Citations

The familial occurrence of intracranial aneurysms suggests the presence of a genetically determined underlying arteriopathy. The pattern of inheritance in these families usually is not known. A family with seven members with intracranial aneurysms is described and, from the literature before 1994, a total of 238 families with 560 affected members (56% female and 44% male) with intracranial aneurysms not associated with a known heritable disease are reviewed. A segregation analysis was performed on 73 of these families. Two members were affected in the great majority of families (79%); five or more members were reported in only eight families (3%). The most common affected kinship was among siblings. Angiographic screening in 12 families detected an intracranial aneurysm in 29% of 51 asymptomatic relatives. Segregation analysis revealed several patterns of inheritance that were consistent with the compiled pedigrees, but no single mendelian model was the overall best fitting, suggesting that genetic heterogeneity may be important. Twenty-two percent of siblings of male probands had an intracranial aneurysm compared with 9% of siblings of female probands (P = .003). Genetic heterogeneity may be important in the genetics of intracranial aneurysms. In families with intracranial aneurysms, siblings of an affected male proband may be at a higher risk of developing an aneurysm than siblings of an affected female proband. Screening for intracranial aneurysms in asymptomatic relatives should be considered in families with two or more affected members. In most families, the nature of the underlying arteriopathy remains obscure.

BACKGROUND AND PURPOSE: The familial occurrence of intracranial aneurysms and cervical artery dissections has been described in different families and supports the hypothesis that a primary arteriopathy may play a role in the pathogenesis of these disorders. Although the basis for this arteriopathy is generally not believed to be similar among cases of intracranial aneurysms and cervical artery dissections, several similarities exist in the epidemiology of these disorders and a common underlying arterial abnormality may be suspected. SUMMARY OF REPORTS: The medical records of all 175 patients with spontaneous dissections of the cervical arteries who were seen at the Mayo Clinic between 1970 and 1989 were reviewed to identify families in which intracranial aneurysms and cervical dissections coexisted. Three families were identified in which intracranial aneurysms and cervical artery dissections were observed among siblings. These families are described in detail. CONCLUSIONS: The familial occurrence of intracranial aneurysms and cervical artery dissections within the same families provides support to the importance of a common underlying arteriopathy in the pathogenesis of both these disorders. The underlying vascular defect may, at least in some cases, be inherited.

PurposeColorectal cancer predominantly occurs in the elderly, but approximately 5% of patients are 50 years old or younger. We sought to determine whether young age is prognostic, or whether it influences efficacy/toxicity of chemotherapy, in patients with advanced disease.MethodsWe analyzed individual data on 6,284 patients from nine phase III trials of advanced colorectal cancer (aCRC) that used fluorouracil-based single-agent and combination chemotherapy. End points included progression-free survival (PFS), overall survival (OS), response rate (RR), and grade 3 or worse adverse events. Stratified Cox and adjusted logistic-regression models were used to test for age effects and age-treatment interactions.ResultsA total of 793 patients (13%) were younger than 50 years old; 188 of these patients (3% of total patients) were younger than 40 years old. Grade 3 or worse nausea (10% v 7%; P = .01) was more common, and severe diarrhea (11% v 14%; P = .001) and neutropenia (23% v 26%; P < .001) were less common in young (younger than 50 years) than in older (older than 50 years) patients. Age was prognostic for PFS, with poorer outcomes occurring in those younger than 50 years (median, 6.0 v 7.5 months; hazard ratio, 1.10; P = .02), but it did not affect RR or OS. In the subset of monotherapy versus combination chemotherapy trials, the relative benefits of multiagent chemotherapy were similar for young and older patients. Results were comparable when utilizing an age cut point of 40 years.ConclusionYoung age is modestly associated with poorer PFS but not OS or RR in treated patients with aCRC, and young patients have more nausea but less diarrhea and neutropenia with chemotherapy in general. Young versus older patients derive the same benefits from combination chemotherapy. Absent results of a clinical trial, standard combination chemotherapy approaches are appropriate for young patients with aCRC.

