Early disturbance of microvascular function precedes chemotherapy-induced intestinal injury.

Intestinal injury 4-48 hr after cytotoxic therapy (etoposide phosphate, 100 mg/kg body weight [bw], intravenously [i.v.]) was studied in rats using ligated intestinal loops. Chromium-51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) and rubidium-86 chloride ((86)RbCl) were deposited intraluminally to determine the extent of the increase in intestinal permeability and ion channel disruption. Evans Blue (EB) was used for detection of endothelial leakage. Intestinal morphology was documented. Endothelial dysfunction, as observed by an increased extravasation of EB, was evident already 4 hr after cytotoxic therapy. Intestinal epithelial injury, as observed by an increase in (51)Cr-EDTA permeation and a decrease in (86)Rb absorption, occurred after 48 hr. Finally, histology disclosed a reduced crypt cell proliferation, displayed as a decrease in Ki67-positive cells. The findings suggest that, in the development of intestinal injury after cytotoxic therapy, endothelial disruption is an early event, whereafter epithelial dysfunction and crypt stem cell arrest occur. This knowledge could be of importance in the design of future intervention trials.

Gastric emptying after autologous haemopoietic stem-cell transplantation: a prospective trial.

Gastroparesis may be involved in the pathophysiology of prolonged nausea and vomiting after haemopoietic stem-cell transplantation (HSCT), but this has not been prospectively investigated. Gastric emptying (GE) was investigated in 20 patients before and 2 months after autologous HSCT. Gastrointestinal symptoms were graded prospectively and oral energy intake was recorded in parallel. Before transplant, all patients were asymptomatic and GE was within the reference range. Post transplant GE was delayed in three patients and three patients reported nausea and/or vomiting. Neither gastrointestinal symptoms nor oral energy intake post transplant discriminated between patients with or without delayed GE. Oral energy intake before transplant was lower (P=0.05), and there was a greater need for total parenteral nutrition (TPN) among patients who developed gastroparesis post transplant (P<0.05). Delayed GE after HSCT was found to be less common than had been believed from retrospective studies. Gastroparesis may be involved in some cases of prolonged nausea and vomiting after autologous HSCT but alternative explanations should be considered. Symptoms consistent with gastroparesis did not correlate with GE. Patients at risk of developing gastroparesis may be found among those with nutritional difficulties before and during the transplant course.

Disturbance of purine nucleotide metabolism: a possible early key event in development of intestinal damage induced by chemotherapy.

Protective strategies to minimize the hematological toxicity in connection with bone marrow transplantation (BMT) have been successful, but toxicity to the gastrointestinal tract prevents further dose escalation and therefore limits the application of the treatment. As it is known that chemotherapy leads to disruption of the intestinal barrier and morphological changes of mitochondria in enterocytes, this study was conducted in order to investigate intestinal energy metabolism and permeability after intensive cytotoxic therapy in rats. Intestinal damage was produced by intraperitoneal administration of the cytostatic etoposide. Intestinal permeability was assessed by a [51Cr]EDTA absorption test and intestinal purine nucleotide content by a high-performance liquid chromatography (HPLC) technique. Four hours after the administration of etoposide, and the next 48 hr, there was a significant increase in the intestinal permeability (P < 0.05) and a significant reduction of the purine nucleotide content in the intestinal epithelial cells (P < 0.01) as compared to control animals. This early disturbance in enterocyte energy metabolism may be a key event in the development of the intestinal damage, induced by chemotherapy, and an explanation for the early disruption of the intestinal barrier demonstrable before morphological changes are evident.

The gut mucosa barrier is preserved during allogeneic, haemopoietic stem cell transplantation with reduced intensity conditioning.

The efficacy of allogeneic, haemopoietic stem cell transplantation (HSCT) is limited by concomitant toxicity. This has led to the development of less toxic, reduced intensity conditioning (RIC) protocols, whose therapeutic benefit is largely related to an associated, immunity-mediated graft-versus-malignancy effect rather than by the cytotoxic treatment itself. Murine HSCT models suggests that acute graft-versus-host disease (GVHD) increases with the intensification of the conditioning regimen mediated by loss of integrity of the gut mucosa barrier. The present study was undertaken to investigate gastro-intestinal (GI) permeability during allogeneic HSCT with RIC. In 17 patients (myeloablative conditioning in nine, RIC in eight), intestinal permeability was assessed by a (51)Cr-EDTA absorption test before the start of cytotoxic treatment the day before stem cell infusion (day -1) and 4, 7 and 14 days after stem cell infusion. Patients receiving RIC did not develop any significant increase in intestinal permeability during the transplantation course but in myeloablatively conditioned patients there was a significant increase in intestinal permeability the day before the stem cell infusion (P < 0.005), on day 4 (P < 0.005), on day 7 (P < 0.01) and on day 14 (P < 0.005) after stem cell infusion, compared with the baseline. Myeloablative conditioning also revealed increased intestinal permeability on day 7 compared with the RIC (P < 0.05). The finding of preserved intestinal-barrier function during allogeneic HSCT with RIC is discussed, with reference to the hypothesis that GI tract damage may be an important initiating event of GVHD.

