Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: proceedings from the 6th International Post-ASH Symposium

Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.     

Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events

Fear learning is a crucial process in the pathogeneses of psychiatric disorders, which highlights the need to identify specific factors contributing to interindividual variation. We hypothesized variation in the serotonin transporter gene (5-HTTLPR) and stressful life events (SLEs) to be associated with neural correlates of fear conditioning in a sample of healthy male adults (n = 47). Subjects were exposed to a differential fear conditioning paradigm after being preselected regarding 5-HTTLPR genotype and SLEs. Individual differences in brain activity as measured by functional magnetic resonance imaging (fMRI), skin conductance responses and preference ratings were assessed. We report significant variation in neural correlates of fear conditioning as a function of 5-HTTLPR genotype. Specifically, the conditioned stimulus (CS⁺) elicited elevated activity within the fear-network (amygdala, insula, thalamus, occipital cortex) in subjects carrying two copies of the 5-HTTLPR S′ allele. Moreover, our results revealed preliminary evidence for a significant gene-by-environment interaction, such as homozygous carriers of the 5-HTTLPR S′ allele with a history of SLEs demonstrated elevated reactivity to the CS⁺ in the occipital cortex and the insula. Our findings contribute to the current debate on 5-HTTLPR x SLEs interaction by investigating crucial alterations on an intermediate phenotype level which may convey an elevated vulnerability for the development of psychopathology.     

Prognostic value of histamine H1 receptor expression in oral squamous cell carcinoma

Objectives

Overexpression of the histamine H1 receptor (H1R) has been described in a variety of tumor models, but experience in oral squamous cell carcinomas (OSCC) is not available. Current adjuvant treatment options for OSCC can be improved by the identification of new targets of therapy. Herein, we evaluated H1R expression in a large patient cohort of OSCC.

Materials and methods

H1R immunoexpression was evaluated in 191 cases of OSCC and two OSCC cell lines BICR56 and BICR3. Scanned images were digitally analyzed using ImageJ and the immunomembrane plug-in. The combined score of computer-assisted semiquantitative analysis was correlated with manually counted percentages of tumor cells by Kendall’s tau (т) correlation coefficient. Disease-free survival times were estimated using the Kaplan–Meier method and were compared by using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model.

Results

H1R was rarely expressed in OSCC but significantly related with advanced tumor stages (n?=?21/191, mean expression 63.5 % of cancer cells in positive tumor samples, 95 % confidence interval of the mean 53.5 to 73.6 %, p?=?0.006). Following univariate analysis, patients with H1R expression showed a significant poorer prognosis (p?=?0.0004). Multivariate analysis revealed H1R expression as an independent prognostic factor (p?=?0.0164). Expression of H1R in cancer cell lines was confirmed by specific staining of OSCC cell lines BICR56 and BICR3.

Conclusion

This is the first study focusing on H1R expression showing a significant poorer DFS rate in the H1R+ patient cohort. Based on these data, H1R activation may promote carcinogenesis in OSCC.

Clinical relevance

Investigation of H1R regulation and its antagonists shows a clear rationale for future supportive anticancer therapies in OSCCs.     

Health-related quality of life and psychiatric symptoms improve effectively within a short time in patients surgically treated for pituitary tumors—a longitudinal study of 106 patients

Background

Reduced health-related quality of life (HRQoL) is a common complaint in patients suffering from pituitary tumors. Although successful tumor treatment has been reported to lead to an improvement in perceived HRQoL, the temporal gradient at which these improvements occur has not been fully addressed.

Methods

Using three validated health-related questionnaires (SF-36, SCL-90-R, QLS-H), we assessed HRQoL in 106 adult patients harboring pituitary tumors (mean age 48.0?±?16.0 years) before as well as 3 and 12 months after initiation of treatment. The AcroQoL questionnaire was additionally applied in acromegalic patients.

Results

There was a significant improvement in all but one scale (role-physical) of the SF-36 questionnaire and all but two scales (interpersonal sensitivity, paranoid ideation) of the SCL-90-R, the QLS-H score and the AcroQoL subscales within 3 months after surgical treatment. The trend to amelioration continued at the 12 month re-assessment, but did not reach statistical significance. Linear regression analyses revealed that younger age and male gender favor a more distinct improvement of HRQoL after treatment.

Conclusions

HRQoL is considerably reduced before treatment for pituitary disease. Improvement is an early postoperative phenomenon and occurs within 3 months after treatment. Men and younger patients are more likely to improve within this time span.     

