Purpose: This study determined the effects of cis -diamminedichloroplatinum(II) on radiation-induced foci formation of γ-H2AX and Rad51 in lymphocytes.
Experimental Design: Twenty-eight cancer ...patients were irradiated for intrathoracic, pelvic, or head and neck tumors and received simultaneous
cisplatin containing chemotherapy. The effect of cisplatin on radiation-induced γ-H2AX and Rad51 foci as a response to ionizing
radiationâinduced DNA double-strand breaks was measured in lymphocytes after in vivo and in vitro radiochemotherapy. The role of DNA-dependent protein kinase and ataxia-telangiectasia mutated kinase in γ-H2AX signaling,
the consequences of altered γ-H2AX foci formation on double-strand break end joining, was studied.
Results: Cisplatin decreased the number of induced γ-H2AX foci in lymphocytes after in vivo or in vitro irradiation by 34% ± 6% at days 0 to 3 after cisplatin ( P < 0.0001) and remained significant until day 6. The variation in this cisplatin effect from patient to patient was larger
than the retest error within the same patient ( P = 0.01). The cisplatin effect was not accompanied by an inhibition of end joining of double-strand break as analyzed using
gel electrophoresis of DNA under neutral conditions. Cisplatin also decreased radiation induced Rad51 foci formation in lymphocytes
after stimulation of proliferation with phytohemagglutinin by 47% ± 6% ( P < 0.0001).
Conclusion: Cisplatin has long-term effects on the early double-strand break response of γ-H2AX and Rad51 foci formation after ionizing
radiation. Inhibition of sensing and processing of double-strand break by γ-H2AX and Rad51 foci formation are important mechanisms
by which cisplatin can alter the radiation response.
Among high-grade malignant non-Hodgkin's lymphomas the updated Kiel classification identifies three major B-cell entities: centroblastic (CB), B-immunoblastic (B-IB), and B-large cell anaplastic ...(Ki-1+) (now termed anaplastic large cell CD30+, B-ALC). The clinical prognostic relevance of this distinction was evaluated in a randomized prospective treatment trial (COP-BLAM/IMVP-16 regimen randomly combined +/- radiotherapy in complete responders) conducted in adult (age 15 to 75) patients with Ann Arbor stage II-IV disease (n = 219) diagnosed by optimal histomorphology (Giemsa staining) and by immunohistochemistry. Overall survival was significantly better in CB lymphoma as compared to B-IB (P = .0002) or B-ALC (P = .046). Relapse-free survival was worse for B-IB (P = .0003) as compared to CB lymphomas. The prognostic differences between CB and B-IB were confirmed by multivariate analyses including the risk factors of the International Index. Overall survival was significantly determined by performance status (P = .0003), serum-LDH (P = .036), and B-IB histology subtype (P = .036). Relapse-free survival was influenced by age (P = .007) and histological subtype (P = .007). Thus, the diagnosis of the CB and B-IB lymphomas by the histological criteria of the Kiel classification was identified as an independent prognostic factor in diffuse large B-cell lymphomas.
We evaluated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; Sandoz Pharma Basel, Switzerland/Schering-Plough Kenil-worth, NJ) as an adjunct to a modified (mainly ...cyclophosphamide and doxorubicine increased 1.5-fold) COP-BLAM regimen in the primary treatment of high-grade malignant non-Hodgkin's lymphomas (NHL). Patients (n = 182; stage ll-IV; age, 15 to 73 years) were randomized to rhGM-CSF (400 μg) or placebo for 7 days subcutaneously after chemotherapy. Efficacy was analyzed for patients receiving at least 70% of study medication (n = 125). The frequency of clinically relevant infection was reduced by rhGM-CSF (28 v 69 infections, 16 v 30 patients, P = .02) with a cumulative probability of remaining infection free in 70% versus 48% (P = .05 log rank test at 190 days). Periods of neutropenia (P = .01 in 5 of 6 courses), days with fever (2.1 v 4.0, P = .04) and days of hospitalization for infection (3.5 v 8.0 days, P = .01) were significantly reduced. Complete response (CR) rates, assessed by prognostic risk, were 15 of 19 (79%) in treated versus 20 of 21 (95%) in controls in the low-risk group (P = .12). In the high-risk group, 31 of 45 (69%) treated patients achieved CR versus 25 of 52 (48%) of controls (P = .04). No difference in survival has been seen after 1 year. Only injection site reactions (45% treated v 7% controls) and rash (26% v 2%) occurred more frequently in treated patients (n = 176). These data show that rhGM-CSF is well tolerated in most patients with NHL, significantly reduces infection, and improves response.
Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara‐C (AC) (NOAC) was active in refractory non‐Hodgkin's lymphoma (NHL) but myelosuppression was dose‐limiting. In a ...pilot study, we investigated the effects of recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM‐CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were > 3.0/nl for 3 consecutive days. Twenty‐three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM‐CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM‐CSF, the median duration of severe neutropenia (< 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM‐CSF (P = 0.0058), and that of thrombocytopenia (<20.0/nl), 3 days versus 7 days (P> 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM‐CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM‐CSF. The following side effects were associated with the administration of rhGM‐CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM‐CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM‐CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM‐CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response.
