Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction.

BACKGROUND: Neuroepithelial transforming gene 1 (NET1) mediates tumour invasion and metastasis in a number of cancers, including gastric adenocarcinoma. It is an indicator of poor prognosis in breast cancer and glioma. This study examined NET1 expression and its prognostic significance in patients with adenocarcinoma of the oesophagogastric junction (AOG). METHODS: NET1 expression was measured by immunohistochemistry in a tissue microarray, constructed from biobanked tissue collected over a 10-year interval, and linked to a prospectively maintained clinical database. RESULTS: Using the Siewert classification for AOG, type I tumours expressed significantly higher levels of NET1, with lowest expression in type III and intermediate levels in type II (P = 0.001). In patients with AOG type III, NET1-positive patients were more likely to be female (P = 0.043), have advanced stage cancer (P = 0.035), had a higher number of transmural cancers (P = 0.006) and had a significantly higher median number of positive lymph nodes (P = 0.029). In this subgroup, NET1-positive patients had worse median overall (15 versus 23 months; P = 0·025) and disease-free (11 versus 36 per cent; P = 0.025) survival compared with NET1-negative patients. CONCLUSION: Although existing data show differences in clinical and prognostic indices across AOG subtypes, there are no studies showing differences in tumour biology. These data suggest NET1, a known mediator of an aggressive tumour phenotype in a number of gastrointestinal cancers, is expressed differentially across AOG subtypes and may be of prognostic significance in the clinical management of this condition.

Two cases of dermatoses koebnerizing within fields of previous radiotherapy.

We describe two patients with newly diagnosed dermatoses localizing to the radiotherapy field following treatment for breast cancer. Patient 1 was a 53-year-old woman who developed bullous morphoea on her left breast two years after radiotherapy. Patient 2 was a 43-year-old woman who developed urticaria pigmentosa on her right breast eight months after radiotherapy and similar lesions gradually developed beyond the radiotherapy field. Both patients experienced a significant delay in diagnosis due to diagnostic confusion and concern over breast cancer recurrence. Irradiated skin demonstrates gradual and sustained alterations in fibrosis due to the production of long-lived cytokines and chemokines. These changes can induce a koebnerizing response in conditions such as morphoea and urticaria pigmentosa. We explore the mechanisms behind radiotherapy-induced skin changes, and highlight the potential for radiotherapy to exacerbate or unmask underlying dermatoses and systemic disease in the months and years following treatment.

Vismodegib in the treatment of advanced BCC.

Basal-cell carcinoma (BCC) is the most commonly diagnosed malignancy, comprising over 80 per thousand of non-melanoma skin cancers. Surgical excision is adequate treatment for most BCC's. Options are however limited for the minority of patients presenting with locally advanced inoperable or metastatic BCC. The Hedgehog signalling pathway is a critical driver in the pathogenesis of both sporadic and hereditary BCC. On 31st January 2012, based on a phase II clinical trial the US Food and Drug Administration approved Vismodegib (Erivedge, Roche) a first-in-class, small-molecule oral Hedgehog-inhibitor for the treatment of locally advanced inoperable and metastatic BCC. We present our experience treating the first Irish patient with this agent.

Investigating a clinically actionable BRAF mutation for monitoring low-grade serous ovarian cancer: A case report.

Low-grade serous ovarian cancer (LGSOC) poses a specific clinical challenge due to advanced presentation at diagnosis and the lack of effective systemic treatments. The aim of this study was to use a precision medicine approach to identify clinically actionable mutations in a patient with recurrent LGSOC. Primary, metastatic and recurrence tissue, and blood samples were collected from a stage IV LGSOC patient. Single-gene testing for clinically actionable mutations (BRAF V600, KRAS and NRAS) and subsequent whole-exome sequencing (WES) were performed. Droplet digital PCR was used to evaluate the presence of an identified BRAF D594G mutation in the matched plasma cell-free DNA (cfDNA). No clinically actionable mutations were identified using single-gene testing. WES identified a BRAF D594G mutation in six of seven tumor samples. The patient was commenced on a MEK inhibitor, trametinib, but with minimal clinical response. A newly designed ddPCR assay detected the BRAF alteration in the matched tissues and liquid biopsy cfDNA. The identification and sensitive plasma detection of a common "druggable" target emphasises the impact of precision medicine on the management of rare tumors and its potential contribution to novel monitoring regimens in this field.

