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Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description. In this study, we aimed to characterize gastric motility and gastric symptoms in response to a liquid meal. We included 20 patients with ME/CFS with abdominal complaints who were recruited to a double-blind randomized placebo-controlled trial of Rituximab. The patients of this sub study were examined with an ultrasound drink test, and gastrointestinal symptoms were evaluated using the Rome III questionnaire and Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) questionnaire. We found that patients commonly reported fullness/bloating (75%), abdominal pain (45%) and nausea (35%). Ultrasound measurements revealed lower proximal measurements of the stomach after a meal (p < 0.01) and larger fasting antral area (p = 0.019) compared to healthy controls. The patients had a stronger symptomatic response to the liquid meal compared to healthy controls regarding epigastric pain, discomfort and nausea (p < 0.05). Ninety percent of the patients reported bowel movement frequencies within the normal range but scored high on bowel habit dissatisfaction and life disruption. The patients presented with fullness/bloating, nausea and epigastric pain, showed signs of impaired gastric accommodation and visceral hypersensitivity, showing that the gastrointestinal symptoms of ME/CFS patients are similar to functional dyspepsia.Key summary Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description. • In this study, patients with ME/CFS had signs of impaired gastric accommodation after a liquid meal. • Out of 20 patients, 15 patients reported fullness/bloating, 9 reported abdominal pain, and 7 reported nausea. The patients showed signs of visceral hypersensitivity on a drink test. • Our findings suggest that patients with ME/CFS share many similarities with patients with Functional Dyspepsia. The findings were not typical for Irritable Bowel Syndrome. Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description. • In this study, patients with ME/CFS had signs of impaired gastric accommodation after a liquid meal. • Out of 20 patients, 15 patients reported fullness/bloating, 9 reported abdominal pain, and 7 reported nausea. The patients showed signs of visceral hypersensitivity on a drink test. • Our findings suggest that patients with ME/CFS share many similarities with patients with Functional Dyspepsia. The findings were not typical for Irritable Bowel Syndrome.

Objective A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS. Study design The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures. Results ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline. Conclusions ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.

This is an open access article under the CC BY license. The etiology of myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is unknown, but involvement of the immune system is one of the proposed underlying mechanisms. Human leukocyte antigen (HLA) associations are hallmarks of immune-mediated and autoimmune diseases. We have previously performed high resolution HLA genotyping and detected associations between ME/CFS and certain HLA class I and class II alleles. However, the HLA complex harbors numerous genes of immunological importance, and there is extensive and complex linkage disequilibrium across the region. In the current study, we aimed to fine map the association signals in the HLA complex by genotyping five additional classical HLA loci and 5,342 SNPs in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria, and 480 healthy Norwegian controls. SNP association analysis revealed two distinct and independent association signals (p ≤ 0.001) tagged by rs4711249 in the HLA class I region and rs9275582 in the HLA class II region. Furthermore, the primary association signal in the HLA class II region was located within the HLA-DQ gene region, most likely due to HLA-DQB1, particularly the amino acid position 57 (aspartic acid/alanine) in the peptide binding groove, or an intergenic SNP upstream of HLA-DQB1. In the HLA class I region, the putative causal locus might map outside the classical HLA genes as the association signal spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotype. Taken together, our results implicate the involvement of the MHC, and in particular the HLA-DQB1 gene, in ME/CFS. These findings should be replicated in larger cohorts, particularly to verify the putative involvement of HLA-DQB1, a gene important for antigen-presentation to T cells and known to harbor alleles providing the largest risk for well–established autoimmune diseases.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value −8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls). We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/ CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10− 7 ), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

Purpose Previous Phase II trials indicated clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in patients with myalgic encephalopathy/chronic fatigue syndrome (ME/CFS). The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs) against rituximab in ME/CFS is unknown. We retrospectively measured rituximab concentrations and ADAs in serum samples from patients included in an open-label Phase II trial with maintenance rituximab treatment (KTS-2-2010) to investigate possible associations with clinical improvement and clinical and biochemical data. Methods Patients with ME/CFS fulfilling the Canadian criteria received rituximab (500 mg/m2) infusions: 2 infusions 2 weeks apart (induction), followed by maintenance treatment at 3, 6, 10, and 15 months. The measured rituximab concentrations and ADAs in serum samples included 23 of 28 patients from the trial. Findings There were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement. Female patients had higher mean serum rituximab concentrations than male patients at 3 months (P = 0.05). There was a significant negative correlation between B-cell numbers in peripheral blood at baseline and rituximab serum concentration at 3 months (r = −0.47; P = 0.03). None of the patients had ADAs at any time point. Implications Clinical improvement of patients with ME/CFS in the KTS-2-2010 trial was not related to rituximab serum concentrations or ADAs. This finding is also in line with a recent randomized trial questioning the efficacy of rituximab in ME/CFS. Rituximab concentrations and ADAs still offer supplemental information when interpreting the results of these trials.

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18–65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5–13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7–21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343–4,334) vs. healthy individuals 1,886 p.u. (range 808–8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention. publishedVersion

The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.

Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m2 × 2 daily and once weekly oxaliplatin 55 mg/m2. Regional hyperthermia aimed at 41.5–42.5 °C for 60 min combined with oxaliplatin infusion. Radical surgery with total or extended TME technique, was scheduled at 6–8 weeks after radiation. From April 2003 to April 2008, a total of 49 eligible patients were recruited. Median number of hyperthermia sessions were 5.4. A total of 47 out of 49 patients (96%) had the scheduled surgery, which was clinically radical in 44 patients. Complete tumour regression occurred in 29.8% of the patients who also exhibited statistically significantly better RFS and CSS. Rate of local recurrence alone at 10 years was 9.1%, distant metastases alone occurred in 25.6%, including local recurrences 40.4%. RFS for all patients was 54.8% after 5 years and CSS was 73.5%. Patients with T50 temperatures in tumours above median 39.9 °C had better RFS, 66.7% vs. 31.3%, p = 0.047, indicating a role of hyperthermia. Toxicity was acceptable.

