Christina Lindemalm

Treatment of myelodysplastic syndromes with retinoic acid and 1α-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study

Abstract: 63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low‐dose ara‐C (arm A) and low dose ara‐C in combination with 13‐cis‐retinoic acid (13‐CRA) and 1α‐hydroxy‐vitamin D3 (1α D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13‐CRA and 1α D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side‐effects than arm A (p = 0.005). Therapeutic effects of 13‐CRA and 1α D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Therapeutic effects of low‐dose cytosine arabinoside, alpha‐interferon, 1α‐hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara‐C, α‐interferon (IFN), 1α‐hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low‐dose ara‐C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara‐C and IDR treatment was generally well‐tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara‐C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.

NK-cell and T-cell functions in patients with breast cancer: effects of surgery and adjuvant chemo- and radiotherapy

Breast cancer is globally the most common malignancy in women. Her2-targeted monoclonal antibodies are established treatment modalities, and vaccines are in late-stage clinical testing in patients with breast cancer and known to promote tumour-killing through mechanisms like antibody-dependent cellular cytotoxicity. It is therefore increasingly important to study immunological consequences of conventional treatment strategies. In this study, functional tests and four-colour flow cytometry were used to detect natural killer (NK)-cell functions and receptors as well as T-cell signal transduction molecules and intracellular cytokines in preoperative breast cancer patients, and patients who had received adjuvant radiotherapy or adjuvant combined chemo-radiotherapy as well as in age-matched healthy controls. The absolute number of NK cells, the density of NK receptors as well as in vitro quantitation of functional NK cytotoxicity were significantly higher in preoperative patients than the post-treatments group and controls. A similar pattern was seen with regard to T-cell signalling molecules, and preoperative patients produced significantly higher amounts of cytokines in NK and T cells compared to other groups. The results indicate that functions of NK and T cells are well preserved before surgery but decrease following adjuvant therapy, which may speak in favour of early rather than late use of immunotherapeutic agents such as trastuzumab that may depend on intact immune effector functions.

A randomised controlled trial of support group intervention after breast cancer treatment: Results on anxiety and depression

Abstract Background. Previous studies have demonstrated that between 20 and 30% of women treated for breast cancer have measurable signs of anxiety and depression compared with 6% in a population of healthy women. Depression has been proposed as a predictive factor for recurrence and survival. The aim of the present study was to evaluate if psychosocial support intervention could influence anxiety and depression during the first year after diagnosis. Material and methods. Newly diagnosed breast cancer patients were randomised between April 2002 and November 2007 and stratified by adjuvant chemotherapy. Of 382 eligible patients, 191 + 191 patients were randomised to intervention group or control group, respectively. Control patients were subjected to standard follow-up routines. The Intervention group had support intervention at the Foundation Lustgården Mälardalen. The rehabilitation lasted one week on a residential basis followed by four days of follow-up two months later. We used the Swedish version of the HAD scale with a cut-off value greater than 10 for clinical symptoms of depression and anxiety. Results. Support group intervention lowered anxiety over time (p < 0.001) but depression was unaffected (p = 0.610). Conclusion. This prospective randomised trial of support group intervention in a large homogenous group of breast cancer women showed a statistically significant effect on lowering anxiety over time. No statistically significant effect of intervention could be seen on depression.

Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study

Immunotherapy is being increasingly utilized for adjuvant treatment for breast cancer (BC). We have previously described immune functions during primary therapy for BC. The present study describes immune recovery patterns during long-term, unmaintained follow-up after completion of adjuvant therapy.A group of patients with primary BC had been treated with adjuvant radio-chemotherapy (RT + CT) 5-fluorouracil, epirubicin and cyclophosphamide (FEC) (n = 21) and another group with radiotherapy (RT) (n = 20) alone. Immunological testing of NK and T-cell functions was performed initially at the end of adjuvant treatment and repeated after 2, 6 and 12 months. NK cell cytotoxicity was significantly higher (P < 0.05) at all time-points in patients than in age-matched controls and did not differ between the two treatments groups during one year observation. In contrast, lower numbers of CD4 T-cells and lower expression of CD28 on T-cells was observed particularly in RT + CT patients and did not normalize during the observation period. The numbers of Treg cells (CD4+CD25high) were low in the RT + CT group during follow-up, as well as expression of TCRξ, Zap70, p56lck, P59fyn and PI3 k in CD4+ cells. In contrast, expression of intracellular cytokines (IFN-γ, IL-2, IL-4) in CD4 and CD8 T cells were significantly higher in RT + CT patients than in the RT group and the difference increased during follow-up. In conclusion, NK-cell cytotoxicity increased during unmaintained long-term follow-up whereas CD4 and regulatory T cells as well as signal transduction molecules remained low following adjuvant radio-chemotherapy.

