Prevalence of anxiety and depression in people with different types of cancer or haematologic malignancies: a cross-sectional study.

AIMS: Cancer patients often present with psychological symptoms that affect their quality of life, physical health outcomes and survival. Two of the most frequent psychiatric comorbidities are anxiety and depression. However, the prevalence of these disorders among cancer patients remains unclear, as studies frequently report varying rates. In the present study, we aimed to provide robust point estimates for the prevalence of anxiety and depression for both a mixed cancer sample and for 13 cancer types separately, considering confounding variables. METHODS: In a sample of 7509 cancer outpatients (51.4% female), we used the Hospital Anxiety and Depression Scale to assess rates of anxiety and depression. Applying ordinal logistic regression models, we compared the prevalence of anxiety and depression between different cancer types, controlling for age and gender. RESULTS: About one third of our sample showed symptoms of anxiety (35.2%) or depression (27.9%), and every sixth patient had a very likely psychiatric condition, with women being more frequently affected. Elderly patients more often showed signs of depression. The prevalence of anxiety and depression was significantly higher in lung and brain cancer patients, than in other cancer patients. Lowest depression rates were found in breast cancer patients. CONCLUSIONS: The prevalence of anxiety and depression is high in cancer patients. Type of cancer is an important predictor for anxiety and depressive symptoms, with lung and brain cancer patients being highly burdened. Considering a personalised medicine approach, physicians should take into account the high prevalence of psychiatric comorbidities and include psychiatric consultations in the treatment plan.

Grey-scale and colour Doppler sonography in the evaluation of children with suspected bowel inflammation: correlation with colonoscopy and histological findings.

AIM: To evaluate the correlation of grey-scale and colour Doppler sonography with colonoscopy and histology to detect bowel inflammation in children. MATERIAL AND METHODS: The records of 72 patients with suspected bowel inflammation were reviewed retrospectively. Patients were included in the study if sonography had been performed up to 30 days before colonoscopy. Grey-scale and colour Doppler sonography were used to evaluate bowel wall thickness and vascularity for the detection of distal bowel inflammation. Findings were correlated with colonoscopy and histological findings. The sensitivity and specificity of sonographic wall thickness to detect inflammation was determined. Spearman's coefficient (rs) was used to determine the correlation of Doppler findings with colonoscopy/histology. RESULTS: Sonograms of 372 bowel segments were evaluated and results were correlated with colonoscopy and histological findings of 352 segments. The sensitivity and specificity of sonographic bowel thickness to detect inflammation in the terminal ileum and the right colon were high; in the other segments, specificity was high but sensitivity was low. The correlation of Doppler sonography with colonoscopy and histology to detect inflammation in the terminal ileum was strong (rs: 0.84; p<0.001) and in the other segments, weak to moderate; when the interval between examinations was shorter than 10 days, the correlation was stronger in all segments. Of nine patients with abnormal small bowel sonograms but normal colonoscopies, three had Crohn's disease. CONCLUSION: Sensitivity and specificity of grey-scale sonography to detect inflammation in the terminal ileum and the right colon were high, and the correlation of Doppler with colonoscopy and histology was very strong in the same segments.

Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serologic parameters and clinical course in lymphoma patients with autoimmune diseases.

BACKGROUND: As patients with B-cell lymphomas suffering from an underlying autoimmune condition undergoing therapy with the CD20 antibody rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) offer the unique possibility of monitoring effects of therapy on various rheumatologic parameters, we have evaluated serologic autoimmune markers and the clinical outcome of patients with autoimmune diseases (ADs) who received lymphoma treatment with R-CHOP during the course of their disease. PATIENTS AND METHODS: We have retrospectively analysed 13 patients with non-Hodgkin's lymphoma who concurrently suffered from ADs and were treated with the R-CHOP regimen. Subjective parameters along with rheumatoid factor (RF) and antinuclear antibodies (ANA) were serially measured. RESULTS: The median levels of RF were 901 IU/ml [inter-quartile-range (IQR) 189-2520] before and 75 IU/ml (IQR 45-644) after therapy (P = 0.028). The median levels of ANA were 800 (IQR 140-2560) before and 100 (40-1280) after therapy (P = 0.027). Ten (77%) patients showed clinical improvement of their autoimmune symptoms, two (15%) reported no difference and one (7%) patient with rheumatoid arthritis-related worsening symptoms during therapy with R-CHOP. The autoimmune-related symptoms recurred after a median time of 7 weeks (IQR 6-8) in seven patients. In terms of lymphoma response, 11 patients achieved a complete remission and two a partial remission. CONCLUSIONS: This analysis indicates that R-CHOP given for lymphoma treatment is also effective for therapy of concurrent rheumatoid diseases. Both rheumatoid parameters as well as clinical symptoms showed a significant decrease during treatment with this immunochemotherapy. The effects on the rheumatic diseases, however, seem to be of limited duration.

Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression.

Lipoprotein lipase (LPL) is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL) related to immunoglobulin V(H) gene (IgV(H))mutational status. We determined gene expression profiles using Affymetrix U133A GeneChips in two groups of B-CLLs selected for either high ('LPL+', n=10) or low ('LPL-', n=10) LPL mRNA expression. Selected genes were verified by real-time PCR in an extended patient cohort (n=42). A total of 111 genes discriminated LPL+ from LPL- B-CLLs. Of these, the top three genes associated with time to first treatment were Septin10, DMD and Gravin (P

Clinical study on the effect of infrared radiation of a tiled stove on patients with hand osteoarthritis.

OBJECTIVE: To explore the effect of infrared radiation of a tiled stove on patients with hand osteoarthritis (OA). METHODS: A randomized controlled crossover study was performed with 45 patients with hand OA. This sample was randomly assigned to two groups: group A [first 3 hours spent three times a week during 3 weeks in a heated tiled stove room ('Stove Period') and after 2 weeks without treatment this group was observed for another 3 weeks ('Control Period')]; and group B (first assigned to the control period and the stove period following the treatment-free period). Assessments included the visual analogue scale (VAS) for general pain, pain in the hands, and global hand function, grip strength, the Moberg Picking-up Test (MPUT), the Australian/Canadian Osteoarthritis Hand Index (AUSCAN), and the Medical Outcomes Study (MOS) 36-item Short-Form Health Status Survey (SF-36). RESULTS: Fourteen (31%) patients improved on the VAS for general pain at the end of the tiled stove period as compared to 10 patients (22%) during the control period (p = 0.314, chi2-test). The AUSCAN pain domain showed a significant improvement after the tiled stove period (p = 0.034). Others pain parameters analysed (VAS for pain in hands and SF-36 bodily pain) showed moderate but not significant improvement (p = 0.682 and p = 0.237, respectively) compared to the control period. CONCLUSION: This study did not prove positive effects of the tiled stove exposure, although the numerical improvement in all pain measures suggests some possible positive effects on this symptom of hand OA.

Wilms' tumour gene 1 (WT1) in human neoplasia.

The transcription factor Wilms' tumour gene 1 (WT1) is important as a prognostic marker as well as in the detection and monitoring of minimal residual disease in leukaemia and myelodysplastic syndromes. Evidence has accumulated over the past decade to show that WT1 is a key molecule for tumour proliferation in a large number of human neoplasms most prominent in acute leukaemias, making it a suitable target for therapeutic strategies. Based on animal results, showing safety and efficacy of immunization with WT1 peptides and protein, early clinical trials in leukaemia have recently been initiated. The First International Conference on WT1 in Human Neoplasia was held in Berlin, March 11--12, 2004. This report reviews the current knowledge on the role of WT1 in tumour promotion and as a diagnostic and therapeutic target, and summarizes the data presented and discussed in this meeting.

High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia.