Cutaneous reactions to adalimumab administration.

Patients receiving antitumour necrosis factor-alpha treatment may develop cutaneous reactions. This human monoclonal antibody is used in the treatment of chronic inflammatory diseases, including arthritis and inflammatory bowel disease. A variety of side effects have been documented ranging from infection and vasculitis through to systemic lupus erythematosus and psoriasis. We report on two arthritic patients treated with adalimumab (Humira, Abbot Laboratories, IL, USA) who developed new onset rashes that resolved with discontinuation of therapy. The frequency of these cutaneous reactions has not been fully established and may benefit from a centralised registry.

Cutaneous T-cell lymphoma presenting as a ten month history of unilateral facial swelling.

A 25-year-old fisherman presented with a ten-month history of unilateral facial swelling involving his lower lip and eyelids. The differential diagnosis for oro-facial swelling is extensive including congenital, infective, inflammatory and neoplastic processes. Biopsies revealed a cutaneous T cell lymphoma.

The role of p21ras in pancreatic neoplasia and chronic pancreatitis.

K-ras mutations have been detected in both ductal cell carcinoma and intraductal papillary mucinous tumor (IPMT) of pancreas. The frequency of this mutation in ductal cell carcinoma is high, whereas in IPMT, it is variable. It has been suggested that the relatively high frequency of this mutation in ductal cell carcinomas compared with IPMT may account for the differences in biological behavior between these tumor types. More recently, the significance of K-ras mutations in pancreatic tissue has been questioned with the demonstration of this mutation in nonneoplastic pancreata. The current study aims to estimate the relative frequency and evaluate the biological significance of K-ras gene mutations in these neoplasms by performing polymerase chain reaction (PCR) assays of microdissected areas of IPMT, ductal cell carcinomas, and resected chronic pancreatitis. The study also investigates whether alterations of p21ras occur in K-ras mutation-negative cases by using immunohistochemical staining for K-, N- and H-ras. K-ras codon 12 mutations were found almost as frequently in IPMT (71%) as in ductal cell carcinomas (78%). They were also associated with the earliest morphological lesion, flat mucinous change. This mutation also was detected in 42% of cases of chronic pancreatitis. Expression of p21ras was found to correlate closely with K-ras mutation status in IPMT and ductal cell carcinoma. Negative staining for pan-ras, H-ras, and N-ras in cases with wild-type K-ras genes suggests that alternative routes of ras gene alteration are not operative in IPMT or ductal carcinoma. The findings suggest that K-ras activation is frequently associated with both IPMT and ductal cell carcinoma. Its high prevalence in nonneoplastic pancreata suggests that it is also associated with self-limited morphological lesions of the pancreas that do not progress to malignancy.

Response of normal aorta to endovascular grafting: a serial histopathological study.

