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.

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.

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.

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.

The Advanced Paramedic Clinical Activity Study (APCAS): an insight into the work of advanced paramedics in the mid-west of Ireland.

BACKGROUND: The Advanced Paramedic (AP) is a relatively recent role in Ireland and refers to a prehospital practitioner with Advanced Life Support (ALS) skills and training. The Advanced Paramedic Clinical Activity Study (APCAS) was initiated to provide an evaluation of the impact of the AP programme on patient care in Ireland. AIM: The aim of this study is to provide an insight into the clinical activity of APs over a 6-month period in the mid-west region of Ireland. METHODS: A prospective study was initiated whereby all ambulance calls dispatched by the regional Ambulance Control Centre were recorded by the attending AP, including calls received via the statutory 999/112 system. Participating APs were asked to complete a separate call log data sheet recording all demographic and clinical information for every call attended during the study period. RESULTS: A total of 17 APs participated and 1,969 ambulance calls were recorded in APCAS. The Mid-Western Regional Hospital, Limerick was the busiest receiving facility. Activity peaked at weekends and was lowest on Tuesdays. Crew response, on-scene times and transport times agree with previous reports. Most common emergencies include medical (12 %), cardiovascular (10%) and altered level of consciousness and seizures (10%). Least common calls include airway and ventilation and environmental emergencies (<1%). CONCLUSIONS: This study provides an insight into the work of APs in the mid-west region of Ireland. It would appear that despite the relative recency of the Irish AP programme, the findings of this study are in line with previous international studies.

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.

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.

Abnormal pulmonary granuloma formation in osteopontin-deficient mice.

Osteopontin is a novel cytokine that is expressed in pulmonary granulomatous disease such as sarcoidosis and tuberculosis. It can regulate macrophage and T cell migration, activation, and cytokine expression, yet its role in granuloma formation and evolution is unknown. We induced hypersensitivity pulmonary granulomas by embolizing Schistosoma mansoni eggs to the lungs of osteopontin-deficient (null mutant) mice and osteopontin-sufficient (wild-type control) mice. Granulomas from osteopontin-null animals were smaller at early time points and contained remarkably few macrophages and macrophage-derived epithelioid cells and giant cells. T cell accumulation was unaffected by osteopontin deficiency. These results demonstrate that osteopontin regulates macrophage accumulation during pulmonary granuloma formation, and may explain the impaired ability of osteopontin-deficient hosts to control mycobacterial disease.

Memory of action events: the role of objects in memory of self- and other-performed tasks.

Encoding action phrases by enactment produces better recall than hearing or reading the action phrase. This study examined whether enactment enhances memory relative to observing another perform the same action. Theories of the enactment effect suggest that the complexity of the action, here manipulated by varying the number of objects involved in an action, may determine whether enactment enhances memory relative to observation. The results revealed a consistent subject-performed task advantage across all object conditions; the size of the effect did not vary with increasing task complexity. Additionally, items that included the use of an object were recalled better than those without objects. The results are consistent with the views of Engelkamp and Zimmer (1997) and Backman, Nilsson, & Kormi-Nouri (1993), who argued that the SPT effect is due to motor and/or sensory encoding.

Generation and hypermnesia.

The multifactor account of the generation effect makes detailed predictions about the effects of generation on item-specific and relational encoding, predictions confirmed in four experiments using a multiple-test methodology. In pure-list designs with unrelated study items, generation produced more interest item gains (indexing greater item-specific processing) and more interest item losses (indexing less relational processing) relative to the read condition. In a mixed-list design, generation produced more gains but did not affect losses. With categorically-related study items, generation produced more gains but fewer losses (indicating enhanced relational encoding). Generation consistently produced hypermnesia whereas reading did so only for related study items. Also, a significant generation effect emerged on later tests under conditions (between-subjects design, unrelated study items) which typically yield no generation effect.

Word frequency and memory: effects on absolute versus relative order memory and on item memory versus order memory.

Word frequency can produce opposite effects on recognition and order memory: Low-frequency words produce greater recognition accuracy, whereas high-frequency words produce superior order memory. The present experiments further delineate the relationship between word frequency and order memory. Experiment 1 indicates that low-frequency words produce worse performance on a measure of absolute order memory but not on a test of relative order, which is consistent with the idea that different forms of information underlie different types of order judgments (Greene, Thapar, & Westerman, 1998). Experiment 2 contrasted high-, low-, and very low-frequency words on recognition memory and absolute order memory. In comparison with high-frequency words, low-frequency words enhanced recognition, whereas very low-frequency words did not. Both low- and very low-frequency words, however, produced worse memory for absolute order. Thus, the relationship between frequency and item memory is an inverted U-shaped function, whereas the relationship between frequency and absolute order memory is direct. This implies that the item-enhancing effects of lower word frequency may be dissociated from its order-disrupting effects.

Perceptual interference at encoding enhances item-specific encoding and disrupts relational encoding: evidence from multiple recall tests.

Interfering with perception during encoding can enhance later memory, a phenomenon known as the perceptual interference effect. This effect is investigated in the context of the item-specific-relational framework (e.g., Hunt & McDaniel, 1993), which suggests that the perceptual interference enhances item-specific encoding and impedes relational encoding. Two experiments performed with multiple recall tests support this view. Prior research indicates that item-specific processing increases item gains across tests, whereas relational processing protects against item losses (e.g., Burns, 1993; Klein, Loftus, Kihlstrom, & Aseron, 1989). Consistent with the item-specific-relational framework, perceptual interference produced significant increases in both item gains and losses relative to a control condition.

Attention and perceptual priming in the perceptual identification task.

Prior research indicates that manipulations of attention during encoding sometimes affect perceptual implicit memory. Two hypotheses were investigated. One proposes that manipulations of attention affect perceptual priming only to the extent that they disrupt stimulus identification. The other attributes reduced priming to the disruptive effects of distractor selection. The role of attention was investigated with a variant of the Stroop task in which participants either read words, identified their color, or did both. Identifying the color reduced priming even when the word was also overtly identified. This result held regardless of whether color and word were presented as a single object (Experiments 1 and 2) or as separate objects (Experiment 4). When participants read and identified a color, the overt order of the responses did not matter; both conditions reduced priming relative to reading alone (Experiment 3). The results provide evidence against the stimulus-identification account but are consistent with the distractor-selection hypothesis.

The effects of levels-of-processing and organization on conceptual implicit memory in the category exemplar production test.

The distinction between item-specific and relational information (Hunt & Einstein, 1981) may be relevant to accounts of conceptual priming in the category exemplar production task. In three experiments, the implications of this hypothesis were tested by examining the effects of organization and levels-of-processing (LOP) on this implicit test. Consistent with the hypothesis, the effects of LOP were greater when study lists were organized by category than when they were presented randomly. Furthermore, when subjects claiming test awareness or intentional retrieval were excluded from the analysis, the LOP effect was reduced (and, in fact, eliminated) in the random list condition but remained robust in the categorized condition. Finally, the experimental design of the LOP manipulation (i.e., mixed-list within, blocked-list within, or between subjects) did not moderate the effects of LOP on this priming task.