We examined the effect of sleep state on the response of genioglossus muscle (EMGgg) activity to total airway occlusion applied at 1) nasal (N) airway [and thus exposing the upper airway (UAW) to pressure changes] and 2) tracheal (T) airway (thus excluding UAW from pressure changes). A total of 233 tests were performed during wakefulness (W), 98 tests in slow-wave sleep (SWS), and 72 tests in rapid-eye-movement (REM) sleep. Prolongation of inspiratory time (TI) of the first occluded effort occurred in all tests irrespective of behavioral state, with the greatest increase seen in awake N tests. Nasal tests augmented EMGgg activity in the first occluded breath and produced a linear increase in EMGgg during occlusion. The EMGgg activity at any given time during nasal occlusion in SWS was less than that recorded during W tests. There was a marked reduction in EMGgg response to N occlusion during REM sleep. The EMGgg activity during awake T tests was significantly less than that of N tests at any given time during occlusion. There was no relationship between the level of EMGgg activity and asphyxia in T tests performed during SWS and REM sleep. Nasal tests decreased the force generated by the inspiratory pump muscles and the central drive to breathing compared with T tests. These results confirm the important role of the UAW in regulating breathing pattern and indicate that both immediate and progressive load-compensating responses during nasal occlusion are influenced by information arising from the UAW.
colorectal cancers have responded to braf kinase inhibitor monotherapy in early-phase trials 14 , raising the possibility that effective treatment may require blockade of one or more additional pathways 15 . Conversely, the clinical response of colorectal cancers to regimens including epidermal growth factor receptor (egfr) inhibitors appears to require both wild-type BRAF and KRAS status [16][17][18] .Because recent laboratory studies have confirmed that de novo resistance to braf inhibitors in BRAF V600E -mutated colorectal cancer is caused by egfr signalling 19,20 , we hypothesised that dual blockade of the braf and egfr pathways might be therapeutically useful, as has been suggested by preclinical data 15 . Moreover, a previous randomized trial of cetuximab combined with the nonspecific Raf inhibitor sorafenib indicated a doubling of the response rate in patients with metastatic colon cancer 21 . Here, we report an end-stage colorectal cancer patient benefiting from combination noncytotoxic drug therapy simultaneously targeting the egfr and braf signalling pathways. CASE REPORTA 78-year-old man presented in 2006 with anemia caused by an obstructive mucinous colorectal cancer of the hepatic flexure. The 75-mm tumour was resected en bloc. Vascular invasion and perineural infiltration were present, and 9 of 21 nodes contained metastases. The mismatch repair proteins mlh1 and pms2 were not detectable by immunohistochemistry.After surgery and biweekly oxaliplatin-based (folfox) adjuvant chemotherapy, our patient remained well until 2010, when rising serum carcinoembryonic antigen (cea) and fluorodeoxyglucose positron-emission tomography heralded recurrence in the right external iliac and inguinal nodes, with involvement of the anterior abdominal wall. Palliative use of oral capecitabine was poorly tolerated because of severe diarrhea and hand-foot syndrome, and it failed to stem the rising cea. Treatment was ABSTRACT Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wildtype colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf-and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.
(18)F-FDG-PET/CT imaging should be performed as late as reasonably possible after tracer administration in order to increase tumour-to-background contrast and thereby improve the sensitivity of demonstrating additional sites of disease. Dual-time-point (18)FDG-PET/CT may be of benefit in the evaluation of intra-abdominal lesions but does not improve the overall evaluation of pulmonary lesions.
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