A random-sequence peptide microarray can interrogate serum antibodies in a broad, unbiased fashion to generate disease-specific immunosignatures. This approach has been applied to cancer detection, diagnosis of infections, and interrogation of vaccine response. We hypothesized that there is an immunosignature specific to ME/CFS and that this could aid in the diagnosis. We studied two subject groups meeting the Canadian Consensus Definition of ME/CFS. ME/CFS (n = 25) and matched control (n = 25) sera were obtained from a Canadian study. ME/CFS (n = 25) sera were obtained from phase 1/2 Norwegian trials (NCT01156909). Sera from six healthy controls from the USA were included in the analysis. Canadian cases and controls were tested for a disease immunosignature. By combining results from unsupervised and supervised analyses, a candidate immunosignature with 654 peptides was able to differentiate ME/CFS from controls. The immunosignature was tested and further refined using the Norwegian and USA samples. This resulted in a 256-peptide immunosignature with the ability to separate ME/CFS cases from controls in the international data sets. We were able to identify a 256-peptide signature that separates ME/CFS samples from healthy controls, suggesting that the hit-and-run hypothesis of immune dysfunction merits further investigation. By extending testing of both our signature and one previously reported in the literature to larger cohorts, and further interrogating the specific peptides we and others have identified, we may deepen our understanding of the origins of ME/CFS and work towards a clinically meaningful diagnostic biomarker. Electronic supplementary material The online version of this article (10.1007/s12035-018-1354-8) contains supplementary material, which is available to authorized users.

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial. Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles. Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients. Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.

Importance Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. Objective To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. Design, Setting, and Participants Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. Interventions After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia. Main Outcomes and Measures The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up. Results A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86;P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98;P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%). Conclusions and Relevance Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted. Trial Registration clinicaltrials.gov Identifier:NCT00003052

Background Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objective To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS. Design Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942). Setting 4 university hospitals and 1 general hospital in Norway. Patients 151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years. Intervention Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74). Measurements Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures. Results Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, -5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, -0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events. Limitation Self-reported primary outcome measures and possible recall bias. Conclusion B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS. Primary Funding Source The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.

The role of consolidative radiotherapy (RT) in advanced diffuse large B-cell lymphoma (DLBCL) is not established.In a population-based retrospective analysis of patients with DLBCL in Western Norway during 2003 to 2008, 170 consecutive patients admitted to Haukeland University Hospital (HUS) and 94 to Stavanger University Hospital (SUS) were included. The mean age was 64 years (range, 17-95 years), 147 patients (56%) were male, 80 patients (30%) had stage I/II, 126 patients (48%) stage III/IV, and 57 patients (22%) had primary extranodal disease.There were no differences between hospitals in patient characteristics, use of rituximab, number of chemotherapy courses or cumulative doses, or in distribution of response categories after chemotherapy. The use of RT was significantly different: 17 patients (23%) received RT at SUS and 92 patients (65%) at HUS (P .001). For 219 patients with International Prognostic Index (IPI) score of 0 to 3, 5-year cancer-specific survival (CSS) was 67% at SUS and 81% at HUS (P = .012). For 73 patients with complete response after chemotherapy there were no differences in survival between patients with and without RT. For 138 patients with any residual mass after chemotherapy, there were highly significant differences in favor of receiving RT (n = 81) versus no RT (n = 57): 5-year CSS 89% versus 69% (P .001), and 5-year overall survival 82% versus 59% (P = .005). The effect of RT on residual mass was evident in most subgroups, mainly in low to intermediate risk, but not in high-risk (IPI 4-5) patients.With the limitations of a retrospective study, these data suggest that consolidative RT might improve survival in DLBCL patients with a residual mass after chemotherapy, also in advanced disease.

BACKGROUND. The incidence of primary central nervous system lymphoma (PCNSL) appears to be increasing in some countries, whereas it is stable in others. Many reports the last decades have suggested that there have been improvements in the treatment of PCNSL. The objective of this study was to analyze time trends in the incidence, clinical features, histologic diagnosis, treatment, and outcome of nonacquired immunodeficiency syndrome (non-AIDS) PCNSL in Norway from 1989 to 2003. METHODS. Patients were identified by a chart review of all patients who had a recorded diagnosis of PCNSL from 1989 to 2003 in The Norwegian Cancer Registry. The histologic and cytologic material from each patient was re-examined by pathologists. Time trends were analyzed according to year of diagnosis grouped into 3 5-year periods: 1989–1993, 1994–1998, and 1999–2003. RESULTS. There were 98 patients who had confirmed, newly diagnosed non-AIDS PCNSL in Norway from 1989 to 2003. The incidence rate increased during the consecutive 5-year periods from 0.89 per million during 1989 to 1993, to 1.74 per million during 1994 to 1998, and to 1.82 per million during 1999 to 2003 (P = .013). Diagnostic delay and overall survival did not improve with time. Survival decreased from 1999 to 2003 compared with survival from 1994 to 1998, which was explained in part by reduced performance status and fewer patients receiving combined chemotherapy and radiotherapy during 1999 to 2003. In multivariate analysis, age ≤50 years, a good performance status, and active treatment (especially combined chemotherapy and radiotherapy) significantly improved survival. CONCLUSIONS. The incidence of PCNSL is increasing in Norway. Despite diagnostic and therapeutic advances over the last decades, neither a reduction in diagnostic delay nor any improvement in overall survival with time was observed. The search for improved understanding of etiology and treatment should be intensified. Cancer 2007. © 2007 American Cancer Society.

Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. Methods In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. Findings Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8–66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. Conclusion In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease. Trial registration ClinicalTrials.gov NCT01156909

This study investigates delay in diagnosing primary central nervous system lymphoma (PCNSL), which has a variable clinical and radiological presentation. Early diagnosis and treatment may improve survival and cause less sequela in PCNSL. Medical records of all new cases of PCNSL morphologically verified while alive or by autopsy in Norway in 1989-1998 were reviewed (n = 74). The time from initial symptom to final morphological diagnosis of PCNSL had a median (mean, range) of 70 (106, 22-330) days in 16 AIDS patients and 75 (157, 8-1285) days in 58 non-AIDS patients. Among non-AIDS patients, the time to diagnosis was longer in patients with no tumour in the first neuroimaging report after initial symptom (p = 0.001). Median (mean, range) time from initial symptom to neuroimaging was 14 (25, 1-60) days in AIDS patients and 21 (88, 1-1095) days in non-AIDS patients. In the non-AIDS group, those presenting with personality change or visual disturbance had more delayed imaging than the others. The time from first neuroimaging examination to final diagnosis in non-AIDS patients had a median (mean, range) of 28 (69, 1-845) days, and was longer when no tumour was indicated in the imaging report (p = 0.005) and if first biopsy did not confirm the diagnosis (p = 0.02). All AIDS patients had their diagnosis of PCNSL first established by autopsy. The time from first neuroimaging to autopsy had a median (mean, range) of 48 (81, 10-270) days. There is a considerable delay in the diagnosis of PCNSL and strategies for earlier diagnosis are thus needed. Physicians should consider early neuroimaging in patients with personality changes or visual disturbance, early renewed imaging in patients with persistent neurological symptoms but no tumour on initial imaging, and early/repeated biopsy of focal brain lesions in both AIDS patients and non-AIDS patients.

BACKGROUND. Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin-containing chemotherapy. It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin. In the current study, the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma. METHODS. Patients with advanced cervical carcinoma were registered prospectively in the U.S., Norway, and the Netherlands. External-beam radiotherapy and brachytherapy were administered for a biologically effective dose ! 86.7 gray. At least 4 courses of weekly cisplatin (40 mg/m 2 ) and 4 sessions of weekly locoregional hyperthermia were added to radiotherapy. RESULTS. Sixty-eight patients with a median age of 45 years were enrolled. Fulldose radiotherapy was delivered to all patients according to plan. At least 4 courses of chemotherapy were received by 97% of patients, and at least 4 courses of hyperthermia treatment were received by 93% of patients. Toxicity was fully comparable to that described for chemoradiotherapy alone, and the median total treatment time was 45 days. Complete remission was achieved by 61 patients (90%). After a median follow-up of 538 days, 74% of patients remained alive without signs of recurrence, and the overall survival rate was 84%. CONCLUSIONS. The combination of full-dose radiotherapy, chemotherapy, and hyperthermia was feasible and effective in a multicenter international setting among patients with advanced cervical carcinoma. A Phase III study comparing this novel triplet with standard chemoradiation, designed to show at least a 15% improvement in overall survival, has been launched. Cancer 2005;104:763‐70. © 2005 American Cancer Society.

The incidence of primary central nervous system lymphoma (PCNSL) has been reported to increase in some parts of the world, while being stable in other regions. In an attempt to characterize the incidence rate, clinical features, treatment, outcome, and prognostic factors of PCNSL in Norway, we report our experience in a large unselected series of patients. Clinical features, histological diagnosis, radiological findings, treatment, and outcome of all patients diagnosed with PCNSL in Norway in the years 1989 � /1998 were registered. During the 10-year period 58 new cases of histologically verified PCNSL were registered in Norway. The annual incidence rate of PCNSL was on average 1.34 cases per million people with a non-significant increasing trend (p� /0.069). For patients diagnosed before death (n� /45) the estimated survival following histological diagnosis was 55%, 47%, and 23% at 1, 2, and 5 years, respectively. In Cox-regression analysis age, WHO performance status and treatment had independent prognostic impact on survival. In the studied decade, there was a non-significant trend towards increased incidence of PCNSL, perhaps due to increased availability of diagnostic imaging, especially magnetic resonance imaging.

This study reports on oncology professionals' knowledge and attitude toward complementary and alternative medicines (CAM), classified according to their primary application as complementary or alternative methods. In June 2002, we conducted a national, multicentre survey of 828 Norwegian oncologists, nurses, clerks and therapeutic radiographers. A response rate of 61% was achieved. Only a few physicians (4%) described their reactions to alternative medicine as positive compared with nurses (33%), therapeutic radiographers (32%) and clerks (55%) (P

Estrogens administered in high doses were commonly used for therapy of advanced breast cancer before the introduction of contemporary endocrine therapy. While the mechanism of the antitumor effect is unknown, in vitro investigations have shown estrogens in high concentrations to be toxic to cell growth. Further, it has been shown that exposure of MCF-7 cells to estrogens in low concentrations may enhance the sensitivity and also lower the toxicity threshold to estrogens. This study was designed to evaluate treatment with diethylstilbestrol (DES) in postmenopausal women with advanced breast cancer becoming resistant to estrogen deprivation. Thirty-two patients with advanced breast cancer previously exposed to multiple endocrine treatment regimens (median 4, range 2-10) were enrolled. Their tumor should have revealed evidence of endocrine sensitivity (previous partial response or at least stable disease foror = 6 months to therapy). Each patient received DES 5 mg t.i.d. Four patients terminated therapy afteror = 2 weeks on therapy due to side effects; another two patients terminated therapy before progression for similar reasons (one patient after SD for 15 weeks and one with a PR after 39 weeks). Four patients obtained CR and six patients PR. In addition, two patients had SD foror = 6 months duration. Five patients had an objective response and one patient a SD lasting foror = 1 year. Our results reveal estrogens administered in high doses may have antitumor effects in breast cancer patients heavily pretreated with endocrine therapy. Such treatment represents a valuable alternative to chemotherapy in selected patients.

