patients with adenocarcinoma of the rectum and rectosigmoid, 39 had a tumour which was considered locally non-resectable (19 patients) or borderline resectable (20 patients). Twenty-eight of these patients received radiation therapy with a daily target dose of 2 Gy up to a total of 46 Gy. If the tumour was still considered non-resectable 3 weeks later, radiation therapy was usually continued up to a total dose of 64 Gy together with 5-fluorouracil. Fifteen patients with a non-resectable tumour received radiation therapy up to a total dose of either 46 Gy (7 patients) or 64 Gy (8 patients). Only two patients underwent resection. Of the 20 patients with a tumour that was considered borderline resectable, 13 received 46 Gy. Nine patients in this group were radically resected. Totally 11 tumours were resected, constituting 39 per cent of the patients who were treated up to 46 Gy or more. Truly locally inoperable tumours in this series were thus rarely converted to extirpative tumours by means of radiation therapy. Most patients with a tumour considered borderline resectable seemed to benefit from the treatment. In addition, the palliative effect of radiation therapy was excellent.
In 72 of 81 consecutively diagnosed patients with Hodgkin's disease pretreatment sera were available for analysis of serum thymidine kinase (S-TK) levels. In relation to clinical parameters, such as stage, histopathology and general symptoms, significant correlations were found with higher (S-TK) levels in advanced disease as well as in patients with B-symptoms. When the prognostic ability was examined, patients in stages IA and IIA could be divided according to S-TK levels into two different groups in relation to disease-free survival. This latter finding makes this serum test interesting as an additional tool in the clinical evaluation and in the therapeutic decision concerning patients with Hodgkin's disease.
One hundred and thirty-three consecutive cases originally classified either as a lymphocytic lymphoma of the B-CLL type or as an immunocytic (IC) lymphoma could be reclassified morphologically and analyzed for the presence of cytoplasmic immunoglobulins (cIg) with the PAP-technique. The morphologic reclassification confirmed the initial diagnosis in most cases, whereas after staining for cIg, the diagnosis was changed in a large number of cases, i.e. from B-CLL to IC, or the reverse, or from IC of the polymorphic subtype (ICp) to 'high-grade' non-Hodgkin lymphoma (NHL). Cases classified as IC were often localized (stage I+II: 22/43) with a long disease-free survival after local radiation therapy, while B-CLL were usually generalized. For patients in stage IV, the prognosis of B-CLL was significantly superior to that of IC, which in turn was superior to the prognosis of cases referred to as 'high-grade' NHL. The difficulties in the morphologic distinction between B-CLL and IC on one hand and between ICp and some 'high-grade' NHL on the other hand, as well as the clinical significance of these distinctions, are discussed.
Palliative chemotherapy can add to the duration and quality of life in patients with advanced pancreatic and biliary cancer, albeit in a limited way. Between March 1995 and October 1997, 31 symptomatic patients were treated with etoposide in a phase II trial. Measurements of objective and subjective responses were performed, the latter by the treating physician and with the method of clinical benefit response (CBR). Quality of life was evaluated with the EORTC QLQ-C30 questionnaire. A partial response was seen in 2 (6%) patients. Subjective responses/quality of life gains were seen in 6 (19%), 7 (23%) and 9 (29%) patients, respectively, with the different methods. Median survival was 4.5 months. WHO grade 3 and 4 toxicity, alopecia excluded, was seen in 20% of the patients. The clinical activity of etoposide is limited, and in the same low range as other drugs in these diseases.
Preoperative radiotherapy lowers local recurrence rates after rectal cancer surgery, as seen in several randomised trials. Postoperative radiotherapy is also effective, although a higher radiation dose is required. In addition, preoperative, but not postoperative (unless combined with chemotherapy) radiotherapy also improves survival slightly. Since the toxicity profile also favours preoperative therapy, this is a more attractive approach. The trials have also shown that a sufficiently high biological dose is required to achieve any influence on local failure rates. If the dose at each radiation fraction is higher (e.g. 5 Gy), the radiation can be given much faster (during one week) than if a 'conventional' fraction size of about 2 Gy is used (4-5 weeks). Surgery can also safely be performed immediately after the end of the short radiation course, but not until several weeks later after conventional radiotherapy. This adds to the practicability of the short schedules. An inappropriate radiation technique was used particularly in one trial using multiple 5 Gy fractions. This resulted in unacceptable acute and late toxicity. However, several other trials have shown that the treatment is safe. Preoperative 5 x 5 Gy is one of the most extensively investigated oncological treatments with proven efficacy. Since the total dose is comparably low (25 Gy), the decreased therapeutic ratio of using fraction sizes above 2 Gy appears to have no clinical relevance. The experience indicates, however, that every therapeutic modality should be used in an optimal way.
