Significance of Histological Response to Preoperative Chemoradiotherapy for Pancreatic Cancer

Background Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. Methods Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods.Results The estimated overall survival (median±SE) in the entire group of patients undergoing resection was 23±4.2 months, with an estimated 3-year survival of 37%±6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation.Conclusions Histological response to neoadjuvant CRT—as measured by residual tumor load—may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.     

Metabolic network failures in Alzheimer's disease: A biochemical road map

Introduction

The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.

Verapamil as an adjunct to local anaesthetic for brachial plexus blocks

Background: Calcium channel blockers potentiate the effects of local anaesthetics. We examined the effect of adding verapamil to local anaesthetic solution on anaesthetic duration in patients undergoing surgery under brachial plexus block.     

Neurohydatidosis

Early and non‐invasive evaluation of hydatid infestation of brain and spine is of paramount importance, especially in endemic areas. We present a spectrum of imaging findings in neurohydatidosis with a brief review of literature.     

Fetal Responses to Vibrotactile Stimulation, A Possible Predictor of Fetal and Neonatal Outcome

Summary: This study measured the antenatal fetal heart rate changes in response to a single vibrotactile stimulus. In a group of 11 normal patients, this resulted in a significant change in the fetal heart rate (P < 0.001). Sixty-eight high risk patients were also tested. In the group of 25 patients whose fetuses showed no response to the stimulus, there were 4 stillbirths and 4 neonatal deaths; 23 of these 25 infants were small for gestational age (SGA) compared to only 15 of the 43 that showed a response to the stimulus.
Fetal habituation to a repeated vibrotactile stimulus was measured in a control group of 40 patients who had a normal antepartum and intrapartum course and delivered infants in an optimal condition. The same was done in a study group of 48 patients who delivered infants that were SGA. These infants were assessed at 1 year of age by the Griffiths Mental Developmental Scale (GMDS). Infants that were SGA did not differ significantly from the control group. However, infants who had a normal antenatal habituation pattern had a significantly better performance (P < 0.01) compared to infants who had an abnormal antenatal habituation pattern.     

Absence of serum-stimulated lipase activity and altered lipid content in milk from a patient with type I hyperlipoproteinaemia

We measured the serum-stimulated lipase activity, fatty acid content, and various biochemical parameters in the breast milk of a lactating mother suffering from familial lipoprotein lipase deficiency and of healthy control subjects. Serum-stimulated lipase activity was virtually undetectable in milk from our patient and the total fatty acid content was low. The fatty acid composition differed from normal showing a marked absolute and relative increase in the content of lauric (C12:0) and myristic (C14:0) fatty acids and considerably reduced levels of oleic (C18:1) and especially linoleic (C18:2) acids. Other fatty acid species showed lesser changes in concentration. Besides a reduced calcium concentration in the milk from our patient, other biochemical parameters were not significantly different from control subjects.     

Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation

Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with K(I) and k(inact) values estimated at 9.9 microM and 0.16 min(-1), respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.     

Co-immunisation with a plasmid DNA cocktail primes mice against anthrax and plague

The protective antigen (PA) of Bacillus anthracis and the V antigen of Yersinia pestis are potent immunogens and candidate vaccine sub-units. When plasmid DNA encoding either PA or V antigen was used to immunise the Balb/c mouse, a low serum IgG titre was detected (log (10)1.0 or less) which was slightly increased by boosting with plasmid DNA. However, when mice immunised with plasmid DNA were later boosted with the respective recombinant protein, a significant increase in titre (up to 100-fold) was observed. Mice primed with a combination of each plasmid and boosted with a combination of the recombinant proteins, were fully protected (6/6) against challenge with Y. pestis. This compared favourably with mice primed only with plasmid DNA encoding the V antigen and boosted with rV, which were partially protected (3/6) against homologous challenge or with mice primed and boosted with plasmid DNA encoding the V antigen which were poorly protected (1/6). Combined immunisation with the two plasmid DNA constructs followed by boosting with a combination of the encoded recombinant proteins enhanced the protective immune response to Y. pestis compared with priming only with plasmid DNA encoding the V antigen and boosting with rV. This enhancement may be due to the effect of CpG motifs known to be present in the plasmid DNA construct encoding PA.