Pneumocyte Apoptosis Induction during Cardiopulmonary Bypass: Effective Prevention by Radical Scavenging Using N-Acetylcysteine

Cardiopulmonary bypass (CPB) and cardioplegic arrest are associated with pulmonary dysfunction. We sought to investigate whether pulmonary ischemia/reperfusion during standard CPB and cardioplegic arrest is associated with reactive oxygen species (ROS)-mediated pulmonary tissue injury and pneumocyte apoptosis induction, and whether ROS scavenging using N-acetylcysteine (NAC) attenuates these alterations. Twelve pigs (41 ± 8 kg) were randomized to receive either NAC (100 mg/kg prior to CPB; n = 7) or placebo (n = 5) and subjected to CPB and 60 min of cold (4°C) crystalloid cardioplegic arrest. We collected lung biopsies prior to CPB, at 60 min CPB, as well as at 30, 60, and 120 min post CPB. Lung specimens were immunocytochemically stained against nitrotyrosine, 8-isoprostaglandin-F₂α, and 8-hydroxy-2′-deoxyguanosine (8-OH-dG) as indicators for ROS-mediated tissue injury and active caspase-3, an apoptosis signal pathway key enzyme. Oxidative stress markers were judged using a scale from 1 to 4 (low to intensive staining), and caspase-3-positive pneumocytes were counted per view field. In placebo, the number of caspase-3-positive pneumocytes significantly increased over time to reach a maximum at 120 min post CPB (p =. 03 vs baseline). NAC significantly prevented caspase-3 activation in pneumocytes (p =. 001 vs Placebo). Pneumocyte nitrotyrosine and 8-OH-dG staining significantly increased over time (p =. 003) in the placebo group, but decreased in the NAC group (p =. 004). In both groups staining for 8-isoprostaglandin-F₂α showed no significant changes. This yields the conclusion that standard CPB and cardioplegic arrest initiate ROS-mediated tissue injury and apoptosis in pneumocytes that can be reduced by NAC. Thus, ROS scavenging using NAC may represent a novel approach to minimize lung injury associated with CPB.     

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric Peritoneal Metastasis

Background

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy. First results obtained with PIPAC in patients with advanced peritoneal metastasis (PM) from gastric cancer (GC) are presented.

Methods

Retrospective analysis: Sixty PIPAC were applied in 24 consecutive patients with PM from GC. 67 % patients had previous surgery, and 79 % previous platinum-based systemic chemotherapy. Mean Peritoneal Carcinomatosis Index (PCI) of 16?±?10 and 18/24 patients had signet-ring GC. Cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m² were given for 30 min at 37 °C and 12 mmHg at 6 week intervals. Outcome criteria were survival, adverse events, and histological tumor response.

Results

Median follow-up was 248 days (range 105–748), and median survival time was 15.4 months. Seventeen patients had repeated PIPAC, and objective tumor response was observed in 12 (12/24?=?50 %): no vital tumor cells?=?6, major pathological response?=?6, minor response?=?3. Postoperative adverse events?>?CTCAE 2 were observed in 9 patients (9/24, 37.5 %). In 3/17 patients, a later PIPAC could not be performed due to non-access. Two patients (ECOG 3 and 4) died in the hospital due to disease progression.

Conclusion

PIPAC with low-dose cisplatin and doxorubicin was safe and induced objective tumor regression in selected patients with PM from recurrent, platinum-resistant GC. First survival data are encouraging and justify further clinical studies in this indication.

     

Murine polyomavirus-like particles induce maturation of bone marrow-derived dendritic cells and proliferation of T cells

We analysed the effects of murine polyomavirus-like particles (PLPs) on bone marrow-derived dendritic cells (BMDCs) and T cells in vitro. BMDCs activated with PLPs up-regulated CD40, CD80, CD86 and major histocompatibility complex (MHC) class II surface markers and produced proinflammatory cytokines. Chimeric PLPs [expressing the ovalbumin (OVA)-peptides OVA(257-264) or OVA(323-339)], but not wildtype PLPs, activated OVA-specific CD8 T cells and OVA-specific CD4 T cells, respectively, indicating both MHC class I and II presentation of the peptides by antigen-presenting cells. Our results suggest that PLPs may be used as vaccine adjuvants priming dendritic cells to induce potent T cell responses.     

Augmented reality–assisted craniofacial reconstruction in skull base lesions — an innovative technique for single-step resection and cranioplasty in neurosurgery

Neurosurgical Review - Defects of the cranial vault often require cosmetic reconstruction with patient-specific implants, particularly in cases of craniofacial involvement. However, fabrication...