Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial.

PURPOSE: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). PATIENTS AND METHODS: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment. RESULTS: The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred. CONCLUSION: The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.     

Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG).

BACKGROUND: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD). PATIENTS AND METHODS: Eligibility criteria included age 18-65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT). RESULTS: A total of 102 patients (median age 34 years, range 18-64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3-61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P <0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS. CONCLUSION: Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).     

Psychological,endocrine and neural responses to social evaluation in subclinical depression

This study aimed to identify vulnerability patterns in psychological, physiological and neural responses to mild psychosocial challenge in a population that is at a direct risk of developing depression, but who has not as yet succumbed to the full clinical syndrome. A group of healthy and a group of subclinically depressed participants underwent a modified Montreal Imaging Stress task (MIST), a mild neuroimaging psychosocial task and completed state self-esteem and mood measures. Cortisol levels were assessed throughout the session. All participants showed a decrease in performance self-esteem levels following the MIST. Yet, the decline in performance self-esteem levels was associated with increased levels of anxiety and confusion in the healthy group, but increased levels of depression in the subclinical group, following the MIST. The subclinical group showed overall lower cortisol levels compared with the healthy group. The degree of change in activity in the subgenual anterior cingulate cortex in response to negative evaluation was associated with increased levels of depression in the whole sample. Findings suggest that even in response to a mild psychosocial challenge, those individuals vulnerable to depression already show important maladaptive response patterns at psychological and neural levels. The findings point to important targets for future interventions.     

Advances in the treatment of Hodgkin lymphoma

In the past decades, Hodgkin lymphoma (HL) has turned from an incurable disease to one with the most favorable prognosis among adult malignancies. This is due to the introduction of effective multi-agent chemotherapy and the optimization of radiation techniques. At present, 80?C90?% of patients achieve long-term remission when receiving appropriate first-line treatment. Even in case of relapse, up to 50?% can be successfully salvaged with high-dose chemotherapy and autologous stem cell transplantation. Thus, current studies do not necessarily aim at increasing treatment efficacy but rather focus on a possible reduction of acute and late toxicity by decreasing treatment intensity if possible. One promising strategy to spare therapy in good-risk patients is early response-adapted treatment stratification according to the result of interim positron emission tomography. The evaluation of novel drugs and the optimization of treatment for elderly HL patients and those with nodular lymphocyte-predominant HL are further aspects that are currently being addressed in ongoing trials. This review will give an overview on more recent clinical trials and discuss possible future strategies for the treatment of HL.     

Apolipoprotein E and Paraoxonase 1 polymorphisms are associated with lower serum thyroid hormones in postmenopausal women

Objective  Autoimmune thyroiditis and overt or subclinical hypothyroidism have been associated with increased prevalence of cardiovascular disease (CVD).
Design  Cross-sectional investigation of the association between gene polymorphisms related to CVD with thyroid function and autoimmunity.
Patients  In total 84 healthy postmenopausal women aged 49–69 years.
Measurements  FT3, FT4, anti-TPO and anti-TG were assessed in the sera of participants. The following polymorphisms were assessed from peripheral lymphocyte DNA: Apolipoprotein E E2/E3/E4, paraoxonase 1 A/B, Glycoprotein IIIa leu33pro, MTHFR ala222val, ApoBarg3500gln, plasminogen activator inhibitor 1 4G/5G, cholesterol 7-α hydroxylase A204C and cholesterol ester transfer protein B1/B2.
Results  A statistically significant correlation was found between Apolipoprotein E and paraoxonase1 polymorphisms and serum thyroid hormones: carriers of the E2 or E4 allele of the ApoE gene had lower levels of FT4 ( P  = 0·0005) than women with the E3/E3 genotype. Carriers of the B allele of paraoxonase 1 gene had lower levels of FT3 compared to women with the wild-type genotype ( P =  0·047). A statistically significant positive association ( P =  0·049) was also observed between anti-TG antibodies and the presence of the E2 allele of the Apolipoprotein E gene.
Conclusions  Polymorphisms of apolipoprotein E and paraoxonase 1 are associated with different levels of thyroid hormone and anti-Tg antibody levels in the study population in this pilot study. The mechanism underlying this association remains to be elucidated.     

Suppressed neutrophil function as a risk factor for severe infection after cytotoxic chemotherapy in patients with acute nonlymphocytic leukemia

 Severe infections are a major problem in patients suffering from acute nonlymphocytic leukemia (ANLL) undergoing myeloablative chemotherapy. Possible factors leading to infectious complications in these patients are suppressed immune defense mechanisms existing prior to therapy, including those involving the neutrophil granulocyte department. In this study we investigated whether neutrophil function as measured by oxidative burst and phagocytosis before the start of treatment correlates with the severity of infection after therapy. Forty-four patients were included, 27 men and 17 women. Their median age was 46 years (range 20–70 years). According to the development of infectious complications the patients were assigned retrospectively to group 1 (no or only mild infections, n=29) or to group 2 (severe infection or death due to infection, n=15). The phagocytic activity was significantly reduced in group 2 as compared with group 1 [113.7±13.7 (SEM) vs 170.0±19.2, mean channel fluorescence;p=0.04]. In contrast, the oxidative burst as measured by FMLP stimulation was pronounced but not significantly enhanced in group 2 (24.8±6.1 vs 14.5±3.4, mean channel fluorescence). In conclusion, patients with severe infections after chemotherapy might already have preactivated neutrophils with suppressed function prior to treatment. Thus, evaluating function parameters could help to estimate the individual risk of infection for a patient with ANLL. Received: July 3, 1998 / Accepted: September 9, 1998     

CT and MR imaging in Hodgkin's disease – present and future

Abstract:  Initial staging of Hodgkin's disease is crucial to determine the location and extent of disease, and is the hallmark for the choice of treatment. At present, the established radiological technique for staging Hodgkin's disease is computed tomography (CT). Modern multidetector row CT scanners allow fast imaging from the scull base to the groins during a single breath hold with a spatial resolution of approximately 1 mm. Both, nodal and extranodal involvement of Hodgkin's disease can be diagnosed with CT. Magnetic resonance (MR) imaging is another useful cross-sectional imaging modality for staging Hodgkin's disease. The development of fast MR imaging techniques has considerably reduced imaging time without compromising the quality of MR images. As a consequence, MR imaging is now considered to be as diagnostic as CT for staging Hodgkin's disease. The excellent soft-tissue contrast and the lack of exposure to ionizing radiation are the main advantages of MR imaging. For the detection of extranodal Hodgkin's disease, MR imaging is superior to assess involvement of the brain, the spinal cord and bone marrow; while CT allows excellent evaluation of lung disease. Common major problems in staging Hodgkin's disease are still the detection of nodal involvement in normal sized lymph nodes and residual tumor masses after therapy. In the future, newly developed lymphotropic contrast agents for MR imaging might be helpful to answer these questions.     

Stress‐induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service

Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC‐vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre‐ and post‐exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symptoms post‐exposure). We found that soldiers with decreased HC volume following military service (i.e., post‐exposure) displayed more PTSD‐related symptoms post‐exposure as well as reduced HC‐vmPFC functional and structural connectivity post‐exposure, compared to soldiers with increased HC volume following military service. In contrast, initial smaller HC volume pre‐exposure did not have an effect on any of these factors. Our results therefore suggest that reduction in HC volume and connectivity with the vmPFC together mark a maladaptive response to stressful military service. As stress‐induced HC volume reductions were previously shown to be reversible, these localized biological markers may carry valuable therapeutic potential. Hum Brain Mapp 34:2808–2816, 2013. © 2012 Wiley Periodicals, Inc.