Citations

Abstract The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]

The increasing use of endonasal techniques and a new 3-dimensional CT-guided imaging system have allowed us to develop a combined, minimally invasive endonasal approach to the pituitary gland. Thus far, more than 30 patients have undergone an endonasal transsphenoidal approach to the sella using a combined endoscopic approach, with additional selective use of the Instatrak CT-guided imaging system for realtime imaging. Our current technique involves obtaining a preoperative CT using a plastic head frame with registration markers. By using this head frame intraoperatively, real-time localization with CT images in axial, coronal, and sagittal planes can be performed. Using endoscopic techniques and a Papavero-Caspar speculum, the sella is exposed. A combined approach using endoscopes, the operating microscope, and real-time localization is undertaken to expose and resect tumors. We have encountered minimal associated complications in our series, and this method has been progressively modified to improve exposure and safety. Because we are able to visualize the sella without a sublabial incision or septal resection, we have nearly eliminated the need for nasal packing, reduced the average hospital stay to 2.5 days, and improved patient satisfaction.

Patients with hypertension have a blunted sensitivity of baroreflex control of heart period. In these patients, baroreflex sensitivity is positively related to heart rate variability and inversely related to blood pressure variability. We hypothesized that this relationship would also be evident in healthy normotensive subjects and that individuals with higher baroreflex sensitivity would have lower ambulatory 24-hour blood pressure. Twenty-four-hour ambulatory blood pressure and heart rate were recorded in 50 healthy, normotensive, nonobese individuals (31 women and 19 men). The baroreflex was assessed using sequential bolus administration of sodium nitroprusside and phenylephrine, and baroreflex sensitivity was calculated as the slope of the relation between systolic blood pressure and R-R interval during the resulting blood pressure transients. Baroreflex sensitivity was inversely correlated to 24-hour average mean arterial pressure ( R =0.49; P <0.001) and positively related to daytime heart rate variability ( R =0.33; P =0.02). In contrast, no relationship was found between baroreflex sensitivity and 24-hour heart rate or blood pressure variabilities. We conclude that the relationship between baroreflex sensitivity and daytime heart rate variability was similar to that reported previously in hypertensive subjects. Furthermore, the inverse relation between baroreflex sensitivity and mean arterial pressure supports the idea that the baroreflex may exert longer-term effects on blood pressure than thought previously.

Abstract The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 × 109/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.

Purpose This report describes the speech characteristics of individuals with a neurodegenerative syndrome called pallido-ponto-nigral degeneration (PPND) and examines the speech samples of at-risk, but asymptomatic, relatives for possible preclinical detection. Method Speech samples of 9 members of a PPND kindred were subjected to perceptual characterization. Speech deterioration patterns were reported for 2 participants followed longitudinally at 6-month intervals. Cross-sectional findings were reported for 3 participants at various stages of disease. Longitudinal and cross-sectional findings were used to guide the examination of 4 at-risk, but asymptomatic, participants. Results Results revealed a progressive mixed dysarthria with hypokinetic, spastic, and flaccid features. It was characterized primarily by vocal tremor and high-frequency vocal flutter, speaking rate abnormalities most often in the direction of slowing, and a tendency toward monopitch. Dysarthria progression was marked by exacerbation and increasing severity of early features, progressive decrease in spontaneous speech output, verbal perseverations, and eventual mutism. Results for at-risk participants revealed preclinical speech abnormalities that preceded other motor signs. Speech results were examined in light of available autopsy findings for site of lesion associations. Conclusion The dysarthria of PPND is an early harbinger of disease onset. It has a mixed presentation, with hypokinetic, spastic, and flaccid features.

Breast cancer now affects 1 in 8 American women and the taxane agent paclitaxel (Taxol ® Bristol-Myers Squibb) is a major tool in the treatment of many such patients. Hand surgeons are therefore likely to encounter upper extremity complications related to the use of taxane therapy. We present an unusual case of a felon developing in a breast cancer patient on paclitaxel therapy with no antecedent history of trauma. Whereas onycholysis and subungual hemorrhage are reported complications of taxane therapy ( Fig. 1 ), an acute felon with or without associated paronychia is an unusual and more aggressive manifestation of this drug-related nail dystrophy.

Purpose There has been a significant increase in surgeon as well as patient interest in arthroscopic treatment of shoulder pathology. We hypothesize that patients have a strong preference for arthroscopic shoulder surgery. Currently, there are no data in the literature reporting on how people perceive open versus arthroscopic shoulder surgery. Methods Prospectively, a total of 202 patients were administered a questionnaire at the offices of 2 fellowship‐trained shoulder surgeons, 1 located at a tertiary referral center (center A) and 1 in private practice (center B). The questionnaire asked a series of questions about specific factors when choosing an orthopaedic surgeon and the preference for arthroscopic or open surgery. In addition, 7 short‐term and long‐term outcomes were listed, and the patient was asked to choose whether open or arthroscopic surgery would provide the best outcome or whether he or she felt that there was no difference. Results Among patients at center A, 88% would prefer arthroscopy if they were to have shoulder surgery, as would 96% of patients at center B. Among patients at center A, 14% would avoid shoulder surgery if the only option was open surgery, as would 25% at center B. The reputation of the surgeon and institution were the primary factors in choosing a surgeon. Recommendation of a former patient and years of surgeon experience were less important factors for patient selection of a shoulder surgeon. Conclusions The study shows that the vast majority of patients perceive multiple advantages of arthroscopic shoulder surgery despite a lack of published data to support many of these assumptions, particularly with regard to expected functional outcome of arthroscopic versus open shoulder surgery. Clinical Relevance Shoulder surgeons should be aware of these perceptions when discussing treatment options with patients. A continued effort should be made to emphasize known scientific data when considering the relative risks and benefits of arthroscopic and open shoulder surgery.