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Flow cytometric DNA analysis was performed in 67 tubular, tubulovilous and villous rectal adenomas with different degree of dysplasia. One of the adenomas contained a focus of early invasive carcinoma. All but one of the 67 adenomas had near diploid DNA histograms; the exception was a tubular adenoma with severe dysplasia but without signs of early invasion. Flow cytometric DNA analyses of adenomas may in some cases provide valuable information. The low frequency of aneuploidy indicates, however, that routine DNA measurements are questionable. Rather, the analysis should be restricted to certain cases like those with high malignant potential, cases with suspected early invasive carcinoma, and adenomas not radically removed.
Local recurrence is a common problem among patients treated surgically for adenocarcinoma of the rectum and rectosigmoid. When a local recurrence has become clinically manifest, curative therapy is virtually impossible. Asymptomatic local recurrences are difficult to find clinically, especially in patients treated with an abdominoperineal resection. In 177 patients who had undergone locally curative surgery and had had an uneventful recovery, a postoperative follow-up program, including computed tomography (CT), was carried out. In 77 per cent (137/177) a mass was observed in the pelvis at the first postoperative CT. This mass partly represents fibrosis due to radiation therapy. The risk of developing local recurrence cannot be foreseen from a CT image. CT should not be performed by routine but only in patients with symptoms in whom local recurrence cannot be verified by clinical examination, and always with CT-guided needle biopsy of the detected mass.
Six patients with mediastinal involvement of Hodgkin's disease were examined with magnetic resonance imaging (MRI) at 0.35 T before and/or at various stages of therapy, with the sequences TR/TE: 500/35, 500/70, 1600/35 and 1,600/70. Before therapy the image intensity of tumour involved lymph nodes deviated considerably from fat and muscle, but no clear difference was discerned between histopathologic subtypes or tumour localizations. After efficient therapy, the tumour image intensities and relaxation rates approached those of muscle and fibrous tissue, but remained at pre-therapy values when the patient was not in full remission. A similar pattern was found in a 'normal-tissue'--'tumour' plot, based on vector analysis of the original sets of 4 images. It is concluded that persistent tumour involvement in the mediastinum may be distinguished from fibrosis and that MRI may thus be of value in the follow-up of patients with Hodgkin's disease.
Twenty-four patients with malignant bone marrow involvement or polycythemia vera, 8 patients with reactive bone marrow and 7 healthy individuals were examined with spin-echo magnetic resonance imaging at 0.35 T and 0.5 T. Signs of an increased longitudinal relaxation time, T1, were found when normal bone marrow was replaced by malignant cells, polycythemia vera or reactive marrow. A shortened T1 was indicated in 4 patients in bone marrow regions treated by radiation therapy; the marrow was most likely hypocellular in these cases. The estimated T1 relaxation times were highly correlated to the cellularity of the bone marrow as assessed by histology. Among patients with close to 100 per cent cellularity neither T1 nor T2 discriminated between the various malignancies or between malignant and reactive, non-malignant bone marrow. Characterization of tissues in terms of normalized image intensities was also attempted, the motive being to avoid approximations and uncertainties in the assessment of T1 and T2. The normalization was carried out with respect to the image of highest intensity, i.e. the proton density weighted image. The results were in agreement with those for T1 and T2. It was concluded that MRI is valuable for assessing bone marrow cellularity, but not for differentiating between various bone marrow disorders having a similar degree of cellularity.
Magnetic resonance imaging (MRI) was compared with chest radiography, computed tomography (CT) and ultrasonography (US) for demonstration of spleen and liver engagement and enlarged lymph nodes in patients with malignant lymphoma. The investigation comprised 24 patients with Hodgkin's disease (HD) and 39 with non-Hodgkin lymphoma (NHL). MRI demonstrated enlarged lymph nodes, distinctly separated from vessels, fat, muscle, liver and occasionally also pancreas without any contrast medium. The distinction between lymph nodes and spleen was, however, poor in the images. In the mediastinum, MRI was superior to chest radiography and had an accuracy similar to that of CT. In the abdomen and the pelvis MRI had slight advantages over CT in detection of enlarged lymph nodes. Compared with US the MRI results were similar in the abdomen and somewhat better in the pelvis. MRI and US were better than CT in revealing HD infiltrates in the spleen. Infiltration of NHL in the spleen was slightly better disclosed at US than at CT and MRI; most of the NHL infiltration, confirmed at histopathology, could, however, not be revealed with any of the modalities, except when the size of the spleen was considered. Regions in the spleen, displayed with low image intensity in the T2 weighted image, were most likely due to increased amount of fibrotic tissue in the lymphomatous lesions. Good demonstration of lymph nodes and lymphomatous lesions in the spleen with MRI required two sequences; one with short TR and TE (T1 weighted image) and one with long TR and TE (T2 weighted image).