Purpose : To examine the effect of infusion of the vasodilator sodium nitroprusside (SNP) on the blood flow in normal tissues and BT 4 An tumors growing subcutaneously or intramusculary in BD IX rats. Methods and Materials : Sodium nitroprusside was given as a continuous intravenous infusion to keep the mean arterial pressure stable at 60 mmHg. The cardiac output, organ blood flow, and perfusion of the BT4An tumors were measured by injection of radiolabelled microspheres at control conditions and after 20 min SNP infusion in each animal. Two series of experiments were performed with two anesthetics with different mechanisms of action, Inactin and the midazolam-fentanyl-fluanisone combination (MFF), to secure reliable conclusions. Results : Cardiac output, heart rate, and blood flow to the skeletal muscles, heart, and liver increased during SNP infusion in either anesthetic group. In the kidneys and particularly in the skin, decreased blood flow by SNP was observed. When located subcutaneously on the foot, the blood flow in the tumor fell to 23.4% and 21.4% of the control values in the MFF- and Inactin-anesthetized animals, respectively. This was accompanied by a similar fall in the blood flow in the foot (tumor bed) itself. In the intramuscular tumor the blood flow fell to 24.8% of the control value in the MFF group, whereas the corresponding figure was 36.2% in the Inactin group. In the surrounding muscle (tumor bed) the blood flow increased significantly, most pronounced in the MFF experiment, where it was tripled. Conclusion : The fall in the tumor perfusion by SNP may be exploited therapeutically to increase the tumor temperature during hyperthermia. Predominant heating of the tumor compared to the tumor bed can be expected if the tumor is growing in or near skeletal muscles.

Purpose: Intraperitoneal hypertonic glucose has previously been shown to induce hyperglycemia, hemoconcentration, and to influence systemic and tumor circulation, and, thus, enhance the effect of thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the optimal timing and the precise mechanisms responsible are not known. The effect of different time intervals between glucose load and thermochemotherapy with ACNU in the treatment of BT 4 An tumors, therefore, was investigated. Changes of serum glucose (Se-glucose), hemoglobin, systemic circulation parameters, tumor pH, and tumor temperature, induced by intraperitoneal glucose and/or hyperthermia, were measured to assess their effect on tumor growth. Methods and Materials: (a): Inbred BD IX rats with BT 4 An tumors on the hind leg were treated with ACNU 7 mg/kg intravenously just before waterbath hyperthermia, and intraperitoneal hypertonic glucose (6 g/kg) at different time intervals before (240-0 min) or immediately after thermochemotherapy. (b): Intratumoral pH and temperature were measured at different intervals after intraperitoneal glucose, and during hyperthermia with or without previous glucose. (c): Hemoglobin, hematocrit, and Se-glucose were measured at different times after intraperitoneal glucose. (d): Mean arterial pressure, pulse pressure, and heart rate were measured for 120 min after intraperitoneal glucose. Results: (a): The number of tumor controls and the growth delay was greatest with glucose 45 min before thermochemotherapy, and least with a time interval of 240 min. Glucose after thermochemotherapy delayed tumor growth. (b): After intraperitoneal glucose alone, intratumoral pH decreased gradually from 6.76 to 5.86 after 240 min. Hyperthermia 120 min after glucose induced a rapid further pH drop, while hyperthermia alone had no significant influence on pH. Intratumoral temperature was higher during hyperthermia in animals given glucose. (c): A substantial rise of Se-glucose and hemoglobin developed. The hemoconcentration was maintained also after reduction of Se-glucose towards normal values. (d): An initial tachycardia, and a reduction of the mean arterial pressure of about 10% 5–45 min after glucose was measured. Conclusions: The data indicate that a complex interaction between gradually reduced tumor pH, hyperglycemia, hemoconcentration, and reduced tumor blood flow, and not a breakdown of systemic circulation, is responsible for the effect of intraperitoneal glucose on thermochemotherapy with ACNU. Interestingly, enhancement of thermochemotherapy effect was also seen when intraperitoneal glucose was given after heat and ACNU.

e17023Background: Standard treatment of locally advanced cervical carcinoma consists of concurrent radiotherapy (including brachytherapy) and chemotherapy (weekly cisplatin 40 mg/m2), or chemoradio...

Published version of an article in the journal: BMC Cancer. Also available from the publisher at: http://dx.doi.org/10.1186/1471-2407-13-9 Open access Background: Faced with a life-threatening illness, such as cancer, many patients develop stress symptoms, i.e. avoidance behaviour, intrusive thoughts and worry. Stress management interventions have proven to be effective; however, they are mostly performed in group settings and it is commonly breast cancer patients who are studied. We hereby present the design of a randomized controlled trial (RCT) evaluating the effectiveness and cost-effectiveness of an individual stress-management intervention with a stepped-care approach in several cancer diagnoses. Method: Patients (>= 18 years) with a recent diagnosis of breast cancer, colorectal cancer, lymphoma, prostate cancer or testicle cancer and scheduled for adjuvant/curative oncology treatment, will consecutively be included in the study. In this prospective longitudinal intervention study with a stepped-care approach, patients will be randomized to control, treatment as usual, or an individual stress-management intervention in two steps. The first step is a low-intensity stress-management intervention, given to all patients randomized to intervention. Patients who continue to report stress symptoms after the first step will thereafter be given more intensive treatment at the second step of the programme. In the intervention patients will also be motivated to be physically active. Avoidance and intrusion are the primary outcomes. According to the power analyses, 300 patients are planned to be included in the study and will be followed for two years. Other outcomes are physical activity level, sleep duration and quality recorded objectively, and anxiety, depression, quality of life, fatigue, stress in daily living, and patient satisfaction assessed using valid and standardized psychometric tested questionnaires. Utilization of hospital services will be derived from the computerized patient administration systems used by the hospital. The cost-effectiveness of the intervention will be evaluated through a cost-utility analysis. Discussion: This RCT will provide empirical evidence of whether an individually administered stress-management programme in two steps can decrease stress as well as maintain or enhance patients' physical activity level, quality of life and psychological well-being. Further, this RCT, with a stepped-care approach, will provide knowledge regarding the cost-effectiveness of an individually administered stress-management programme whose aim is to help and support individual patients at the right level of care.