Remission inversion and no transplant-related mortality--a single centre experience of autologous stem cell transplantation in malignant lymphoma.

Between 1989 and 1998 93 patients with malignant lymphoma were treated, in our centre, with high-dose chemotherapy and autologous stem cell transplantation. Diagnosis according to the REAL-classification were: 38 patients with high-grade lymphoma (diffuse large B-cell lymphoma (DLCL) (n = 26), anaplastic T-cell (n = 5), lymfoblastic (n = 3) and others (n = 4)), 31 patients with low-grade lymphoma (follicular (n = 18), mantle cell (n = 4), B-CLL (n = 3) and others (n = 6)) and, finally, 24 patients with Hodgkin's disease. The source of stem cells was bone marrow (14 patients), peripheral blood stem cells (64 patients) or a combination of both sources (15 patients). There was no early ( < 100 days) transplant-related mortality. One patient died 11 months post-transplant in unexplained liver failure and all other causes of death were related to relapse of lymphoma. So far, no case of myelodysplastic syndromes or secondary acute leukacmia's has occurred. Overall survival (OS) and progression-free survival (PFS) are: (a) DLCL (26 patients, 4-year probability) OS 40%. PFS 33%; (b) follicular (18 patients, 3-year probability) OS 79%, PFS 52%; (c) Hodgkin's lymphoma (24 patients, 5-year probability) OS 65%, PFS 55%. Out of 52 evaluable patients, 34 (65%) have reached remission inversion. The most important findings are no early transplantation-related mortality, remission inversion in a majority of patients, and so far no cases of secondary myelodysplastic syndromes (MDS) acute myelogenous leukaemias (AML). Concerning OS and PFS, our results seem to be in accordance with other centres.

Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience.

BACKGROUND: Despite improved treatment results achieved in Hodgkin's disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB-IVB) of HD in younger patients in an unselected population-based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post-CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected. PATIENTS AND METHODS: Between 1985-92, 307 patients between 17-59 yr of age (median 36) were diagnosed with HD in stages IIB-IVB in 5/6 health care regions in Sweden. Median follow-up time was 7.8 yr (1.3-13). Retrospectively, laboratory parameters were collected. RESULTS: In total, 267 (87%) patients had a complete response (CR). The overall and disease-free 10-yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT + RT. In univariate analyses survival was affected by age, stage IVB, bone-marrow involvement, B-symptoms, S-LDH, S-Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant. CONCLUSIONS: The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

Gut mucosa barrier preservation by orally administered IgA-IgG to patients undergoing bone marrow transplantation: a randomised pilot study.

Intensive cytotoxic therapy with bone-marrow transplantation (BMT) allows a potential cure for haematological malignancies. Protective strategies to minimise haematological toxicities have been successful and currently toxicity to the gastro-intestinal tract is the major cause of treatment-related morbidity and the dose-limiting factor that prevents further dose escalation. In a randomised, placebo-controlled trial we investigated whether an oral immunoglobulin preparation (IgA-IgG) can diminish intestinal toxicity with autologous BMT. IgA-IgG (n = 6) and placebo (n = 7) were orally administered from 1 day prior to the start until 1 week after the termination of the cytotoxic treatment (a total of 14 days). Intestinal toxicity was assessed by a 51Cr-EDTA absorption test for intestinal permeability and by the clinical criteria laid down by the WHO for the period before the start of the cytotoxic treatment, 1 day prior to stem-cell infusion and 4, 7, 10 and 14 days after stem-cell infusion. In the placebo group there was a significant increase in intestinal permeability on day 4 (P < 0.005) and on day 7 (P < 0.05) after stem-cell infusion, compared with the baseline, which was not seen for IgA-IgG. In addition, patients receiving IgA-IgG had significantly less intestinal permeability on day 4 (P < 0.05) and on day 7 (P < 0.05), compared with the placebo group. No significant, positive effect as regards clinical toxicity was observed. Oral administration of IgA-IgG to patients undergoing intensive cytotoxic therapy prior to BMT seems to have a protective effect on the gut mucosa barrier which is normally disrupted by this therapy.

A qualitative study to explore the experience of fatigue in cancer patients.

Fatigue--which is a complex, multicausal, and multidimensional subjective experience--is today the most frequently reported symptom from patients with cancer. The aim of this study was to explore the experience of fatigue in cancer patients and to describe the categories and dimensions of the symptoms. A qualitative method--grounded theory--was used. Unstructured, tape-recorded interviews with 15 cancer patients were used for data collection. The categories found in this study illustrate fatigue as a process. Three major categories were found: (1) experiences (of loss, need, malaise, psychological stress, emotional affection, abnormal weakness, difficulties in taking the initiative); (2) consequences (social limitation, affected self-esteem, affected quality of life); and (3) actions (coping). The categories were constructed on the basis of dimensions with subordinated qualities. Knowledge concerning the different expressions of fatigue is important in caring for patients with cancer. The results from this study may contribute to a better understanding of how a cancer patient can experience and express fatigue and how the symptoms may affect the patient.

Gastro-intestinal toxicity related to bone marrow transplantation: disruption of the intestinal barrier precedes clinical findings.