We investigated the pattern of lipoprotein lipase (LPL) expression in B-cell chronic lymphocytic leukemia (B-CLL) and assessed its prognostic relevance. Expression of LPL mRNA as well as protein was highly restricted to leukemic B cells. The intensity of intracellular immunoreactivity of LPL was higher in samples of patients with unmutated immunoglobulin heavy-chain variable region genes (IGV(H)) compared to those with mutated IGV(H) genes. LPL mRNA levels in peripheral blood mononuclear cells (PBMNC) from 104 CLL patients differed by 1.5 orders of magnitude between cases with mutated (N=51) or unmutated (N=53) IGV(H) (median: 1.33 vs 45.22 compared to normal PBMNC). LPL expression correlated strongly with IGV(H) mutational status (R=0.614; P<0.0001). High LPL expression predicted unmutated IGV(H) status with an odds ratio of 25.90 (P<0.0001) and discriminated between mutated and unmutated cases in 87 of 104 patients (84%). LPL expression was higher in patients with poor risk cytogenetics. High LPL expression was associated with a shorter treatment-free survival (median 40 vs 96 months, P=0.001) and a trend for a shorter median overall survival (105 months vs not reached). Our data establish LPL as a prognostic marker and suggest functional consequences of LPL overexpression in patients with B-CLL.

Novel molecular diagnostic and therapeutic targets in chronic lymphocytic leukaemia.

B-cell lymphocytic leukaemia (B-CLL) is an indolent non-Hodgkin's lymphoma and the most frequent leukaemia. However, after many years, the incurable disease CLL has again become an exciting subject for research. Recently, both serum and molecular markers have been identified which could be used to predict the outcome of patients in early stages. With the advent of microarray analysis, novel diagnostic and therapeutic targets have been discovered. Here we describe the molecular strategies for target identification and validation. An evaluation of some established, and the most promising novel factors, with their diagnostic and prognostic applications is given. Potential therapeutic target molecules and their inhibitors are reviewed.

High expression of activation-induced cytidine deaminase (AID) mRNA is associated with unmutated IGVH gene status and unfavourable cytogenetic aberrations in patients with chronic lymphocytic leukaemia.

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation of B-cells. We investigated the expression of AID mRNA by real-time polymerase chain reaction (PCR) in peripheral blood mononuclear cells of 80 patients with B-CLL. AID expression was detected in 45 of 80 patients (56%) at various levels, but was undetectable in 35 patients (44%). AID PCR positivity was associated with unmutated IGV(H) gene status (22 of 25 patients; P=0.002) and unfavourable cytogenetics (18 of 23 patients with deletion in 11q or loss of p53; P=0.040). Using a threshold level of 0.01-fold expression compared to Ramos control cells, even more significant associations were observed (P=0.001 for IGVH; P=0.002 for cytogenetics). A correlation was observed between individual AID levels and the percentage of V(H) homology (R=0.41; P=0.001). AID positivity predicted unmutated IGV(H) status with an odds ratio of 8.31 (P=0.003) and poor risk cytogenetics with an odds ratio of 3.46 (P=0.032). Significance was retained after adjustment for Binet or Rai stages. AID mRNA levels were stable over time. These data suggest a potential role of AID as a prognostic marker in B-CLL.

WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies.

Among clinicians, initial awareness of the Wilms' tumor gene was limited mostly to pediatric oncologists. Almost a decade ago, overexpression of Wilms' tumor 1 (WT1) was observed in adult acute leukemia. Subsequent studies indicated that WT1 overexpression occurs in most cases of acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Limited tissue expression of WT1 in adults suggests that WT1 can be a target for leukemia/MDS therapy. WT1 expression in stem/progenitor cells remains unsettled. However, lack of progenitor cell suppression by WT1 antisense or WT1-specific cytotoxic T cells provide some assurance that WT1 expression in progenitor cells is minimal or absent. Immunotherapy-based WT1 approaches are furthest along in preclinical development. WT1-specific cytotoxic lymphocytes can be generated from normals and leukemic patients. In mice, WT1 vaccines elicit specific immune responses without evidence of tissue damage. In this paper, we review studies validating the immunogenicity of WT1 and propose that leukemia and MDS may be a good clinical model to test the efficacy of a WT1 vaccine.

WT1-specific serum antibodies in patients with leukemia.