An attempt was made to explore whether relaxation times and/or normalized image intensities obtained from magnetic resonance imaging (MRI) can separate malignant and non-malignant lymphomatous tissue. Spin-echo (SE) techniques with repetition times of 500 and 1,500 ms and echo times of 35 and 70 ms were used for estimating T1 and T2. Estimation of T1 and T2 with such a low number of spin-echo sequences resulted in considerable variation in the data especially when T1 was long. Similar information was also extracted by normalizing the image intensities to the 'proton density' image (1,500/35), and the spread of the data was then markedly reduced. Therefore, the method of normalizing was considered a more appropriate way of handling the image data when only a few sequences were available. No significant difference could be discerned in the MRI parameters between normal spleens and spleens infiltrated with malignant lymphoma, between normal livers and livers in patients with malignant lymphoma and between lymph nodes with low or high grade non-Hodgkin lymphoma. Lymphomatous tissue had similar MRI characteristics irrespectively of whether the cells were malignant or not, or located in spleens or in lymph nodes. The main biologic explanation for variation in data seems to be mostly the variable amounts of fibrosis, necrosis, oedema and/or iron content.
Twenty-one consecutive patients with anal carcinoma of squamous cell type were evaluated by transanorectal ultrasonography (Brüel & Kjaeer) prior to radiation therapy. The normal anal anatomy, with three distinct layers, was easily demonstrated both in vitro and in vivo. The middle, low echogenic layer corresponded above the dentate line to the muscularis propria and more distally to the internal and external sphincters. A hypoechoic area, representing tumour, was detected in all patients. Using the ultrasound findings, it appeared possible to classify the depth of tumour invasion into four levels with respect to whether or not invasion had reached or penetrated beyond the muscular wall or into adjacent organs. Eighteen of 21 tumours had penetrated the muscular wall. In 3 cases low echogenic, rounded structures, interpreted as enlarged lymph nodes, were identified. The ultrasonographic findings were compared with digital staging. Tumour invasion had penetrated the muscular wall in 2 out of 3 stage T1 patients and in 10 out of 11 stage T2 patients. Prospective studies will show whether estimates of tumour size and depth of invasion in relation to various normal structures, as judged by ultrasonography, are of value prognostically and for the choice of therapy.
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In 545 consecutive patients undergoing elective or emergency surgery for colorectal cancer (370 colon and 175 rectum), mortality and morbidity were analysed in different age groups with special reference to patients over 80 years old. In that group, 33% had an emergency operation, compared with 18% below that age. Postoperative mortality after elective surgery ranged from 3 to 11% in the different age groups, but was not significantly related to age. In contrast, postoperative in-hospital mortality after emergency surgery was high (38%) among those older than 80 years, compared with 6% below 75 years and 24% between 76 and 80 years. Postoperative morbidity, i.e. infections and cardiovascular disease, increased with age, as did the length of hospital stay. Five-year survival, independent of age, was poorer after emergency surgery than after elective surgery. It is concluded that elective colorectal resection for cancer in elderly patients is a safe procedure.
Using cytofluorometric single-cell DNA analysis, the pattern of nuclear DNA content was determined in preoperative biopsies from 166 unselected primary adenocarcinomas of the rectum or rectosigmoid. The pattern was aneuploid (AN) in 125 (75%) of the tumours, was aneuploid (AN) in 125 (75%) of the tumours, near-diploid with aneuploid cells (ND-anc) in 26 (16%) and near-diploid (ND) in 15 (9%). The DNA content was not related to tumour stage or degree of differentiation. The clinical course tended to be more favourable in patients with ND tumour than in those with AN or ND-anc pattern. The nuclear DNA content in rectal carcinoma thus can be estimated in preoperative biopsies, and the pattern may serve as a prognostic parameter.