Patients given preoperative radiotherapy (31.5 Gy in 18 fractions) in a prospective, randomized trial of presumably operable rectal adenocarcinoma, were examined for a possible relation between bowel toxicity manifested as diarrhoea, and tumour size in the operative specimen, in addition to recurrence rate. The group requiring drugs for diarrhoea had significantly smaller tumours at surgery (2.5 cm versus 3.5 cm, p > 0.05). Patients without significant radiation-induced diarrhoea had also more recurrences (37.5% against 14.3%, p = 0.01). The disease-specific survival rate was also significantly better (p = 0.02) at 1.5 and 10 years in patients with diarrhoea WHO grade 3 and 4; 89.5%, 75.9% and 65.1% compared to 83.5%, 49.3% and 44.4% in patients with no or minimal radiation-induced loose bowels. These results indicate that the reaction of the normal bowel to radiation may correlate to radiation sensitivity of tumours derived from the same tissue.

Background Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients. Methods and Findings In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening. Conclusion The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS. Trial registration ClinicalTrials.gov NCT00848692

The effect of thermochemotherapy with cisplatin or carboplatin was compared in the BT 4 -cell line. In vitro . BT 4 C-cells were treated with different concentrations of cisplatin or carboplatin, with or without simultaneous hyperthermia. In vivo : Inbred BD IX rats with transplanted glioma-like BT 4 A or glioblastoma-like BT 4 An tumors on the hind leg were treated with cisplatin (4 mg/kg) or carboplatin (50 mg/kg), with or without local hyperthermia. In vitro the benefit of adding hyperthermia to chemotherapy was similar for cisplatin and carboplatin. For both cisplatin and carboplatin, the difference of treatment effect between thermochemotherapy and chemotherapy alone increased with higher drug concentrations. In vivo hyperthermia clearly enhanced the effect of carboplatin on BT 4 A tumors. When treating BT 4 An tumors, thermochemotherapy with cisplatin or carboplatin was equally effective. Both combinations were superior to treatment with hyperthermia alone. Local toxicity and weight loss following thermochemotherapy were comparable when substituting cisplatin with carboplatin.

BACKGROUND AND PURPOSE: Studying imaging findings of non–acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma (PCNSL), we hypothesized that the imaging presentation has changed with the increasing incidence of PCNSL and is related to clinical factors (eg, time to diagnosis and the patient9s being diagnosed alive or at postmortem examination). MATERIALS AND METHODS: Chart and histologic reviews of patients recorded as having PCNSL during 1989–2003 in the Norwegian Cancer Registry identified 98 patients with non-AIDS PCNSL; 75 had available imaging. CT and MR images from the first diagnostic work-up after onset of symptoms but before histologic diagnosis were reviewed. RESULTS: CT and/or MR imaging in the 75 patients revealed no lesion in 10 (13%), a single focal lesion in 34 (45%), multiple focal lesions in 26 (35%), and disseminated lesions in 5 (7%) patients. All together, we identified 103 focal lesions (single/multiple): 63% in white matter, 56% abutting the ventricular surface, and 43% in the frontal lobes); 100% (102/102 lesions evaluated with contrast) showed contrast enhancement. The median time from imaging to diagnosis for patients with no, single, multiple, or disseminated lesions was 32, 3, 5, and 3 weeks, respectively (P = .01). Patients with no or disseminated lesions were more often diagnosed at postmortem examination (P = .06). Imaging findings were practically unchanged during the consecutive 5-year periods. CONCLUSIONS: White matter periventricular contrast-enhancing single or multiple focal lesions were typical of non-AIDS PCNSL. No or disseminated lesions heightened the risk of delayed or postmortem diagnosis. Although the incidence of non-AIDS PCNSL has increased, its presentation at imaging remains unchanged.

Purpose To elucidate changes in gene expression after treatment with regional thermochemoradiotherapy in locally advanced squamous cell cervical cancer. Methods and Materials Tru-Cut biopsy specimens were serially collected from 16 patients. Microarray gene expression levels before and 24 h after the first and second trimodality treatment sessions were compared. Pathway and network analyses were conducted by use of Ingenuity Pathways Analysis (IPA; Ingenuity Systems, Redwood City, CA). Single gene expressions were analyzed by quantitative real-time reverse transcription–polymerase chain reaction. Results We detected 53 annotated genes that were differentially expressed after trimodality treatment. Central in the three top networks detected by IPA were interferon alfa, interferon beta, and interferon gamma receptor; nuclear factor κB; and tumor necrosis factor, respectively. These genes encode proteins that are important in regulation cell signaling, proliferation, gene expression, and immune stimulation. Biological processes over-represented among the 53 genes were fibrosis, tumorigenesis, and immune response. Conclusions Microarrays showed minor changes in gene expression after thermochemoradiotherapy in locally advanced cervical cancer. We detected 53 differentially expressed genes, mainly involved in fibrosis, tumorigenesis, and immune response. A limitation with the use of serial biopsy specimens was low quality of ribonucleic acid from tumors that respond to highly effective therapy. Another “key limitation” is timing of the post-treatment biopsy, because 24 h may be too late to adequately assess the impact of hyperthermia on gene expression.

Background Primary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989–2003. Methods We identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry (by law recording all cases of cancer in Norway) and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases (by law recording all cases of AIDS in Norway). Results Twenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989–2003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1–2.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy. Conclusion This is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.