WT1 is an oncogenic protein expressed by the Wilms' tumor gene and overexpressed in the majority of acute myelogenous leukemias (AMLs) and chronic myelogenous leukemias (CMLs). The current study analyzed the sera of patients with AML and CML for the presence of antibodies to full-length and truncated WT1 proteins. Sixteen of 63 patients (25%) with AML had serum antibodies reactive with WT1/full-length protein. Serum antibodies from all 16 were also reactive with WT1/NH2-terminal protein. By marked contrast, only 2 had reactivity to WT1/COOH-terminal protein. Thus, the level of immunological tolerance to the COOH terminus may be higher than to the NH2 terminus. The WT1/COOH-terminal protein contains four zinc finger domains with homology to other self-proteins. By implication, these homologies may be related to the increased immunological tolerance. Results in patients with CML were similar with antibodies reactive to WT1/full-length protein detectable in serum of 15 of 81 patients (19%). Antibodies reactive with WT1/NH2-terminal protein were present in the serum of all 15, whereas antibodies reactive with WT1/COOH-terminal protein were present in only 3. By contrast to results in leukemia patients, antibodies reactive with WT1/full-length protein were detected in only 2 of 96 normal individuals. The greater incidence of antibody in leukemia patients provides strong evidence that immunization to the WT1 protein occurred as a result of patients bearing malignancy that expresses WT1. These data provide further stimulus to test therapeutic vaccines directed against WT1 with increased expectation that the vaccines will be able to elicit and/or boost an immune response to WT1.

Immunity to WT1 in the animal model and in patients with acute myeloid leukemia.

The Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular, and ovarian cancers and melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1 peptides and antibody responses specific for WT1 protein. Screening of multiple murine cancer cell lines identified 2 murine cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1. Immunization with MHC class I binding peptides induced WT1 peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1 peptide-immunized animals. WT1 peptide immunization did not show any effect on TRAMP-C tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with leukemia was evaluated for pre-existing antibody responses. Western blot analyses showed WT1-specific antibodies directed against the N-terminus portion of the WT1 protein in the sera of 3 of 18 patients with acute myeloid leukemia (AML). (Blood. 2000;96:1480-1489)

Wilms' tumour gene (wt1) expression at diagnosis has no prognostic relevance in childhood acute lymphoblastic leukaemia treated by an intensive chemotherapy protocol.

Expression of the Wilms' tumour gene (wt1) has been demonstrated in a large proportion of human acute leukaemias and is thought to play a role in leukaemogenesis. Recent observations in adult patients with acute leukaemia suggest that wt1 gene expression is a poor prognostic factor. In childhood acute leukaemia, the clinical role of wt1 gene expression has not been established. We have therefore investigated bone marrow samples from 50 children with acute lymphocytic leukaemia at the time of diagnosis for the presence of wt1 transcripts to determine whether wt1 gene expression is associated with specific characteristics of leukaemic cells and whether it is predictive of response to treatment. All patients were treated according to the ALL-BFM 90 protocol. The median observation time was 30 months. Wt1 transcripts were detected by RT-PCR in 60% of the diagnostic samples. Wt1 PCR positive patients showed a higher median leukocyte and peripheral blast cell count than wt1 negative patients. High and intermediate risk patients more frequently displayed wt1 transcripts than low risk patients. No correlation between wtl gene expression and FAB type, immunophenotype, co-expression of myeloid antigens or karyotype has been observed. Furthermore, there was no correlation between wt1 gene expression at diagnosis and achievement of complete remission (CR) and no difference in disease-free survival (DFS) or overall survival (OS) between wt1 positive and negative patients (p > 0.1). These data indicate that (1) wt1 gene expression at diagnosis is detected more frequently in patients with high leukocyte and peripheral blast cell counts, but is not associated with specific characteristics of leukaemic cells, (2) wt1 gene expression is not an independent prognostic factor for CR, DFS or OS in childhood ALL treated by an intensive therapy protocol.

Immunophenotypic characterization of human bone marrow endosteal cells.