OBJECTIVE: To examine the histological changes caused by the presence of the endovascular stented graft in the native aorta. DESIGN AND INTERVENTION: Case series. Twenty Western crossbred adult male sheep underwent endovascular placement of an infrarenal aortic stented graft, using the Bard aortic aneurysm repair device catheter delivery system (Bard Vascular Systems, Dovermill, Mass). Six self-expanding wire hooks at the proximal anchor allow fixation to the aorta. After 1 month (n=6), 3 months (n=6), and 6 months (n=8), the animals underwent repeated angiography and intravascular ultrasonography to study the aorta and the graft. The aorta was explanted en bloc with the left renal artery, pressure perfused with a formalin gluteraldehyde solution, and then underwent histological examination with hematoxylin-eosin, trichrome, and elastic tissue staining. MAIN OUTCOME MEASURES: Description of histological changes at various intervals after endovascular stented graft placement. RESULTS: Significant histological findings include (1) complete incorporation of the grafts into the aortic wall, with a pseudointima of smooth muscle cells and collagen; (2) a foreign-body reaction around the graft; (3) an organized blood clot noted between the graft and the aortic wall, without evidence of recent blood flow through the perigraft space or the lumbar vessels; and (4) focal replacement by collagen of the inner one third to one half of the media at the proximal anchor sites. CONCLUSION: There was good incorporation of the graft without evidence of pressure necrosis, bleeding around the graft, or flow in the occluded lumbar vessels.

An unusual case of Behçet's syndrome: triggered by typhoid vaccination?

A case of Behçet's syndrome in a 32-year-old woman occurring shortly after her third vaccination against typhoid fever is described. Scleritis and pyoderma gangrenosum were unusual manifestations of BS that occurred in this case. Treatment benefit was provided by mycophenolate mofetil and etanercept. As bacterial antigens have been proposed as potential triggers for the onset of BS, it is possible that the syndrome was precipitated by typhoid vaccination in this patient.

Improving cardiopulmonary resuscitation skills retention: effect of two checklists designed to prompt correct performance.

Previous research has shown that regardless of an individual's experience, life support skills such as cardiopulmonary resuscitation (CPR) are poorly performed as soon as 1 month following training. The purpose of this study was to compare the effects of two checklists designed to prompt correct CPR performance. We compared the performance of 169 undergraduate students, at the time of course assessment, with retention testing that occurred 2 months following the course assessment. Students were randomly assigned to a control group, a short version of a CPR checklist and a longer more detailed version. Two groups of variables were created: procedural and compression-ventilation variables. In addition, an overall-performance variable was created, summarizing performance on the procedural variables. Binary variables were assessed with chi 2-tests of independence. One-way ANOVAs, using 'group' as the between-subjects factor, were used to assess each continuous variable. Comparisons between groups yielded significant differences of P < 0.05. The long checklist generally led to superior performance on the procedural variables. The results support the hypothesis that remembering the steps of CPR is too complex for some. Though preliminary, the findings of this study indicate that the detailed checklist was an effective strategy to improve the post-course performance of CPR.

BCL-2 expression and inhibin-A in adrenal neoplasms: a comparative study.

Differential diagnosis between adrenal cortical and adrenal medullary lesions may be difficult in many cases. Different immunohistochemical, histochemical tools as well as ultrastructural diagnostic techniques have been employed to aid in differentiating between these lesions. Recently, both inhibin-A and BCL-2 have been shown to stain selectively adrenal cortical tissue and its derived neoplasms but not adrenal medulla or pheochromocytomas. In this study we compared the staining reactions of inhibin-A and BCL-2 in cases of adrenal cortical adenomas and carcinomas as well as pheochromocytomas. We found that both inhibin-A and BCL-2 stained cortical derived tissues, but not medullary derived tissues. Staining intensity for inhibin-A was significantly weaker than for BCL-2. We found that fixation techniques may influence the staining reactivity, as some cases did not immunoreact with any of the antibodies. We conclude that both inhibin-A, and, preferentially, BCL-2 are useful additions to a staining protocol to help in the differential diagnosis of cortical and medullary neoplasms.

A new generation endovascular graft for repair of abdominal aortic aneurysms.