Long-term follow-up of a randomized study of support group intervention in women with primary breast cancer

BACKGROUND Despite a fairly good prognosis, many breast-cancer patients suffer from symptoms such as anxiety, depression and fatigue, which may affect health-related quality of life and may persist for several years. The aim of the present study was to perform a long-term follow-up of a randomized study of support group intervention in women after primary breast cancer treatment. MATERIALS AND METHODS Three hundred and eighty two women with primary breast cancer were randomized to support group intervention or control group, 181 in each group. Women in the intervention group participated in 1 week of intervention followed by 4 days of follow-up 2 months later. This is a long-term follow-up undertaken, in average, 6.5 years after randomization. Patients answered the questionnaires the European Organisation for Research and Treatment of Cancer, quality of life questionnaire (EORTC QLQ-C30) and the breast cancer module questionnaire (BR 23), the hospital anxiety and depression scale (HAD) and the Norwegian version of the fatigue scale (FQ). RESULTS After adjusting for treatment with chemotherapy, age, marriage, education and children at home, there was a significant improvement in physical, mental and total fatigue (FQ), cognitive function, body image and future perspective (EORTC QLQ C30 and BR23) in the intervention group compared with controls. The proportion of women affected by high anxiety and depression scores were not significantly different between the groups. CONCLUSION Support intervention significantly improved cognitive function, body image, future perspective and fatigue, compared with to the findings in the control group.

Blood clonal B cell excess at diagnosis in multiple myeloma: Relation to prognosis

112 patients with multiple myeloma have been studied at diagnosis for the presence of blood clonal B‐cell excess (CBE), defined as a ratio between k+ and λ+ lymphocytes outside the normal range (0.9‐3.5). 48 patients (43%) had CBE. The increase in light chain‐bearing lymphocytes was always that of the M component light chain isotype. The proportions of patients exhibiting CBE were the same in different stages. The response frequency was not influenced by the presence of CBE. However, patients with CBE had a shorter remission duration time (p < 0.001) and total survival (p < 0.05) than those without CBE. This was also noticed when each clinical stage was analyzed separately. Moreover, survival was shorter in patients with a large fraction of CBE than in those with a small one. Cox regression analysis revealed that CBE was a much stronger predictor of remission duration than age, clinical stage and renal dysfunction. CBE and response to initial treatment independently were the best factors to indicate survival. It is suggested that analysis of CBE should be included in the clinical characterization of untreated patients with multiple myeloma.

Cell-mediated immunity in human acute myeloblastic leukemia

SummaryLymphocyte stimulation tests with autologous myeloblasts were performed in 31 patients with nonlymphatic acute leukemia. Twenty-five patients were receiving chemotherapy combined with immunotherapy; six received chemotherapy only. Thirteen nonleukemic patients with various disorders and six healthy control patients were also studied.It was found that 4/15 patients in 9/38 tests had autologous lymphocytes stimulated by autologous circulating myeloblasts. Bone marrow cells also effected stimulation, significantly more often if the marrow was taken in relapse than when it was taken in remission.However, so-called immunotherapy with allogeneic leukemic myeloblasts and BCG could not be shown to increase these frequencies. Nor did it significantly increase the degree of stimulation measured as DNA synthesis in lymphocytes.Moreover, nonleukemic bone marrow cells from patients with other disorders also stimulated autologous lymphocytes in 1/13 patients. No recognition of autologous myeloblasts was observed when the responding lymphocytes were taken in incomplete remission or during the month preceding relapse.

Effects of immunotherapy and chemotherapy on immunocompetence. A study of patients with acute myeloblastic leukemia in remission

SummaryThe immunocompetence of 33 patients with acute myeloblastic leukemia in remission and treated with cytostatics (CT) was studied. In addition to cytostatics some of the patients were given immunotherapy (CT+IT).In an attempt to demonstrate immunization against allogeneic leukemic blast cells (or their extracts) or immunostimulation after immunotherapy or, alternatively, immunodepression after maintenance chemotherapy without immunotherapy, delayed hypersensitivity tests and lymphocyte stimulation tests were performed. In most cases PHA seemed to be a stronger stimulator than allogeneic lymphocytes and these seemed to be stronger than allogeneic blasts, although no difference was statisically significant.No significant differences were found in vitro or in vivo between the reactions of CT and CT+IT patients or their lymphocytes to allogeneic myeloblasts or to allogeneic lymphocytes. However, numerically, in vitro and in vivo CT+IT patients reacted more to myeloblasts, CT patients more to lymphocytes. This could suggest antigens on leukemic myeloblasts that are not found on lymphocytes. With present methods we could demonstrate neither immunodepression in patients given only chemotherapy nor nonspecific immunostimulation after immunotherapy. There was no significant difference between the two treatment groups in lymphocyte reactivity against PHA and allogeneic lymphocytes. Nor was the lymphocyte reactivity different from that in a group of healthy persons.Decreasing lymphocyte reactivity to PHA and allogeneic lymphocytes seemed to herald relapse.

Existential aspects are neglected in the evaluation of support-intervention in breast cancer patients.

Existential aspects are neglected in the evaluation of support-intervention in breast cancer patients