Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF^V600E models showed acquired drug resistance, one BRAF^V600E model had a complete and durable response, and a BRAF^V600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.     

The aromatase inhibitor anastrozole is ineffective in the treatment of precocious puberty in girls with McCune-Albright syndrome

CONTEXT: Precocious puberty (PP) in girls with McCune-Albright syndrome (MAS) is characterized by episodic development of large unilateral ovarian cysts followed by sudden onset of vaginal bleeding. Some patients experience frequent bleeding as well as accelerated linear growth and advanced skeletal maturation. The use of anastrozole for the treatment of PP in this condition has not been well studied. OBJECTIVE: The objective of the study was to determine the safety and efficacy of the aromatase inhibitor anastrozole for the treatment of PP in girls with MAS. DESIGN AND SETTINGS: This was a prospective international multicenter study in which subjects received anastrozole 1 mg daily for 1 yr. PATIENTS: Twenty-eight girls 10 years of age or younger with MAS and progressive PP were enrolled. MAIN OUTCOME MEASURES: Vaginal bleeding, rate of skeletal maturation (change in bone age over change in chronological age), growth velocity, and uterine/ovarian volumes were measured. These indices were compared with a 6-month pretreatment interval. RESULTS: No difference in vaginal bleeding (mean number of days per year) was noted. Mean change in DeltaBA/DeltaCA, which was 1.25 +/- 0.77 at baseline, was -0.25 +/- 1.02 at study end (P = 0.22). Average growth velocity z score was 1.40 +/- 3.15 at study entry and 0.26 +/- 2.71 at 12 months (P = 0.10). Mean ovarian/uterine volumes were unaffected by anastrozole, and no significant adverse events occurred. CONCLUSIONS: Although it appears safe, anastrozole for 1 yr was ineffective in halting vaginal bleeding, attenuating rates of skeletal maturation, and linear growth in girls with MAS. Pharmacological strategies other than anastrozole should be pursued for the treatment of PP in this population.     

Prevalence of leptospiral infection in Texas cattle: implications for transmission to humans

Of 1193 Texas slaughterhouse cattle serum samples assayed for anti-leptospiral antibodies by microscopic agglutination testing, 262 (22%) reacted with serovar pomona and 179 (15%) with serovar hardjo. Of 300 urine samples tested for leptospiral DNA by a polymerase chain reaction assay, 106 (35%) were positive. The high prevalence of leptospiral infection of cattle represents potential threats to human health and agricultural economics.     

Low hemoglobin levels in children with in idiopathic growth hormone deficiency

Multiple lines of evidence have implicated the growth hormone (GH) axis in the regulation of erythropoiesis. To test the hypothesis that GH deficiency is associated with hematologic abnormalities, we analyzed pretreatment hemoglobin levels in 100 children with GH deficiency. Hemoglobin levels were decreased in children with GH deficiency compared with age-corrected norms.     

Ist die infrainguinale Rekonstruktion der arteriellen Strombahn mit autologer Vene im Stadium der limitierenden Klaudikation gerechtfertigt?

Infrainguinal arterial reconstruction for intermittent claudication has been discouraged because of fear of bypass graft failure, significant perioperative complications, and limb loss. This may be worse than the natural history of the disease. In our study, we retrospectively evaluated all infrainguinal bypass procedures performed in the past 10 years.From October 1988 to December 1998, we performed 421 infrainguinal arterial reconstructions, 115 (27.2%) for debilitating claudication and 306 (72.8%) for critical ischemia in 410 patients. The average age was 73.2 years (range 20–86 years). There were significantly more diabetics with critical ischemia (183 versus 14, P=0.000). Other risk factors (smoking, hypertension, hyperlipidemia) were evenly distributed in both groups. Follow-up was scheduled in our vascular laboratory.The primary patency rates were 64.8% for intermittent claudication and 54.2% for critical ischemia at 7 years (P value not significant), and the primary assisted patency rates were 86.1% and 79.3%, respectively (P value not significant). There were 2 patients (1.7%) with limb loss in the follow-up period (3 and 5 years after operation, respectively). Both patients were diabetics, who had to be amputated with patent grafts because of progressive forefoot gangrene. The 30-day mortality rate was 0.8% (1 patient died on the second postoperative day due to cardiac failure).In our experience, patients with debilitating claudication have to be managed by a team of angiologists, radiologists, and vascular surgeons. The use of autologous vein, intraoperative angioscopy, and a scheduled follow-up program may be the cornerstones for excellent long-term results. These results justify operation in selected cases.     