Although hyperthermia has been shown to increase the effect of some cytotoxic drugs both in vitro and in vivo, there is sparse data on the interaction of the two modalities during fractionated treatment in vivo. In vitro data suggest that, parallel to development of thermotolerance, turmour cell sensitivity to drugs may be modified.Thermotolerance in tumour and surrounding normal tissue and the sensitivity to the alkylating agent BCNU given alone i.p., or as thermochemotherapy, was investigated in the subcutaneously transplanted BT4An rat glioma.Tumours treated by 44°C water bath hyperthermia alone minutes after the priming hyperthermia were initially sensitive to hyperthermia, but decreased heat sensitivity developed during continued heating. Thermotolerance in the skin was greatest at 24 h. When the skin reaction was compared with the effect on tumours, a therapeutic gain using hyperthermia alone was seen at 168 h.Tumours were most sensitive to BCNU just after the priming hyperthermia, least sensitive a...

As low-dose metronomic cyclophosphamide (CTX) and hyperthermia (HT) both exert antitumour effects in part through antiangiogenic mechanisms, interactive effects of the two modalities were explored.Subcutaneously implanted rat tumours (BT4An) were treated with CTX 35 mg/kg i.p. three doses a week for two weeks, local water-bath HT yielding mean tumour temperature of 43 degrees C for one hour at day 0, both modalities combined (CTX-HT(0)), or saline. TUNEL assays, immunohistochemical staining of thrombospondin 1 (TSP-1) and real time RT-PCR of TSP-1 mRNA were analysed the first three hours after completed treatment day 0.Metronomic dosed CTX (p=0.006) and HT (p0.001) both delayed tumour growth. The combined regimen was superior to either modality alone (p0.001). Complete tumour regressions were observed in CTX (6%), HT (12%), and CTX-HT(0) (41%) treated rats. TSP-1 protein was specifically upregulated in the vascular matrix of tumours receiving CTX (weak), HT (moderate) and CTX-HT(0) (strong). In contrast, reduced expression of TSP-1 protein was observed in tumour cells after HT alone and CTX-HT(0). TUNEL assays indicated induction of apoptosis by HT and CTX-HT(0) 90 minutes after end of the first treatment.A single session of local HT enhances the effects of low-dose metronomic CTX, possibly in part mediated through a differential effect on TSP-1 protein levels in tumour cells and tumour vasculature.

R.D. Issels, L.H. Lindner, P. Ghadjar, P. Reichardt, P. Hohenberger, J. Verweij, S. Abdel-Rahman, S. Daugaard, C. Salat, Z. Vujaskovic, R. Wessalowski, H.R. Duerr, F. Ploner, O. Mella, M. Schmidt, U. Mansmann, K.W. Jauch, C. Belka, W. Hiddemann, A. Gronchi. Klinikum der Univers. Munchen-Groshadern Klinikum Grosshadern, Medical Clinic III, Munchen, Germany; Klinikum der Universitat Munchen, Medizinische Klinik III, Munich, Germany; Charite Universitatsmedizin Berlin, Klinik fur Radio-Onkologie und Strahlentherapie, Berlin, Germany; Helios Klinikum Berlin-Buch, Interdisziplinare Onkologie, Berlin, Germany; Universitatsklinikum Mannheim, Spezielle chirurgische Onkologie, Mannheim, Germany; Erasmus Medical Center, Medical Oncology, Rotterdam, Netherlands; Rigshospitalet, Pathology, Copenhague, Denmark; University of Maryland, Translational Radiation Sciences, Baltimore, USA; Universitatsklinikum Duesseldorf, Klinik fur Kinder-Onkologie − Hamatologie und Immunologie, Duesseldorf, Germany; Klinikum der Universitat Munchen, Tumororthopadie, Munich, Germany; Universitatsklinikum Graz, Klinische Onkologie, Graz, Austria; Haukeland University Hospital, Medical Oncology, Bergen, Norway; Ludwig Maximilians Universitat Munchen, Institut fur Medizinische Informatik − Biostatistik und Epidemiologie, Munich, Germany; Klinikum der Universitat Munchen, Klinik fur Chirurgie, Munich, Germany; Klinikum der Universitat Munchen, Klinik fur Strahlentherapie, Munich, Germany; 16 Istituto Nazionale dei Tumori, Chirurgia dei Sarcoma, Milano, Italy

Homocysteine (Hcy) is a sulfur amino acid formed from methionine during transmethylation. Once formed, it is either remethylated to methionine or irreversibly catabolized to cystathionine. The remethylation is catalyzed by methionine synthase (EC 2.1.1.13), which requires cobalamin as cofactor and 5-methyltetrahydrofolate as substrate (1) . This explains why the fasting total homocysteine (tHcy) concentration is related to overall folate or cobalamin status and that increased tHcy has been used to diagnose deficiencies of these vitamins (2)(3)(4) . Methotrexate (MTX) is an antifolate drug that inhibits dihydrofolate reductase, thereby depleting the cells of reduced folates, including 5-methyltetrahydrofolate (5) . In cell culture studies, MTX inhibits Hcy remethylation, leading to increased Hcy export to the medium (6)(7)(8) . Plasma tHcy is a sensitive indicator of the antifolate effect of MTX, as demonstrated by an increased plasma tHcy concentration. The increase is maximal after ∼2 days in psoriasis patients given only 25 mg of MTX (9) . In cancer patients receiving intermediate or high doses of MTX, there is a rapid increase in plasma tHcy within hours. However, the increased tHcy induced by MTX is normalized after rescue therapy with folinic acid (7)(10) . We have previously shown that tHcy clearance in folate-deficient subjects with hyperhomocysteinemia is close to that observed in healthy individuals (11) . However, it has been suggested that folate status predominately affects concentrations of fasting, i.e., low tHcy concentrations. Therefore, the present study was undertaken to examine tHcy elimination in subjects with plasma tHcy within reference values and to investigate whether the antifolate effect of MTX had any influence on plasma clearance. This was carried out by monitoring elimination of [14C]Hcy injected …

