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C W Langberg

Publications and source records attributed to C W Langberg.

16 recordsLinked to original sources
PubMed2000

Treatment-time-dependence models of early and delayed radiation injury in rat small intestine.

BACKGROUND: The present study modeled data from a large series of experiments originally designed to investigate the influence of time, dose, and fractionation on early and late pathologic endpoints in rat small intestine after localized irradiation. The objective was to obtain satisfactory descriptions of the regenerative response to injury together with the possible relationships between early and late endpoints. METHODS: Two- and 26-week pathologic radiation injury data in groups of Sprague-Dawley rats irradiated with 27 different fractionation schedules were modeled using the incomplete repair (IR) version of the linear-quadratic model with or without various time correction models. The following time correction models were tested: (1) No time correction; (2) A simple exponential (SE) regenerative response beginning at an arbitrary time after starting treatment; and (3) A bi-exponential response with its commencement linked to accumulated cellular depletion and fraction size (the 'intelligent response model' [INTR]). Goodness of fit of the various models was assessed by correlating the predicted biological effective dose for each dose group with the observed radiation injury score. RESULTS: (1) The incomplete repair model without time correction did not provide a satisfactory description of either the 2- or 26-week data. (2) The models using SE time correction performed better, providing modest descriptions of the data. (3) The INTR model provided reasonable descriptions of both the 2- and 26-week data, confirming a treatment time dependence of both early and late pathological endpoints. (4) The most satisfactory descriptions of the data by the INTR model were obtained when the regenerative response was assumed to cease 2 weeks after irradiation rather than at the end of irradiation. A fraction-size-dependent delay of the regenerative response was also suggested in the best fitting models. (5) Late endpoints were associated with low-fractionation sensitivity and treatment-time dependence even in animal groups that exhibited minimal early mucosal reactions. CONCLUSION: Radiation injury scores in this rat small intestinal experimental model cannot be adequately described without time correction. 'Consequential' mechanisms contribute to the development of late effects, even in animals that do not develop severe early mucosal injuries. The initiation of the regenerative response is subject to a fraction-size-dependent mitotic delay and is linked to the level of accumulated cellular depletion. The response does not cease at the end of therapy but probably continues until maximal healing has taken place.

Animals↗
PubMed2000

[Can radiotherapy reduce the frequency of restenosis after coronary angioplasty?].

Today, percutaneous transluminal coronary angioplasty (PTCA) is the most important treatment modality for coronary artery disease. However, restenosis occurs in 20-40% of the vessels in spite of the use of stents. Intravascular radiation therapy has reduced the frequency of restenosis in both animal studies and clinical trials. Recent randomized trials have shown a reduction in the order of 30% after irradiation. A number of techniques which use different sources of radiation (beta vs. gamma radiation) are under investigation. This review gives and update of intravascular radiation therapy, including a discussion of ongoing trials. There is a great need, also in Norway, for treatment modalities that reduce the frequency of restenosis after PTCA. It would seem imperative that we start a discussion of whether and when intravascular radiation therapy should be available in Norway. Implementation requires planning on a national level with regard to investment in equipment and training.

Angioplasty, Balloon, Coronary↗
PubMed1999

[Normal tissue radiation toxicity in radiotherapy of localized prostatic cancer].

Radical radiotherapy of prostate cancer has to balance tumour control against the risk of radiation injury of normal tissue. The normal tissue toxicity is the main dose-limiting factor, and consequently a limiting factor of the curative potential of prostate cancer by irradiation. The SOMA scale is a new toxicity scoring system that registers late side effects from the most important anatomical sites. The SOMA scale is internationally approved and facilitates a standardised evaluation of radiation toxicity. The scoring system is based on four main components: subjective, objective, management and analysis. The SOMA scoring system was applied to a group of 21 patients from Ullevaal Hospital who were given intentionally curative radiation therapy for localised prostate cancer. The SOMA scale scoring system appears to be a valuable tool in the evaluation of normal tissue toxicity. It may contribute to a new standard in quality assurance of radiation therapy of prostate cancer.