Interactions of a history of migration with the course of pain disorder

OBJECTIVE: Previous studies indicate that sociocultural factors affect the course of pain disorder. We investigated the role of nationality as an indicator of cultural factors, and of the degree of inclusion (DI) in Swiss society as an indicator of the migration process on the course of pain disorder. METHOD: In a semiprospective case-control study, outcome was assessed after a 2-year follow-up in 57 patients treated for pain disorder by phone interview with the patients. One Swiss patient was matched with two Spanish or Italian patients living in Switzerland. Patients' appraisal of course of illness (PACI) and of current general health (PACGH) were assessed as the sum score of their ratings of general well-being, handicap in everyday life, work ability, mood and pain. Family physicians were also asked to rate patient's course of illness. DI in Swiss society was assessed according to type of work permit, age at immigration and fluency in the language of the receiving country. RESULTS: Swiss patients evaluated their PACI [H(1,56) = 4.30; P = .0038] and PACGH [H(1,56) = 9.04; P = .003)] more favourably than patients from Italy and Spain. This difference was confirmed by the family physician's evaluation of the course of illness. A similar difference in outcome was found in favour of foreign patients with a higher DI. CONCLUSION: These results indicate that, in addition to sociocultural factors, the DI affects the outcome of pain disorder in patients with a history of migration.     

Endovascular treatment of a post-traumatic thoracic false aneurysm in an adolescent. A case report

A 17 year old healthy young man suffered a motor-vehicle accident with severe polytrauma. During the rehabilitation a slight hypertension and a blood pressure difference of 30-40 mmHg between arms and legs was recognized. Mindful of a possible aortic lesion, an angio-magnetic resonance imaging (MRI) showed a 2.7x4.2 cm thoracic false aneurysm at the descending aorta. About 1 month after initial trauma, a Talent stent was implanted. The postinterventional period was uneventful. The patient was discharged on the 5th postoperative day.     

Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia

OBJECTIVE: Optic nerve hypoplasia (ONH) is a heterogeneous disease with variable findings of pituitary insufficiency, CNS and neurodevelopmental abnormalities. We characterized the spectrum of endocrinopathy in a cohort of children with ONH and attempted to correlate the presence of different midline CNS findings with the degree of hypopituitarism. The correlation of variable CNS abnormalities with the presence of a seizure disorder and neurodevelopmental delay was also examined. METHODS: Charts of 56 patients with ONH referred to our endocrine clinics between 1990 and 2000 were reviewed. Neurodevelopmental assessment was based on questionnaires sent to families during the study period. RESULTS: Forty-six patients (82%) had hypopituitarism, with growth hormone deficiency being the most common endocrinopathy. All patients with diabetes insipidus, hypocortisolism, and hypogonadotropin hypogonadism also had combined pituitary hormone deficiency. Evolving pituitary hormone deficiency was observed in two of 37 patients diagnosed with hypopituitarism in the first 3 years of life. No single midline CNS finding correlated with the presence of hypopituitarism or a seizure disorder. However, hydrocephalus or a seizure disorder was more commonly seen in patients with developmental delay. CONCLUSION: ONH is a heterogeneous disorder with possible multifactorial etiologies. All patients with this diagnosis deserve a comprehensive endocrine and neurodevelopmental evaluation.