The incidence of primary central nervous system lymphoma (PCNSL) has been reported to increase in some parts of the world, while being stable in other regions. In an attempt to characterize the incidence rate, clinical features, treatment, outcome, and prognostic factors of PCNSL in Norway, we report our experience in a large unselected series of patients. Clinical features, histological diagnosis, radiological findings, treatment, and outcome of all patients diagnosed with PCNSL in Norway in the years 1989-1998 were registered. During the 10-year period 58 new cases of histologically verified PCNSL were registered in Norway. The annual incidence rate of PCNSL was on average 1.34 cases per million people with a non-significant increasing trend (p=0.069). For patients diagnosed before death (n=45) the estimated survival following histological diagnosis was 55%, 47%, and 23% at 1, 2, and 5 years, respectively. In Cox-regression analysis age, WHO performance status and treatment had independent prognostic impact on survival. In the studied decade, there was a non-significant trend towards increased incidence of PCNSL, perhaps due to increased availability of diagnostic imaging, especially magnetic resonance imaging.

A large suprasellar, partly cystic, contrast-enhancing tumor was resected from a 19-year-old woman who presented with bitemporal visual field defects and reduced visual acuity. Grossly, the tumor was brown and located in the subarachnoid space. Histologically, it was composed of spindle and pleomorphic cells, including giant tumor cells, with markedly pleomorphic nuclei. Reticulin fibers surrounded single cells and small groups of cells. Very few mitotic figures were found in the tumor, and no necrosis or microvascular proliferation was seen. The tumor thereby resembled a pleomorphic xanthoastrocytoma. Many of the tumor cells contained a dark-brown intracytoplasmic pigment, shown to be melanosomal melanin by ultrastructural examination. Immunohistochemical examination demonstrated that the pigment was present in glial tumor cells. Only four cases of pigmented astrocytic tumors have been published, none of these were suprasellar. Our patient received fractionated radiotherapy with a total dose of 48.6 Gy 14 months after gross total removal of the tumor. She is alive without relapse after 12-year follow-up.

This study compares attitudes to the proposed new Alternative medicine act that would give Norwegian practitioners of alternative medicine more scope in treating patients with cancer.In June 2002 a questionnaire on alternative and complementary medicine was distributed among 156 physicians, 414 nurses, 164 radiation therapists and 94 administrative staff members in the five Norwegian university hospitals responsible for cancer treatment. 61% returned the questionnaire.Of all respondents, 29% described themselves as having a positive attitude to alternative medicine. When the health services can offer no healing or palliative treatment to offer, 41% of the physicians and 60% of other health care workers were of the opinion that alternative practitioners could treat cancer. More than 50% of respondents were of the opinion that the patients themselves had the right to determine whether or not to use alternative medicine. When health authorities require communication between practitioners and physicians more than 70% of all health care workers felt that this contact had to be in writing.Most health care workers treating cancer are of the opinion that practitioner of alternative medicine might treat cancer if the health services have no healing or palliative treatment. Required contact between physicians and alternative practitioners must be in writing.

AIthough intensity-modulated radiotherapy (IMRT) may increase the therapeutic ratio of radiotherapy for a range of malignancies, only a few IMRT treatments have yet been performed in the Nordic countries. The scores derived from a national survey to assess Norwegian oncologists' expectations of IMRT are presented. A questionnaire was distributed to all consultants in oncology at Norwegian radiotherapy clinics. Summary scores of daily general radiotherapy workload (DGRTW), acquaintance with IMRT (AI) and expectations of IMRT (EI) were derived. Thirty-nine questionnaires (67%) were returned from a total of 58 oncologists. The oncologists' scores on the AI scale (mean score: 7.5 out of 21) were rather low. Their AI scores were found to be positively correlated with their DGRTW. Higher scores on the EI scale were documented (mean score: 6.2 out of 14): 15 oncologists (39%) rated IMRT as one of the three major contributors to potentially increased cancer survival. Oncologists treating patients with prostate, head and neck, gastrointestinal and CNS tumours had higher EI scores than the other oncologists (7.7 vs. 5.1; p = 0.01). The Norwegian radiation oncologists' expectations of IMRT are high in terms of both the potential clinical benefit and the rate of implementation. This should encourage the radiotherapy communities to continue (or rapidly initiate) their efforts in providing the routines required for safe implementation of IMRT.

There are two evidence based therapeutic options for locally advanced cervical cancer: Radiotherapy and concurrent chemotherapy (cisplatin alone or combined with other drugs) or radiation and hyperthermia, documented in randomised trials. The weight of evidence is less for the most advanced stages. Combination of all three options are currently tested in several centres with good clinical response and acceptable toxicity. Based on a pragmatic approach we propose to proceed with a trial selecting cisplatin concurrent with radiation therapy as the standard arm to be compared with the same regimen with the addition of hyperthermia once a week.

