Lung cancer: From single-gene methylation to methylome profiling

DNA methylation as part of the epigenetic gene-silencing complex is a universal occurring change in lung cancer. Numerous studies investigated methylation of specific genes in primary tumors, in serum or plasma samples, and in specimens from the aerodigestive tract epithelium of lung cancer patients. In most studies, single genes or small numbers of genes were analyzed. Moreover, it has been observed that methylation of certain genes can already be detected in samples from the upper aerodigestive tract epithelium of cancer-free heavy smokers. These findings indicated that methylation of certain genes may be a useful biomarker for prognosis, disease recurrence, early detection, and lung cancer risk assessment. So far, several genes were identified which seem to be of worse prognostic relevance when they were found to be methylated. In addition, it has been shown that a panel of markers may be relevant to predict disease recurrence after surgery. In comparison to analysis of single or small numbers of genes, methods for genome-wide detection of methylation were developed recently. These approaches are focused on either pharmacological re-activation of methylated genes followed by expression microarray analysis or on microarray analysis of sodium bisulfite-treated or affinity-enriched methylated DNA sequences. With currently available methods for the simultaneous detection of methylation, up to 28,000 CpG islands can be analyzed. Overall, we are just at the beginning of translating these findings into the clinic and there is hope that future patients will benefit from these results.     

Impaired lipopolysaccharide-inducible tumor necrosis factor production in vitro by peripheral blood monocytes of patients with viral hepatitis

We investigated lipopolysaccharide-induced tumor necrosis factor production in vitro by peripheral blood monocytes from patients with various liver diseases. Tumor necrosis factor production was found to be significantly reduced in patients with chronic hepatitis B (n = 17; 135 +/- 30 pg tumor necrosis factor/ml; mean +/- S.E.M.) and patients with chronic non-A, non-B hepatitis (n = 15; 212 +/- 22 pg tumor necrosis factor/ml) compared with healthy control individuals (n = 47; 411 +/- 40 pg tumor necrosis factor/ml; p less than 0.0005 and p less than 0.01, respectively). This reduced tumor necrosis factor production was not only seen with an optimal stimulating concentration of lipopolysaccharide (100 ng/ml) but also with suboptimal concentrations (0.1 ng/ml). In contrast to patients with chronic viral hepatitis, monocytes from patients with alcohol-induced cirrhosis (n = 26; 444 +/- 49 pg tumor necrosis factor/ml), primary biliary cirrhosis (n = 7; 412 +/- 81 pg tumor necrosis factor/ml) and alcohol-induced fatty liver changes (n = 5; 401 +/- 62 pg tumor necrosis factor/ml) produced normal amounts of tumor necrosis factor when stimulated with an optimal concentration of lipopolysaccharide. Lipopolysaccharide (0.1 ng lipopolysaccharide/ml)-stimulated peripheral blood monocytes of patients with chronic hepatitis B (n = 15; 102 +/- 32 pg/ml) or non-A, non-B hepatitis (n = 13; 97+/- 16 pg/ml) could not be induced to produce more tumor necrosis factor either when prestimulated with gamma-interferon (170 +/- 45 pg/ml and 149 +/- 32 pg/ml, respectively), a lymphokine known to activate monocytes, or with the cyclooxygenase inhibitor indomethacin to reduce the suppressive effect of prostaglandin E2 (148 +/- 40 pg/ml and 153 +/- 45 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunopathogenesis and therapeutic approaches in acquired immunologic deficiency syndrome (AIDS)

The immunopathogenesis of AIDS and the problems arising from the infection of immunocompetent cells with the human immunodeficiency virus (HIV) are being discussed. Recent investigations point at the fact that CD4-positive T cells are not the only targets of HIV, but that also other cells of the immune system which are involved in the generation of the immune answer might be affected by the infection. This could result from a direct effect of HIV upon the respective cell function or as a consequence of other cells involved in the regulation of the immune response. Although many efforts are being undertaken, no clear-cut therapeutic modality has been yet discovered to counter the effects of HIV upon the immune system.     

Significance of hormone receptors of breast cancer cells for the duration of a disease-free interval

The importance of the presence of hormone receptors of cells derived from breast cancer tissue for the duration of the relapse-free interval was evaluated in 41 patients with stage II breast cancer. After modified radical mastectomy with axillary lymphadenectomy the patients received radiotherapy and adjuvant polychemotherapy and/or hormone therapy. There was no indication of metastases in any patient at the time of operation. There was a significant correlation of the relapse-free interval to tumor size (p less than 0.05), to the number of involved lymph nodes (p less than 0.0005), and also to the presence of the progesterone receptor (PgR), which seemed to play a more important role in this context than the oestrogen receptor (ER) (p less than 0.001). We conclude from this study that the evaluation of the PgR in breast cancer cells is important for the prognosis of the duration of the relapse-free interval.     

Association between continuity of care in Swedish primary care and emergency services utilisation: a population-based cross-sectional study

Objective: The primary objective of this study was to determine the association between longitudinal continuity of care (CoC) in Swedish primary care (PC) and emergency services (ES) utilisation.

Study design: A cross-sectional analysis of longitudinal population data. Setting. PC centres, out-of-hours PC facilities and emergency departments (EDs) in Blekinge County in southern Sweden. Subjects: People of all ages who lived in Blekinge County and who had made two or more visits per year to a general practitioner (GP) during office hours from 1 January 2012 to 31 December 2014.

Main outcome measure: ES utilisation.