Abstract Learning Objectives After completing this course, the reader will be able to: Explain the difference in survival prediction between response criteria (WHO) when used as a two-level variable (CR/PR vs. other) and as a three-level variable (CR/PR vs. SD vs. PD).Describe the limited benefit of using actual tumor measurements over traditional criteria (as a three-level variable) in predicting survival in colorectal cancer. This article is available for continuing medical education credit at CME.TheOncologist.com Purpose. We explored the prognostic value of actual tumor measurements (TM) versus World Health Organization (WHO) criteria as three-level (responder, stable, and progression) and two-level (responder and non-responder) variables at 12 and 24 weeks as predictors of survival in Intergroup Trial N9741, a phase III trial in metastatic colorectal cancer (CRC). Methods. All patients with measurable disease (N = 1,188) were included. The percentage changes in TM from baseline to 12 and 24 weeks were calculated. The prognostic values of TM versus WHO criteria (as three- and two-level variables) at 12 and 24 weeks were compared, using Cox models for overall survival (OS) in a landmark analysis, adjusting for baseline tumor size, performance status, and treatment arm. Results. Tumor status at 12 weeks by WHO criteria (three or two levels) or actual TM were all strongly associated with OS. Actual TM provided no meaningful additional benefit compared with the three-level WHO criteria. Tumor status at 24 weeks was also strongly associated with survival, but added no additional prognostic value compared with the 12-week assessment. At 12 weeks, actual TM improved prognostic characterization of patients with WHO status of response, but provided no additional value in patients with stable disease or progression. Conclusions. In N9741, the use of actual TM, or following tumor status beyond 12 weeks, did not improve survival prediction compared with a single three-level response assessment at 12 weeks, suggesting that 12-week tumor status could be an appropriate phase II trial endpoint in metastatic CRC.

Newly generated T cells are unable to respond to antigen/MHC. Rather, post-selection single-positive thymocytes must undergo T cell maturation to gain functional competency and enter the long-lived naive peripheral T cell pool. This process is poorly understood, as no gene specifically required for T cell maturation has been identified. Here, we demonstrate that loss of the transcriptional repressor NKAP results in a complete block in T cell maturation. In CD4-cre NKAP conditional knockout mice, thymic development including positive selection occurs normally, but there is a cell-intrinsic defect in the peripheral T cell pool. All peripheral naive CD4-cre NKAP conditional knockout T cells were found to be functionally immature recent thymic emigrants. This defect is not simply in cell survival, as the T cell maturation defect was not rescued by a Bcl-2 transgene. Thus, NKAP is required for T cell maturation and the acquisition of functional competency.

Abstract Purpose: Only a limited number of genetic studies have been conducted in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization (aCGH) in formalin-fixed paraffin-embedded (FFPE) specimens and compare the results with matched, frozen tumor specimens. Experimental Design: We conducted aCGH in FFPE tissues from PCNSL. Results were compared with matched, paired, frozen tumors. Results: Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes, with a median of 23 CNAs per patient (range, 17–47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, and 9p21.3 and gain of 12q12-q24.33 were the commonest CNAs. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). Conclusions: The results obtained are encouraging. Larger archival tissue collections can now be analyzed to complement the still fragmented knowledge we have of the genetic basis of the PCNSL. Clin Cancer Res; 17(13); 4245–53. ©2011 AACR.

Background. Statins are an important part of the treatment plan for patients with type 2 diabetes. However, patients who are prescribed statins often take less than the prescribed amount or stop taking the drug altogether. This suboptimal adherence may decrease the benefit of statin initiation. Objective. To estimate the influence of adherence on the optimal timing of statin initiation for patients with type 2 diabetes. Method. The authors use a Markov decision process (MDP) model to optimize the treatment decision for patients with type 2 diabetes. Their model incorporates a Markov model linking adherence to treatment effectiveness and long-term health outcomes. They determine the optimal time of statin initiation that minimizes expected costs and maximizes expected quality-adjusted life years (QALYs). Results. In the long run, approximately 25% of patients remain highly adherent to statins. Based on the MDP model, generic statins lower costs in men and result in a small increase in costs in women relative to no treatment. Patients are able to noticeably increase their expected QALYs by 0.5 to 2 years depending on the level of adherence. Conclusions. Adherence-improving interventions can increase expected QALYs by as much as 1.5 years. Given suboptimal adherence to statins, it is optimal to delay the start time for statins; however, changing the start time alone does not lead to significant changes in costs or QALYs.

Abstract Objective: The aim was to formulate practice guidelines for endocrine evaluation and treatment of pituitary incidentalomas. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails and one in-person meeting. Conclusions: We recommend that patients with a pituitary incidentaloma undergo a complete history and physical examination, laboratory evaluations screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. We recommend that patients with incidentalomas not meeting criteria for surgical removal be followed with clinical assessments, neuroimaging (magnetic resonance imaging at 6 months for macroincidentalomas, 1 yr for a microincidentaloma, and thereafter progressively less frequently if unchanged in size), visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm (6 months and yearly), and endocrine testing for macroincidentalomas (6 months and yearly) after the initial evaluations. We recommend that patients with a pituitary incidentaloma be referred for surgery if they have a visual field deficit; signs of compression by the tumor leading to other visual abnormalities, such as ophthalmoplegia, or neurological compromise due to compression by the lesion; a lesion abutting the optic nerves or chiasm; pituitary apoplexy with visual disturbance; or if the incidentaloma is a hypersecreting tumor other than a prolactinoma.