A 27-year-old male patient with ataxia telangiectasia (AT) developed atypical chronic lymphocytic leukemia with increasing bone marrow infiltration in the absence of organomegaly. One-third of the ...leukemia cells expressed a mature suppressor/cytotoxic T cell phenotype (T3+ T4- T6- T8+ T10-), two-thirds demonstrated additional help-er/inducer T cell-associated antigens (T3+ T4+ T- T8+ T10-), and a small fraction reacted with a natural killer (NK) cell-specific monoclonal antibody (Leu 11+). The proliferative response to stimulation in vitro with lektines and various monoclonal antibodies resembled the proliferation pattern of mature thymocytes: The cells responded to phytohemagglutinin (PHA), concanavalin A (ConA), stimulation of the T3-Ti receptor complex with Sepharose-bound anti-T3, and stimulation of the sheep erythrocyte receptor protein with anti-T112 and anti-T113 in conjunction with exogenous interleukin-2 (IL 2); they failed, however, to proliferate after stimulation with anti-T112 and anti-T113 alone. There was no response in the mixed lymphocyte reaction (MLR) and no suppression of the MLR between two healthy donors. Antibody-dependent cell-mediated cytotoxicity and NK activity could not be demonstrated. Cytogenetic analysis revealed complex clonal aberrations, including an interstitial deletion of the long arm of chromosome 14 concerning bands q21-31, loss of chromosome 20, and loss of the Y chromosome. Cytostatic chemotherapy was of little use and caused serious side effects, whereas leukapheresis proved effective in reducing the tumor load. The clinical data and laboratory findings in this case correspond to three previously described patients with AT who developed chronic T cell leukemia. Thus, in adult patients with AT, malignant proliferation of cytogenetically marked and phenotypically heterogeneous mature T cells seems to be a frequent complication.
The release of novel genetically modified (GM) virus applications into the environment for agricultural, veterinary, and nature-conservation purposes poses a number of significant challenges for risk ...assessors and regulatory authorities. Continuous efforts to scan the horizon for emerging applications are needed to gain an overview of new GM virus applications. In addition, appropriate approaches for risk assessment and management have to be developed. These approaches need to address pertinent challenges, in particular with regard to the environmental release of GM virus applications with a high probability for transmission and spreading, including transboundary movements and a high potential to result in adverse environmental effects. However, the current preparedness at the EU and international level to assess such GM virus application is limited. This study addresses some of the challenges associated with the current situation, firstly, by conducting a horizon scan to identify emerging GM virus applications with relevance for the environment. Secondly, outstanding issues regarding the environmental risk assessment (ERA) of GM virus applications are identified based on an evaluation of case study examples. Specifically, the limited scientific information available for the ERA of some applications and the lack of detailed and appropriate guidance for ERA are discussed. Furthermore, considerations are provided for future work that is needed to establish adequate risk assessment and management approaches.
For many psychotherapies, like Eye Movement and Desensitization Reprocessing (EMDR) therapy, there is an ongoing discussion about the role of specific versus non-specific mechanisms in their ...effectiveness However, experimental research directly examining the potential role of non-specific mechanisms is scarce. Here, we address the role of a non-specific factor that is often put forward for EMDR, namely treatment effectiveness expectations, within a laboratory model of EMDR therapy.
In a lab-based (N = 96) and an online experiment (N = 173), we gave participants verbal instructions to manipulate their treatment expectations. Instructions emphasized EMDR's effectiveness or ineffectiveness. Then, participants were asked to recollect an unpleasant autobiographical memory with or without making eye-movements.
In line with previous studies, we found significant reductions of reported vividness and emotionality of negative autobiographical memories in the eye-movements condition. These reductions did not differ between the verbal suggestions conditions in both experiments, suggesting a limited effect of treatment effectiveness suggestions.
Treatment effectiveness expectations were not successfully manipulated by the suggestions manipulation. This suggests that treatment expectations may be more difficult to influence than anticipated, thus limiting the interpretation of our findings.
These findings tentatively corroborate the results of two earlier reports, suggesting that the effects of verbal suggestions about treatment effectiveness in a laboratory model of EMDR therapy may be limited.
•Outcome expectations are thought to partly explain psychotherapy effectivity.•Few studies have addressed this for EMDR therapy.•We report result of two laboratory analogue studies (N = 96; N = 173).•Treatment effectivity suggestions were not effective to change expectations.•Intervention effects were not moderated by treatment effectivity suggestions.
Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder. During this treatment, patients recall traumatic memories while making horizontal eye ...movements (EM). Studies have shown that EM not only desensitize negative memories but also positive memories and imagined events. Substance use behavior and craving are maintained by maladaptive memory associations and visual imagery. Preliminary findings have indicated that these mental images can be desensitized by EMDR techniques. We conducted two proof-of-principle studies to investigate whether EM can reduce the sensory richness of substance-related mental representations and accompanying craving levels. We investigated the effects of EM on (1) vividness of food-related mental imagery and food craving in dieting and non-dieting students and (2) vividness of recent smoking-related memories and cigarette craving in daily smokers. In both experiments, participants recalled the images while making EM or keeping eyes stationary. Image vividness and emotionality, image-specific craving and general craving were measured before and after the intervention. As a behavioral outcome measure, participants in study 1 were offered a snack choice at the end of the experiment. Results of both experiments showed that image vividness and craving increased in the control condition but remained stable or decreased after the EM intervention. EM additionally reduced image emotionality (experiment 2) and affected behavior (experiment 1): participants in the EM condition were more inclined to choose healthy over unhealthy snack options. In conclusion, these data suggest that EM can be used to reduce intensity of substance-related imagery and craving. Although long-term effects are yet to be demonstrated, the current studies suggest that EM might be a useful technique in addiction treatment.
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