Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

Background

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.

Methods/design

The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment.

Discussion

The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.     

Lead exposure and children's intelligence: Do low levels of lead in blood cause mental deficit?

It has come to be generally accepted that low levels of lead exposure may result in mental deficit. This causal inference is based on claimed time precedence of the lead exposure and on biological plausibility. The objective of this study is to argue that mental deficit causes pica which causes lead exposure (i.e. to support the theory of reverse causation).

Methodology:

The literature since the 1930s has been interpreted in the light of our own long experience in the investigation of lead exposure in children and adults to support the arguments in favour of reverse causation.

Results:

The arguments for reverse causation are based on: (i) analogy with mental retardation which causes increased lead exposure; (ii) the results of published prospective studies that show a special relationship between blood lead levels at 24 months and intelligence tested later, exactly what would be predicted by the reverse causation theory; and (iii) on an alternative explanation for mental retardation following lead encephalopathy (i.e. that mental retardation following encephalopathy is due to anoxia and not due to a direct destructive effect on the brain neurones). The arguments, which have been proposed for the conventional view, are rejected for the following reasons: (i) none of the prospective studies have found a relationship between cord blood lead levels and intelligence tested later, undermining the argument based on time precedence of lead exposure; and (ii) there is no convincing evidence that lead poisoning, short of encephalopathy, causes mental retardation.

Conclusion:

We believe that the reverse causation hypothesis is a more plausible explanation of the facts.     

The survival motor neuron protein in spinal muscular atrophy

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non- SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.      

Linkage disequilibrium mapping of the Nova Scotia variant of Niemann–Pick disease

Niemann-Pick type D (NPD) disease is a severe degenerative disorder of the nervous system characterized by the accumulation of tissue cholesterol and sphingomyelin. Because of a founder effect, it is unusually common in southwestern Nova Scotia, Canada. We have confirmed that almost all patients from 20 affected sibships descended on both sides from a small group of Acadians who settled in this region in about the year 1767. Previously using classic linkage analysis of this large kindred, we defined the critical gene region to a 13-cM chromosome segment between D18S869 and D18S66. Seven ESTs have been positioned within this interval. Carstea et al. (Niemann Pick C disease gene: homology to mediators of cholesterol homeostasis. Science 1997: 277: 232-235) recently demonstrated that one of these ESTs is the Niemann-Pick type C (NPCI) gene, the gene disrupted in most patients with NPC disease, and we have shown that a G3097-->T mutation in the NPC1 gene is also responsible for NPD. Here we report the development of five new polymorphic microsatellite markers and the testing for complete linkage disequilibrium in our single large NPD kindred that allowed us to reduce the NPD critical region to a 1-cM (1.3-1.6 Mb) interval between D18S1398 and D18S1108. In contrast, Carstea et al., using classic linkage analysis, required more than 18 unrelated NPC families to reduce the NPC1 critical region to a 5-cM interval. Our work supports the finding that NPD is an allelic variant of NPC1, and illustrates the power of large kindreds, which are common in Atlantic Canada and other relatively isolated areas, for gene mapping and identification.     

Mediastinal tumors: evaluation with suprasternal sonography

Twelve patients with mediastinal masses evaluated by computed tomography (CT) and histologically verified were evaluated sonographically by means of the suprasternal approach. Eleven of 12 mediastinal tumors could be visualized sonographically, mainly as hypoechoic and perivascularly situated masses, and could be located topographically with a fair degree of certainty. Suprasternal sonography is particularly useful in the detection of small, perivascular lymphomas of the supraaortic branches. In patients with problematic CT findings, particularly children and patients with allergies to contrast media, suprasternal sonography can provide important additional information. Moreover, suprasternal sonography can be used to determine the consistency and to monitor the treatment of mediastinal tumors. Finally, the suprasternal approach is suitable for sonographically guided biopsies of mediastinal tumors.     

Optimization of Thermocautery in Excisional Dermatologic Surgery

PURPOSE: Electrosurgery is routinely used in cutaneous surgery for hemostasis. Thermocautery can be used in patients with implantable cardiac devices. This technique relies on heat without electrical current passing through the patient to produce hemostasis. The temperatures and utility of a commercially available, adjustable thermocautery unit are examined. METHODOLOGY: Tip temperature of the commercially available thermocautery unit was measured in air and tissue via a type E thermocouple (0.002 in. diameter) around the unit's tip. Time intervals of 20 to 30 seconds were recorded at device settings 1 to 9 in air and 3 to 8 on surgical patients (Institutional Review Board approval obtained). RESULTS: In vitro analysis demonstrated predictable temperatures at increasing settings in air: 350 to 900 degrees C. Analysis in vivo during surgery demonstrated similar findings. Tissue contact decreased tip temperature by approximately 50% from in vitro values, and use in a bloody field caused a further decrease in the tip temperature. CONCLUSION: The thermocautery unit examined is an effective and safe unit to achieve hemostasis. In addition, the temperature may be adjusted as opposed to hand-held units that operate at in vitro temperatures exceeding 1,400 degrees F. Hemostasis at approximately 100 to 400 degrees C provided optimal hemostasis.     

Transforming growth factor β1 regulates the expression of CCN2 in human keratinocytes via Smad‐ERK signalling

Connective tissue growth factor (CCN2/CTGF) and transforming growth factor β1 (TGF‐β1) are important regulators of skin wound healing, but controversy remains regarding their expression in epithelial cell lineages. Here, we investigate the expression of CCN2 in keratinocytes during reepithelialisation and its regulation by TGF‐β1. CCN2 was detected in the epidermis of healing full‐thickness porcine wounds. Human keratinocytes were incubated with or without 10 ng/ml TGF‐β1, and signalling pathways were blocked with 10‐μM SIS3 or 20‐μM PD98059. Semi‐quantitative real‐time PCR was used to study CCN2 mRNA expression, and western blot was used to measure CCN2, phosphorylated‐ERK1/2, ERK1/2, phosphorylated‐Smad3 and Smad2/3 proteins. CCN2 was transiently expressed in neoepidermis at the leading edge of the wound in vivo. In vitro, CCN2 expression was induced by TGF‐β1 at 2 hours (7·5 ± 1·9‐fold mRNA increase and 3·0 ± 0·6‐fold protein increase) and 12 hours (5·4 ± 1·9‐fold mRNA increase and 3·3 ± 0·6‐fold protein increase). Compared with inhibiting the SMAD pathway, inhibiting the mitogen‐activated protein kinase (MAPK) pathway was more effective in reducing TGF‐β1‐induced CCN2 mRNA and protein expression. Inhibition of the MAPK pathway had minimal impact on the activity of the SMAD pathway. CCN2 is expressed in keratinocytes in response to tissue injury or TGF‐β1. In addition, TGF‐β1 induces CCN2 expression in keratinocytes through the ras/MEK/ERK pathway. A complete understanding of CCN2 expression in keratinocytes is critical to developing novel therapies for wound healing and cutaneous malignancy.     

老年人群亚健康成因及运动处方干预探讨

从当前我国老年退休人群亚健康现状出发,运用文献资料法对老年人群这一特殊群体的亚健康成因进行了探讨与分析,指出社会环境因素、饮食营养因素、生活行为因素、精神心理因素以及自身躯体因素是其产生亚健康状态的主要原因,同时提出了相应的运动干预对策,以其为改善老年人群亚健康状态提供科学依据。