Aged↗
PubMed1997

[Temporary radiation-induced hypo-salivation in a child].

This case report deals with the diagnosis and treatment of hyposalivation after radical radiation therapy and cytotoxic treatment of a metastasising nasopharyngeal carcinoma in an eight-year old girl. After cancer treatment the patient suffered from xerostomia, and pronounced hyposalivation was demonstrated. Frequent chewing of sugar-free gum and use of lozenges was recommended, and the patient was followed up for one year. During this time, the values for unstimulated whole saliva increased by a factor of five, and stimulated whole saliva values increased as well, but less so. Two years after cancer treatment, the patient no longer suffers from xerostomia.

Child↗
PubMed1997

Increased transforming growth factor beta (TGF-beta) immunoreactivity is independently associated with chronic injury in both consequential and primary radiation enteropathy.

PURPOSE: Radiation enteropathy is characterized by sustained increase in transforming growth factor beta (TGF-beta) immunoreactivity and connective tissue mast cell (CTMC) hyperplasia that may be responsible for progressive fibrosis and lead to clinical complications. We examined to what extent these chronic molecular and cellular phenomena are associated with acute mucosal breakdown (consequential injury) and/or direct (primary) radiation injury in late-responding compartments. METHODS AND MATERIALS: Rat small intestine was exposed to 50.4 Gy x-irradiation given either over 18 days (2.8 Gy daily or 5.6 Gy every other day) or 9 days (2.8 Gy twice daily or 5.6 Gy daily). Intestinal complications were recorded and groups of animals were euthanized at 2 and 26 weeks to assess subacute and chronic injury. Histopathologic changes were assessed with a radiation injury scoring system (RIS), total TGF-beta immunoreactivity was quantified with computerized image analysis, and CTMC hyperplasia was assessed in toluidine blue-stained sections. RESULTS: TGF-beta immunoreactivity and CTMC hyperplasia colocalized in areas of injury and were highly significantly correlated. Increased fraction size and decreased overall treatment time were associated with increased RIS (p < 0.01 and p < 0.00001), increased TGF-beta immunoreactivity (p = 0.01 andp < 0.001), and degree of CTMC hyperplasia (p = 0.01 and p < 0.001). Postradiation CTMC numbers increased across treatment groups from 2 to 26 weeks (p < 0.01). TGF-beta immunoreactivity was independently associated with chronic intestinal wall fibrosis (p = 0.003). CONCLUSION: This in vivo study supports in vitro evidence linking increased TGF-beta immunoreactivity and mast cell hyperplasia and strongly suggests their involvement in the molecular pathogenesis of both primary and consequential radiation enteropathy.

Animals↗
PubMed1996

Timing of concomitant boost irradiation affects incidence and severity of intestinal complications.

PURPOSE: In an effort to increase the therapeutic ratio of radiation therapy, so-called "nonstandard" irradiation regimens are being used more frequently. One such regimen, concomitant boost, entails giving a second daily fraction during part of the treatment course, thus reducing the total treatment time and decreasing the opportunity for tumor cell proliferation during treatment. The probability of tumor control is, therefore, increased for a given total dose. Timing of the boost, i.e., whether it is given early or late during the treatment course, affects both normal tissue and tumor response. This study assessed the influence of timing of a second daily boost on the development of intestinal radiation injury in a rat model. METHODS AND MATERIALS: A functionally intact segment of distal ileum was sutured to the inside of the scrotum in 52 orchiectomized, male Sprague-Dawley rats. After a 3-week postoperative recovery period, the intestine contained in the "scrotal hernia" was irradiated. All rats received a total dose of 50.4 Gy, given over a 12-day period as two different boost regimens, daily fractions of 2.8 Gy plus six concomitant boost doses of 2.8 Gy. The early boost group received the additional boost during the first 6 days and the late boost group received the additional boost during the last 6 days. The boost was given 6 h after the daily fraction. Groups of rats were sacrificed at 24 h (acute changes), 2 weeks (subacute changes), and 26 weeks (chronic changes) after the end of the irradiation schedule. Radiation injury was assessed by frequency of radiation-induced complications, histopathologic radiation injury score, collagen content, and epithelial cytokinetics. RESULTS: Radiation injury in the early boost group was significantly more severe than in the late boost group in terms of incidence of complication and histopathologic injury. Relative collagen content of irradiated intestine was significantly increased in the early boost group when compared to the late boost group at 2 weeks and at 26 weeks. Irradiated intestine in the early boost group exhibited decreased labeling index at 2 weeks, whereas irradiated intestine in the late boost group exhibited normal labeling index and increased total crypt cellularity at 2 weeks. CONCLUSION: When small intestine has to be included in the treatment field during radiation therapy, concomitant boost should be given towards the end of the radiation schedule, after the onset of compensatory proliferation, to minimized the risk of subsequent complications.