Results: Eight-thousand one-hundred and eighty-five people were included in the study. CoC was quantified using three different indices—Usual Provider of Care index (UPC), Continuity of Care index (CoCI), and Sequential Continuity index (SECON). The CoC that the PC centres could offer their enrolled patients varied significantly between the different centres, ranging from 0.23–0.57 for UPC, 0.12–0.43 for CoCI, and 0.25–0.52 for SECON. Association between the three CoC indices and ES utilisation was computed as an incidence rate ratio which ranged between 0.50 and 0.59.

Conclusion: Longitudinal CoC was shown to have a negative association with ES utilisation. The association was significant and of a magnitude that implies clinical relevance. Computed incidence rate ratios suggest that patients with the lowest CoC had twice as many ES visits compared to patients with the highest CoC.     

Validation of AAST EGS Grade for Acute Pancreatitis

Background

The AAST recently developed an emergency general surgery (EGS) disease grading system to measure anatomic severity. We aimed to validate this grading system for acute pancreatitis and compare cross sectional imaging-based AAST EGS grade and compare with several clinical prediction models. We hypothesize that increased AAST EGS grade would be associated with important physiological and clinical outcomes and is comparable to other severity grading methods.

Methods

Single institution retrospective review of adult patients admitted with acute pancreatitis during 10/2014–1/2016 was performed. Patients without imaging were excluded. Imaging, operative, and pathological AAST grades were assigned by two reviewers. Summary and univariate analyses were performed. AUROC analysis was performed comparing AAST EGS grade with other severity scoring systems.

Results

There were 297 patients with a mean (±SD) age of 55?±?17 years; 60% were male. Gallstone pancreatitis was the most common etiology (28%). The overall complication, mortality, and ICU admission rates were 51, 1.3, and 25%, respectively. The AAST EGS imaging grade was comparable to other severity scoring systems that required multifactorial data for readmission, mortality, and length of stay.

Conclusions

The AAST EGS grade for acute pancreatitis demonstrates initial validity; patients with increasing AAST EGS grade demonstrated longer hospital and ICU stays, and increased rates of readmission. AAST EGS grades assigned using cross sectional imaging findings were comparable to other severity scoring systems. Further studies should determine the generalizability of the AAST system.Level of Evidence: IVStudy Type: Single institutional retrospective review

     

Initial clinical experiences in a large Austrian patient sample with immunodeficiency syndrome (AIDS): I. Type and course of encountered infections

This study presents a report on the first clinical experiences gained in 68 hospitalized HIV antibody-positive patients from Austria, covering a period of twelve months. 36 patients (52.9%) belonged to risk group I or Ib (homo- or bisexual), whereas 26 (38.2%) patients were i.v. drug abusers (risk group II). 5 (7.4%) patients fulfilled the criteria of stage II of the CDC classification of HIV-associated clinical symptoms, 10 (14.7%) were classified as stage III and the remaining 53 patients (78%) as stage IV. The most frequent and also the most serious problem was the development of opportunistic infections. Multiple infections were found in 45.7% of all cases. Kaposi's sarcoma was found in 9 patients who all belonged to risk group I. During the entire observation period 10 patients died as a consequence of HIV-1-induced immunodeficiency and the resulting opportunistic infections and/or neoplasms.     

Effect of elevated serum prolactin concentrations on cytokine production and natural killer cell activity.

In vitro and in vivo studies in rodents and human suggested an immunostimulatory effect of prolactin. The aim of the present study was to determine the impact of chronically elevated serum prolactin concentrations on the immune system in patients with prolactinomas. For this purpose parameters of the humoral and cellular immune system were studied in seven patients with prolactinomas on two occasions (1) when their serum prolactin concentration had been normalized through treatment with dopamine agonists and (2) when their serum prolactin concentration was high. Serum concentrations of immunoglobulines, interleukin 1, 3 and 6, TNF-alpha, interferon-gamma and the soluble interleukin 2 receptor, leukocyte subsets and the natural killer cell activity were found to be within the normal range on both occasions, i.e. at normal and at high serum prolactin concentrations. The assumption could be made that long-lasting elevation of serum prolactin concentration induces adaptive changes when the acute stimulatory effects of prolactin on several parameters of the immune system have subsided.     

Poor-risk high-grade gliomas in three survivors of childhood acute lymphoblastic leukaemia—an overview of causative factors and possible therapeutic options

Purpose  Malignant high-grade gliomas are the most common secondary neoplasms in children cured of acute lymphoblastic leukaemia (ALL). Although many predisposing factors exist (including systemic or intrathecal chemotherapy, young age, brain infiltration and genetic predispositions), cranial irradiation appears to be the strongest one. Methods  Three cases of secondary high-grade gliomas (two multiform glioblastomas, grade IV; one anaplastic astrocytoma, grade III) developed in ALL survivors (F–M, 1:2) 3 to 6.3 years after stopping ALL therapy according to BFM-90 trial. Results  All tumours were supratentorial, contrast-enhancing, space-occupying, highly advanced and aggressive. Possible risk factors and current therapeutic options for paediatric ALL and malignant gliomas are reviewed and discussed. Conclusions  Prognosis in secondary malignant gliomas in children is poor (overall survival of 5, 10 and 19 months) despite intense therapy. Thus, protocols for paediatric ALL reduce prophylactic cranial irradiation in favour of intrathecal and intravenous high-dose MTX. Nevertheless, ALL survivors must undergo systematic, long-term surveillance for early detection of intracranial neoplasms.