Olav Mella

High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy

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 for ≥6 months to therapy). Each patient received DES 5mg t.i.d. Four patients terminated therapy after ≤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 for ≥6 months duration. Five patients had an objective response and one patient a SD lasting for ≥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.

Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

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

CT and MR Imaging Features of Primary Central Nervous System Lymphoma in Norway, 1989–2003

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 patients 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.

Increasing incidence and continued dismal outcome of primary central nervous system lymphoma in Norway 1989-2003 : time trends in a 15-year national survey.

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.

Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome.

Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n=268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and β adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high β2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder. We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and β adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing β adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.

Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series

BackgroundChronic fatigue syndrome (CFS) is a disease of unknown aetiology. A patient with CFS had unexpected, marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkins disease. We reasoned that the transient CFS recovery was related to methotrexate treatment, which induces immunomodulation in part through B-cell depletion.MethodsIn a case series, this patient and two additional CFS patients were B-cell depleted by infusion of the monoclonal anti-CD20 antibody rituximab.ResultsAll three had improvement of all CFS symptoms. Patients 1 and 2 had major amelioration from 6 weeks after intervention, patient 3 slight improvement from the same time, but then improved markedly from 26 weeks after intervention. The symptomatic effect lasted until weeks 16, 18 and 44, respectively. At relapse, all were retreated with a single (patient 1) or double rituximab infusion (patients 2 and 3). Again, all three had marked symptom improvement, mimicking their first response. After new symptom recurrence, patients 1 and 2 were given weekly oral methotrexate, patient 1 having effect also from this agent. Patients 1 and 2 were again treated for a third rituximab infusion after new relapse, again with a marked clinical benefit. No unexpected toxicity was seen.ConclusionThese observations suggest that B-lymphocytes are involved in CFS pathogenesis for a subset of patients. Benefit for all CFS symptoms, the delayed symptom relief following B-cell depletion, the kinetics of relapses, and the effect also from methotrexate treatment, provide suggestive evidence that B-cells play a significant role in the ongoing clinical features, and that CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function. More systematic investigations of this therapeutic strategy, and of its biological basis, are now needed.

Diagnostic delay in primary central nervous system lymphoma.

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.

Combretastatin A-4 and hyperthermia;a potent combination for the treatment of solid tumors

BACKGROUND AND PURPOSE 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. MATERIAL AND METHODS 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. RESULTS 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 (P<0.005). 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. CONCLUSIONS 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.

Combined hyperthermia and cis-diamminedichloroplatinum in BD IX rats with transplanted BT4A tumours

Effects on tumours and toxicity of locally applied waterbath hyperthermia (44 degrees C, 60 min) and cis-diamminedichloroplatinum (cis-DDP) were investigated in BD IX rats with transplanted BT4A tumours on the hind foot. The effect of cis-DDP at doses of 2, 3 and 4 mg/kg measured as tumour growth time, defined as time to reach five times the tumour volume at treatment, increased in a drug dose-dependent manner by using hyperthermia. Moderate systemic hyperthermia at a mean of 41 degrees C during the second half of the treatment also increased the tumour regrowth delay of cis-DDP. Skin reactions after local hyperthermia did not increase in this cis-DDP dose range, but systemic toxicity of the drug was markedly enhanced by hyperthermia. At histological evaluation, hyperthermia at 44 degrees C resulted in marked vasodilatation, red blood cell pooling and haemolysis, with a seemingly almost complete central tumour perfusion shutdown lasting up to five days after treatment. The combination of cis-DDP and hyperthermia resulted in additional cell death especially at the tumour periphery and at depth near the tendon and muscle. This in vivo study confirms in vitro data indicating cis-DDP as a candidate for clinical trials combined with hyperthermia. As both the tumour and systemic side effects of cis-DDP are enhanced by hyperthermia, caution is advocated when applying high drug doses with systemic hyperthermia.

DO ACUTE SIDE-EFFECTS DURING RADIOTHERAPY PREDICT TUMOUR RESPONSE IN RECTAL CARCINOMA ?

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.