Animals↗
PubMed1996

Association of transforming growth factor beta (TGF-beta) immunoreactivity with specific histopathologic lesions in subacute and chronic experimental radiation enteropathy.

Irradiated intestine consistently exhibits increased immunoreactivity of transforming growth factor beta-1 (TGF-beta 1). It is not known whether this increase occurs secondary to mucosal barrier disruption (consequential injury) or to injury in late-responding tissue compartments (primary radiation enteropathy). This study therefore assessed the association between TGF-beta immunoreactivity and specific consequential and primary histopathologic alterations. A small bowel loop was fixed inside the scrotum in male rats and subsequently exposed to either 18 daily fractions of 2.8 Gy or nine daily fractions of 5.6 Gy orthovoltage X-radiation. Radiation-induced induced intestinal complications were recorded and groups of animals were euthanized 2 and 26 weeks post-irradiation. Radiation injury was assessed with a histopathologic radiation injury score (RIS). Total TGF-beta was detected immunohistochemically and measured with interactive computerized image analysis. The image analysis technique yielded highly reproducible quantitation data. The 2.8-Gy group maintained mucosal integrity and had fewer intestinal complications, lower RIS and lower TGF-beta levels than the 5.6-Gy group. There was highly significant correlation between TGF-beta immunoreactivity and radiation injury at both observation times (P < 0.001 and P < 0.0001). At 2 weeks, TGF-beta immunoreactivity correlated with mucosal ulceration (P = 0.002), epithelial atypia (P = 0.005), and serosal thickening (P = 0.0004). At 26 weeks, TGF-beta levels correlated significantly with six of seven histopathologic parameters, most strikingly with vascular sclerosis (P = 0.0003). We conclude that mucosal barrier breakdown is closely associated with increased TGF-beta immunoreactivity in consequential radiation enteropathy. The highly significant correlation between TGF-beta expression levels and alterations in late-responding tissue compartments also suggest a role for TGF-beta in primary radiation enteropathy.

Acute Disease↗
PubMed1996

Optimal interfraction interval to minimize small bowel radiation injury in treatment regimens with two fractions per day: an experimental study in a rat model.

BACKGROUND: Normal tissue damage in fractionated radiotherapy is influenced by a number of factors including sublethal damage repair and cellular proliferation. The therapeutic benefit of regimens with multiple fractions per day may thus be offset by increased normal tissue injury if there is insufficient time between daily fractions. We examined the influence of interfraction interval on radiation injury of the intestine, an organ at significant risk during treatment of abdominal and pelvic tumors. METHODS: A total of 150 male rats were orchiectomized, and a functionally intact loop of small bowel was sutured to the inside of the scrotum. The intestine within this 'artificial hernia' was irradiated twice daily for 9 days with 2.8 Gy fractions at intervals of 0, 2, 4, 6, or 8 h. Animals were observed for development of radiation-induced intestinal complications and euthanized at either 2 weeks and 26 weeks for subsequent histopathologic examination of irradiated and shielded intestine. RESULTS: Increasing the interfraction interval from 0 to 6 h was associated with a statistically significant reduction in intestinal complications (from 53% to 0%, P < 0.001), and in Radiation Injury Score (RIS) (from 10 to 6, P < 0.01) in long-term observed animals. Extending the interfraction interval to 8 h did not confer additional benefit. CONCLUSION: An interfraction interval of 6 h minimizes the risk of chronic radiation enteropathy in this rat model.