Background and purpose: Combretastatin A-4 disodium phosphate (CA-4) enhances thermal damage in s.c. BT4An rat gliomas. We currently investigated how CA-4 and hyperthermia affect the tumor microenvironment and neovasculature to disclose how the two treatment modalities interact to produce tumor response. Methods: By confocal microscopy and immunostaining for von Willebrand factor, we examined the extent of vascular damage subsequent to CA-4 (50 mg/kg) and hyperthermia (waterbath 44°C, 60 min). The influence on tumor oxygenation was assessed using interstitial pO2-probes (Licox system) and by immunostaining for pimonidazole. We examined the direct effect of CA-4 on the tumor cell population by flow cytometry (cell cycle distribution) and immunostaining for β-tubulin (cytoskeletal damage). Results: Whereas slight vascular damage was produced by CA-4 in the BT4An tumors, local hyperthermia exhibited moderate anti-vascular activity. In tumors exposed to CA-4 3 h before hyperthermia, massive vascular damage ensued. CA-4 reduced the pO2 from 36.1 to 17.6 mmHg (P=0.01) in the tumor base, and tumor hypoxia increased slightly in the tumor center (pimonidazole staining). Extensive tumor hypoxia developed subsequent to hyperthermia or combination therapy. Despite a profound influence on β-tubulin organization in vitro, CA-4 had no significant effect on the cell cycle distribution in vivo. Conclusion: Our results indicate that the anti-vascular activity exhibited by local hyperthermia can be augmented by previous exposure to CA-4.

Attacking tumor vasculature is a promising approach for the treatment of solid tumors. The tubulin inhibitor combretastatin A-4 disodium phosphate (CA-4) is a new vascular targeting drug which displays a low toxicity profile. We wanted to investigate how CA-4 influences tumor perfusion in the BT4An rat glioma and how the vascular targeting properties of CA-4 could be exploited to augment hyperthermic damage towards tumor vasculature.We used the (86)RbCl extraction technique to assess how CA-4 influences tumor perfusion, and the tumor endothelium was examined for morphological changes induced by the drug. We combined CA-4 (50 mg/kg i.p.) with hyperthermia (44 degrees C, 60 min) at different time intervals to evaluate how therapy should be designed to affect tumor growth, and we studied the tumors histologically to assess tissue viability.We found that CA-4 induced a profound, but transient reduction in tumor perfusion 3-6 h postinjection. If hyperthermia was administered 3-6 h after injecting CA-4, massive hemorrhagic necrosis developed, and tumor response was significantly enhanced compared to simultaneous administration of the two treatment modalities (P0.005). CA-4 alone had no influence on tumor growth and failed to disrupt the vasculature of the BT4An solid tumors. Interestingly though, a mild endothelial edema was observed in some tumor areas 3 h after injecting CA-4.We conclude that the combination of CA-4 and hyperthermia is a potent therapeutic option for BT4An tumors, but the selection of adequate time intervals between CA-4 and hyperthermia are imperative to obtain tumor response.

Purpose: To investigate the toxicity of combretastatin A-4 disodium phosphate (CA-4) and its vascular effects in the subcutaneous (s.c.) BT 4 An rat glioma, and additionally, to determine the tumor response of CA-4 combined with hyperthermia. Methods and Materials: For assessment of drug toxicity, rats were given 50, 75, or 100 mg/kg CA-4 and followed by daily registration of weight and side effects. Interstitial tumor blood flow was determined by laser Doppler flowmetry in rats injected with 50 mg/kg CA-4. In the tumor response study we administered CA-4 50 mg/kg alone or combined with hyperthermia (waterbath 44°C for 60 min) 0 or 3 h later. Results: We found that CA-4, at a well-tolerated dose of 50 mg/kg, induced a considerable time-dependent decrease in the tumor blood flow. Tumor blood flow was reduced by 47–55% during the first 110 min after injecting CA-4, and thereafter remained decreased until the measurements were terminated. Administering CA-4 3 h before hyperthermia yielded the best tumor response and increased tumor growth time significantly compared with simultaneous administration of CA-4 and hyperthermia ( p = 0.03). Interestingly, CA-4 alone did not influence tumor growth. Conclusion: CA-4 induces a gradual reduction in tumor blood flow which can be exploited to sensitize the BT 4 An tumor for hyperthermia.

Purpose The effect of a decrease in the mean arterial blood pressure (MAP) induced by sodium nitroprusside (SNP) on the tumor temperature during hyperthermia (HT), and on the cytotoxic effect of HT, was studied in the BT4An tumor transplanted to the hind limb of BD IX rats. Experiments with two different anesthetics, pentobarbital and the midazolam/fentanyl/fluanisone combination (MFF), were performed to secure reliable conclusions. Methods and materials In the tumor response experiments local waterbath HT at 44.0 degrees C was given for 60 min. Sodium nitroprusside was administered as a continuous intravenous infusion to lower the MAP to 60 or 80 mmHg during HT. In two other experiments the temperature at the base of the tumor during HT was measured before and during SNP infusion. In animals without tumor the temperature was measured subcutaneously on the foot during HT with or without SNP-induced hypotension. Results When SNP was given to lower the MAP to 60 mmHg during HT in MFF anesthetized animals, the median tumor growth time (TGT) was 70 days, compared to 14.5 days in the HT alone group. The corresponding figures were 127 and 12.1 days with pentobarbital anesthesia. In the HT + SNP group, more than 40% cure was observed in both experiments. No cures were seen in any of the other groups. Hyperthermia alone prolonged the TGT slightly, whereas SNP given alone had no effect, compared to controls. When the MAP was lowered to 80 mmHg by SNP infusion during HT (MFF anesthesia), the median TGT was 19.9 days, which was significantly longer than that in the HT alone group (10.9 days). In the MAP range from 60 to 120 mmHg, a nearly linear relationship between the MAP and the tumor temperature was found during HT in MFF anesthetized animals. With both anesthetics, the median temperature at the base of the tumor was about 0.8 degrees C higher during HT when the MAP was lowered to 60 mmHg by SNP. In animals without tumors, the temperature subcutaneously on the foot was 0.3 and 0.4 degrees C higher during SNP infusion in the MFF and pentobarbital group, respectively. Conclusion We have developed a small animal model in inbred rats feasible for exploring the influence of a stable blood pressure reduction induced by SNP, on the effect of HT given alone or in combination with other treatment modalities to a transplantable tumor. The greatly increased cytotoxic effect of local waterbath HT in the present tumor response experiments is probably a consequence of increased tumor temperature during SNP infusion.