In order to determine the relationship between bone marrow (bm) endosteal cells (EDC) and hemopoietic progenitors, we have analyzed the immunophenotype of EDC using various antibodies (Ab) against mesenchymal antigens. The Ab were applied on paraffin sections of normal bm (iliac crest, n=17; talus, n=1; phalanx, n=1), myeloregenerative bm (after chemotherapy), and hematologic disorders (acute myeloid leukemia (AML), n=8; chronic myeloid leukemia (CML), n=6; myelodysplastic syndromes (MDS), n=14; severe aplastic anemia (SAA), n=4; essential thrombocythemia (ET), n=2; idiopathic (primary) osteomyelo-fibrosis (IMF), n=1; polycythemia vera (PV), n=1). In normal bm, EDC were found to react with Ab against vimentin, tenascin, alpha-smooth muscle actin, osteocalcin, CD51, and CD56, but did not react with Ab against CD3, CD15, CD20, CD34, CD45, CD68, or CD117. An identical phenotype of EDC was found in AML, MDS, SAA, ET, IMF, PV, myeloregenerative bm, and peripheral bones lacking active hemopoiesis (talus, phalanx). In patients with CML, EDC reacted with Ab to CD51, but did not react with Ab to CD56. Based on their unique antigen profile, EDC were enriched from normal bm by enzyme digestion and cell sorting. However, these enriched cells (CD56+, CD45-, CD34-) did not give rise to hemopoietic cells under the culture conditions used, i.e. in the presence of the growth factors IGF-1, bFGF, SCF, IL-3, and GM-CSF Together, our data do not support the hypothesis that EDC are totipotent mesenchymal progenitors giving rise to hemopoietic cells.

Telomere length shortening is associated with disease evolution in chronic myelogenous leukemia.

We studied telomere length in the peripheral blood leukocyte samples of a large group of patients with chronic myelogenous leukemia (CML) by Southern blot hybridization using the (TTAGGG)4 probe. The average telomere length expressed as the peak telomere repeat array (TRA) of the peripheral blood samples obtained from a group of 34 healthy age-matched controls ranged between 7.6 and 10.0 kb and the mean peak TRA was 8.7 kb. Forty-one patients in the chronic phase of CML were studied; 32/41 (78%) showed telomere reduction (<7.6 kb) relative to age-matched controls and the mean peak TRA was 6.4 kb (range 4.0-10.6 kb). Serial samples were analysed from 12 patients at both chronic phase and during disease progression. The leukocyte DNA of all 12 patients in accelerated phase and/or blast crisis showed telomere reduction relative to age-matched controls and the mean peak TRA was 4.1 kb (range 3.0-5.4 kb). The peak TRA in the accelerated or blast phase was reduced compared with the corresponding paired sample in the chronic phase in all cases studied. These data show that a marked reduction in telomere length is associated with disease progression in CML.

Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia.

The WT1 gene is expressed in 73-100% of patients with acute myelogenous leukemia (AML) and is thought to play a role in maintaining the viability of leukemic cells. WT1 has been proposed as a marker for minimal residual disease in leukemia. We obtained serial blood or bone marrow samples from patients with de novo AML at diagnosis, during therapy, and up to 95 months after diagnosis and analyzed for WT1 gene expression by RT-PCR to determine whether gene expression was predictive of relapse. Forty-four patients had WT1-positive AML and achieved a complete remission (CR) following chemotherapy and 24 patients underwent unrelated donor (n = 4), sibling donor (n = 13) or autologous (n = 7) marrow transplantation. After achieving CR 62% of the patients became WT1-negative, while 38% remained WT1-positive. There was no difference in the disease-free survival (DFS) and survival from remission between WT1-positive and -negative patients (P > 0.1). Following BMT, 32% of the patients analyzed in CR within the first 100 days after transplantation were WT1 PCR positive. Detection of WT1 transcripts within 100 days following BMT did not affect DFS and overall survival (OS) after transplantation (P > 0.1). Ten of 11 patients who are in continuous CR following chemotherapy or BMT for more than 3 years were transiently WT1-positive during the observation period. Four of these patients displayed the WT1 transcript at the last examination. Thirteen of 39 patients were WT1 PCR negative within 4 months before clinical onset of relapse and eight patients were WT1 PCR negative at time of relapse. These data indicate that: (1) achievement of WT1 negativity is not associated with longer DFS, survival from remission, or OS after transplantation; (2) not all patients who relapse become WT1 positive again; (3) long-term remitters frequently display the WT1 transcript. Thus, we conclude that the monitoring of WT1 gene expression by qualitative RT-PCR during treatment and CR is of very limited value.