Animals↗
PubMed1996

Relationship between intestinal fibrosis and histopathologic and morphometric changes in consequential and late radiation enteropathy.

Intestinal fibrosis is a marked feature of late radiation enteropathy. This study assessed the time dose fractionation relationships of radiation-induced fibrosis in order to elucidate possible pathogenetic mechanisms. In 290 male Sprague-Dawley rats, a loop of small bowel was transposed to the left side of the scrotum. Three weeks later, the transposed segment was irradiated with either single dose or various fractionated regimens. The animals were observed for radiation-induced intestinal complications and killed in groups, 2 and 26 weeks after completion of irradiation. A semiquantitative histopathologic radiation injury score, morphometry of the submucosa, submucosal arterioles, intestinal surface area, and relative collagen content were used as endpoints. Fibrosis, measured by collagen assay and radiation injury score, increased with total dose, increasing fraction size and reduction in overall treatment time. This paralleled the results of morphometric assessment of mucosal surface area. Differences in vascular morphometry were only statistically significant in response to changes in total dose and fraction size and not with changes in overall treatment time. We conclude that fibrosis increases with increasing observation time, increasing fraction size, increasing total dose, and reduction of interfraction interval. Consequential injury, occurring as a result of disruption of mucosal integrity, seems to be an important mechanism for development of intestinal fibrosis. In contrast, vascular injury is relatively independent of this mechanism.

Animals↗
PubMed1996

Influence of fraction size on the development of late radiation enteropathy. An experimental study in the rat.

The use of large fraction sizes in radiotherapy may be associated with an increased risk of complications from late responding normal tissues. However, in the intestine, chronic injury may develop either as primary late effect or secondary to disruption of mucosal integrity as so-called consequential injury. Mucosal damage is relatively less sensitive to changes in fraction size than late reacting, slowly proliferating cells. The relationship between fraction size and chronic radiation enteropathy in a given situation may thus depend on which of the two mechanisms that predominates. Most previous studies of the influence of fraction size on radiation injury are confounded by differences in treatment time. The present study was therefore designed to assess subacute and chronic radiation enteropathy after three different fractionation regimens where fraction size was the only experimental variable. A total of 96 male Sprague-Dawley rats were orchiectomized and a functionally intact loop of small intestine was transposed into the left scrotum. These 'scrotal hernias' containing intestine were subsequently exposed to 50.4 Gy localized fractionated irradiation over 18 days with either 2.8 Gy every 24 h, 4.2 Gy every 36 h, or 5.6 Gy every 48 h. Control animals were sham irradiated. The animals were observed for development of intestinal complications (intestinal obstruction or enterocutaneous fistula formation) up to 6 months after irradiation. Histologic damage was assessed in groups of animals at 2 weeks (subacute injury) and 26 weeks (chronic injury), using a previously validated radiation injury score (RIS). RIS increased significantly with increasing fraction size at both observation times. However, the increase was more pronounced at 26 weeks than at 2 weeks. Increased chronic injury was characterized by increased incidence and severity of mucosal ulceration, serosal thickening, vascular sclerosis and intestinal wall fibrosis. We conclude that increasing fraction size increases both subacute and, even more markedly, chronic injury in the intestine. With the fractionation regimens used here, the chronic radiation enteropathy develops as a combined consequential and primary late effect, but the primary mechanism predominates.

Acute Disease↗
PubMed1995

Models for estimating the risk of ulcers in the small intestine after localized single or fractionated irradiation.