BACKGROUND: Several endovascular grafts are currently being evaluated for repair of abdominal aortic aneurysms (AAA). The goals of our study were twofold. First was to develop a new endovascular graft with several advantages over previous devices: (1) smaller size (16 fr), (2) recapturability (the device can be partially deployed and then recaptured and moved to a new location or entirely removed if needed), and (3) accuracy and ease of placement. Our second goal was to develop an animal model in which a full-scale prototype of the device could be tested. METHODS: Our final endovascular graft prototype was developed after extensive in-vitro testing, and trials of earlier prototypes in dog, pig, and female sheep models. Uncastrated male sheep, 75 to 100 kg, were chosen as the animal model in which to test the device. These animals had infrarenal aortas that were comparable to that of small humans, with diameters of 12 to 15 mm. Two models were used: (1) native infrarenal aorta, and (2) artificial infrarenal aneurysm. Pre-implant and postimplant angiography and intravascular ultrasound were used to evaluate graft placement, and were repeated prior to euthanasia and necropsy. RESULTS: The final prototype was implanted in 22 animals. Sixteen animals had the device placed in their native infrarenal aorta. Three animals were sacrificed immediately after implantation, and 6 more were euthanized after 2 weeks (n = 2), 6 weeks (n = 2), and 3 to 4 months (n = 2). In 7 animals the device is still in place. All procedures were successful. Pathology confirmed complete exclusion of the aorta and thrombosis of all lumbar branches covered by the graft. There was no evidence of graft malposition, migration, or perigraft leak, and no evidence of significant vessel injury on histology. Six animals had artificial aneurysms surgically created and then repaired with the device. A technical error resulted in a failure in 1 case; the remaining aneurysms were all successfully excluded. CONCLUSIONS: We report the development of a new endovascular prosthesis for the repair of AAA. Newer design features provide for smaller delivery size (16 fr), facilitate accurate placement, and provide the option when the device is partially deployed to recapture and reposition the device if necessary. In addition, we have developed an animal model in which this device, and future endovascular aortic devices, can be tested.

Perceptual interference improves explicit memory but does not enhance data-driven processing.

Nairne (1988) has recently demonstrated that interfering with the perceptual processing of an item at study improves later memory for that item. Nairne hypothesized that interfering with perceptual processes induces a data-driven generation process that enhances the representation of visual information. Using a variant of Nairne's procedure, we both replicated his original findings and tested his hypothesis that enhanced data-driven processing causes the current effect. The results of studies using free recall and perceptual identification tests were inconsistent with Nairne's hypothesis. We consider several alternative interpretations in the General Discussion.

The effects of perceptual interference at encoding on organization and order: investigating the roles of item-specific and relational information.

Interfering with the perceptual processing of a stimulus can improve memory. The perceptual-interference effect was investigated from the perspective of the item-specific/relational encoding distinction. This perspective suggests that perceptual interference enhances item-specific encoding but disrupts the encoding of relational and order information. The results of 6 experiments were largely consistent with this view. In Experiments 1 and 2, perceptual interference (a hypothesized item-specific manipulation) and list organization (a relational manipulation) both enhanced free recall but had opposite effects on a measure of relational processing (category clustering). Increasing list organization increased clustering, whereas perceptual interference decreased clustering. In addition, perceptual interference typically decreased memory for order. Finally, when order information was an important determinant of free recall, the perceptual-interference effect was eliminated or reversed. When reliance on order information was lessened, the perceptual-interference effect reemerged.

The effects of perceptual interference at encoding on implicit memory, explicit memory, and memory for source.

Interfering with stimulus identification can enhance later explicit memory performance. This counterintuitive (and theoretically unexpected) phenomenon was investigated in 5 experiments. Perceptual interference enhanced category-cued recall (a conceptually driven explicit test) but had no effect on a comparable implicit memory test, category-exemplar production. This dissociation was obtained across higher levels of priming and with high-frequency as well as low-frequency exemplars. Furthermore, although perceptual interference enhanced old-new recognition memory, it did not enhance rhyme recognition (a data-driven explicit test) or source discriminability. Explanations based on enhanced semantic elaboration or enhanced encoding of spatio-temporal context do not account for the perceptual-interference effect. An account based on compensatory processing of higher level perceptual representations remains viable and is discussed in terms of the transfer-appropriate processing framework and the item-specific-relational distinction.