The intensive cytotoxic treatment given in connection with bone marrow transplantations induces severe injury to the gut consistent with an increase in intestinal permeability. Currently, extent of the gut injury is assessed by inspecting the mouth and recording symptoms deriving from the gastro-intestinal tract. The aims of this study were to evaluate whether changes in permeability correlate with clinical assessment of gut toxicity, according to the WHO criteria, and also to examine the duration of intestinal permeability after high-dose chemotherapy. In 18 consecutive patients undergoing bone marrow transplantation, gastrointestinal permeability was assessed by a 51Cr-EDTA absorption test before the start of cytotoxic treatment, and 4, 7, 10 and 14 days after stem-cell infusion. In another seven patients, permeability was assessed 2 days after the start of cytotoxic treatment, and 1, 7 and 14 days after stem cell infusion. During the same period, oral- and non-oral clinical toxicity according to the WHO criteria were recorded. Permeability increased significantly 2 days after the start of cytotoxic treatment (P < 0.05), on day 1 (P < 0.05), on day 4 (P < 0.0005), on day 7 (P < 0.0005) and on day 10 (P < 0.005) after stem cell infusion, compared with pre-treatment permeability. Despite significant barrier dysfunction, clinical toxicity was very moderate in the early transplantation course. Gastro-intestinal, but not oral clinical toxicity requiring therapy, was consistent with a significant increase in permeability compared with no clinical toxicity or toxicity not requiring therapy. Similarly, cumulative gastro-intestinal, but not oral toxicity correlated positively with the increase in permeability. The permeability test was unable to predict the severity of the clinical gastro-intestinal toxicity.

Ascorbate preserves gastric mucosal metabolism and microcirculation after hemorrhagic shock and retransfusion in rats.

The gastric mucosal microcirculation and purine nucleotide metabolism were studied in rats after hemorrhagic shock and retransfusion. The mucosal surface density of perfused vessels (SDPV) and the mucosal levels of ATP, ADP, AMP, IMP, hypoxanthine and uric acid were measured following 15 min of hemorrhagic shock and 10 and 30 min after retransfusion, and the effects of pretreatment with allopurinol or ascorbate were studied. During shock there was a dephosphorylation of nucleotides and a decline in the SDPV. Retransfusion led to an additional reduction in the SDPV, but a complete restoration of preshock nucleotide levels 30 min after retransfusion. Allopurinol accelerated early rephosphorylation of nucleotides without effects upon SDPV while ascorbate completely preserved the mucosal level of energy-rich nucleotides 15 min after hemorrhagic shock and increased SDPV during early reperfusion. The results showed that there was a renewal of energy stores in gastric mucosa after hemorrhagic shock and retransfusion although parts of the vascular bed were not reperfused. The mucosal energy depletion after 15 min of hemorrhagic shock and part of the mucosal vessel injury after retransfusion were prevented by pretreatment with ascorbate.

Gastric mucosal microcirculation and purine nucleotide metabolism after retransfusion of rats in hemorrhagic shock.

Gastric mucosal microcirculation and purine nucleotide metabolism were studied after hemorrhagic shock and retransfusion in rats. The number of perfused microvessels and the concentration of adenosine triphosphate, adenosine monophosphate, inosine monophosphate, inosine, hypoxanthine, xanthine, and uric acid were investigated in mucosal biopsy specimens after 15 or 45 min of hemorrhagic shock and after 15 min of shock followed by 30 min of retransfusion. During shock a dephosphorylation of nucleotides and a decrease in the number of perfused microvessels occurred, the more the longer the duration of the shock period. Retransfusion led to an additional reduction in the number of perfused microvessels, but there was a partial restoration of high-energy phosphate metabolites in those areas of the mucosa which maintained a blood flow. The results indicate that there is a renewal of energy stores in gastric mucosa after hemorrhagic shock and reperfusion, although parts of the vascular bed are not reperfused.

Changes in gastric mucosal microcirculation and purine nucleotide metabolism during hemorrhagic shock in rats.

Intravital fluorescence microscopy and morphometry were used to study the microcirculation in the rat gastric mucosa during and after hemorrhagic shock. Under control conditions the circulation appeared homogeneous and unaffected by superfusion with 0.1 N HCl. During hemorrhagic shock, scattered areas of the mucosa lost circulation. Morphometry showed that the number of perfused mucosal vessels decreased significantly in the abluminal part of the mucosa both in perfused and ischemic areas, the reduction being most pronounced in the ischemic areas, where the number of perfused luminal vessels also decreased significantly. During reperfusion, bleedings occurred from the mucosa. A key finding was that the bleedings always had their origin at the border zone between ischemic and perfused areas. After hemorrhagic shock adenosine triphosphate and energy charge levels dropped significantly in both perfused and ischemic areas but with significantly lower levels in the ischemic areas. The hypoxanthine levels increased in both perfused and ischemic areas. The experiments show that local mucosal ischemia and accelerated nucleotide degradation are of pathogenetic importance in the development of stress ulcers after hemorrhagic shock. The border zone between circulated and ischemic areas seems to be an area of special interest.