Subacute and chronic ulcerations of the intestinal mucosa are important causes of serious complications following radiation therapy for abdominal or pelvic tumours. We describe dose-response models for estimating the risk of mucosal ulcers in the small intestine after uniform, localized single or fractionated (once-daily) X-ray exposure. The models were fitted to data for ulceration incidence, based on a 26 week post-irradiation follow-up of male Sprague-Dawley rats which received a wide range of single and fractionated once-daily 250 kV X-ray doses to a short loop (partial volume) of transposed, but functionally intact, small intestine. The models presented for single (Weibull (W)) and fractionated (modified Weibull (MW)) exposures of a partial volume of tissue allow estimation of the risk of radiation-induced injury. While the W model is not new, its adaptation to partial volume irradiation and the MW model are. Isoeffect relationships are presented for the uniform fractional dose Ds(i%) associated with an i% (e.g. 0%, 5%, 10%, 50%) risk of intestinal mucosal ulcers as a function of the number of once-daily dose fractions, where Ds(0%) represents the threshold fractional dose. Although the Ds(5%) and Ds(0%) estimates provided for intestinal mucosal ulcers are based on animal data, the ratio Ds(0%)/Ds(5%) and more generally ratios Ds(j%)/Ds(i%) (where i not equal to j), are presumed to apply to humans. The indicated ratios are predicted to be independent of the partial volume irradiated and the number of once-daily dose fractions, and may be independent of radiation quality. Isoeffect equations are also presented that apply to circumstances where different partial volumes within the same reference volume (i.e. the total volume of tissue considered) receive different doses, but the dose within a given partial volume is uniformly distributed. These isoeffect equations provide a means of converting non-uniform dose within a reference volume to uniform isoeffect dose to the total reference volume and may have applications outside the field of radiation therapy (e.g. evaluating effects of non-uniform exposure of the small intestine or skin by a hot particle).

Abdominal Neoplasms↗
PubMed1994

Significance of overall treatment time for the development of radiation-induced intestinal complications. An experimental study in the rat.

BACKGROUND: Late normal tissue reactions generally are believed to be independent of treatment time. However, previous studies suggest a relationship between acute mucosal injury and development of intestinal obstruction and enterocutaneous fistula formation. Thus, the pathogenesis of late intestinal complications may be complex, and mucosal cell proliferation during treatment may be important. This study assessed the influence of overall radiation treatment time on development of intestinal injury and complications after localized fractionated irradiation of rat ilium. METHODS: Ninety-four male rats underwent orchiectomy, and a loop of small intestine was transposed to the scrotum. Orthovoltage irradiation was administered to the transposed, but functionally intact, intestine using 9 fractions of 5.6 Gy with interfraction intervals of 24, 48, or 72 hours. The animals were observed for complications and killed in groups 2 and 26 weeks after irradiation for assessment of injury. Incidence of intestinal complications and quantitative and semiquantitative histopathologic assessment of injury were used as endpoints. RESULTS: Increasing total treatment time by extending interfraction intervals from 24 to 48 hours significantly reduced radiation injury and the incidence of intestinal complications. Differences in mucosal and fibrotic changes were most prominent. No significant differences were found between groups with interfraction intervals of 48 and 72 hours. CONCLUSIONS: Overall treatment time significantly influenced development of chronic radiation enteropathy. Thus, rapidly proliferating cells, as found in the intestinal mucosa, appear to be involved in the pathogenesis of intestinal complications. This probably represents consequential damage secondary to disruption of mucosal integrity.

Animals↗
PubMed1994

Expression of fibrogenic cytokines in rat small intestine after fractionated irradiation.

The molecular and cellular mechanisms that regulate the radiation-induced fibrotic response in the intestine are not known. In addition to increased amounts of connective tissue, inflammatory cell aggregates are often found, especially in conjunction with acute or chronic mucosal ulcerations. These inflammatory cells are a major source of cytokines that influence connective tissue metabolism. Hence, a possible link may exist between the cellular inflammatory response and fibrosis. This preclinical study examined the influence of fractionated irradiation on the expression of three inflammatory/fibrogenic cytokines in rat small intestine. A rat intestinal transposition model was used for localized fractionated irradiation of a 3-4-cm segment of small bowel. Fifty-nine male Sprague-Dawley rats were irradiated or sham irradiated with 9 daily fractions of 5.2 Gy. Expression of Interleukin 1 alpha (IL-1 alpha), Transforming growth factor beta 1 (TGF-beta 1), and Platelet derived growth factor-AA (PDGF-AA) was assessed by immunohistochemistry. Irradiated and unirradiated intestine was examined 24 h, 14 days, and 26 weeks after completion of irradiation. Unirradiated intestine exhibited immunohistochemical expression of IL-1 alpha, TGF-beta 1 and PDGF-AA that conformed to known staining patterns in normal tissue. Irradiated intestine showed increased expression of all three cytokines at all assessment times. The increased cytokine expression correlated with fibrosis and inflammatory cell infiltrates in irradiated intestine. This was particularly evident in areas with mucosal ulcerations. Fractionated irradiation of small intestine elicits increased expression of IL-1 alpha, TGF-beta 1, and PDGF-AA in areas of acute and chronic radiation injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Influence of fractionation schedule on development of intestinal complications following localized irradiation. An experimental study in the rat.

This study examined the relationship among time-dose-fractionation, development of intestinal complications, and histopathologic radiation injury in rat small bowel. In 177 rats, a functional loop of rat ileum was surgically transposed to the left scrotum. Three weeks later, fractionated irradiation was delivered to the transposed intestine as 2.8 Gy or 5.6 Gy daily fractions, or as 2.8 Gy twice daily with 12 hours' interval. Eleven experimental groups received total doses ranging from 28 Gy to 90 Gy. The animals were observed for intestinal complications, and groups of animals were killed 2 and 26 weeks after completion of irradiation for assessment of injury. Radiation injury was assessed by a semiquantitative histopathologic scoring system and by the frequency of lethal intestinal complications. Both increased fraction size and reduced overall treatment time increased the severity of subacute and chronic radiation injury, as well as frequency of intestinal complications. We conclude that rapidly proliferating cells (mucosal epithelium) play a pivotal role in the pathogenesis of radiation enteropathy and mechanisms other than radiation-induced mitotic cell death are pathogenetically involved.

Animals↗
PubMed1992

Tolerance of rat small intestine to localized single dose and fractionated irradiation.

The tolerance of rat small intestine to localized single-dose and fractionated irradiation was assessed. In 168 rats, bilateral orchiectomy was performed and a loop of small intestine was transposed to the left part of the scrotum. Beginning 3 weeks postoperatively, single dose (18-24 Gy) or fractionated (4.2 Gy or 5.6 Gy per fraction) x-irradiation was delivered to the transposed intestine. The animals were observed for complications, and groups of animals were killed 2 and 26 weeks after completion of irradiation for assessment of injury. Mortality (i.e. the occurrence of lethal intestinal complications) and a semiquantitative histopathologic scoring system were used as endpoints to assess the degree of radiation injury. The most frequent intestinal complications were enterocutaneous fistula formation and intestinal obstruction. Logistic regression analysis ov complications data was used to estimate LD50 values and the alpha/beta ratio. There was good correlation between histopathologic scores and the incidence of lethal complications. The estimated LD50 values were 22.1 +/- 0.5 Gy, 37.0 +/- 4.4 Gy and 51.0 +/- 5.3 Gy for the single dose regimen and the fractionated regimens of 5.6 Gy and 4.2 Gy respectively. The estimated alpha/beta ratio was 10.7 +/- 2.4 Gy. The goodness of fit of the linear-quadratic isoeffect model to our data was satisfactory. Our results indicate that acute mucosal damage may be pathogenetically involved in the development of intestinal complications.

Animals↗