Citations

Purpose To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome. Patients and Methods Patients with previously treated NSCLC received pemetrexed (500 mg/m2 intravenous) combined with bevacizumab (15 mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a one-stage Fleming design for detecting a true success rate of at least 70%, was the proportion of patients who were progression free and on treatment at 3 months. Polymorphisms in genes responsible for pemetrexed transport (reduced folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated with treatment outcome. Results Forty-eight evaluable patients (14 females and 34 males) received a median of four cycles (range, one to 20 cycles). The most common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%), dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of the first 42 patients met the success criteria. Median overall survival (OS) and progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The exon 6 (2522)C→T polymorphism in SLC19A1 correlated with 3-month progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C→T polymorphism in GGH correlated with OS (P = .04). Conclusion The study did not meet its primary end point. However, the median PFS time of 4 months is promising. Pharmacogenetic studies in larger cohorts are needed to definitively identify polymorphisms that predict for survival and toxicity of pemetrexed.

Object Stereotactic radiosurgery (SRS) has proven to be a safe and effective treatment for many patients with intracranial meningiomas. Nevertheless, the morbidity associated with radiosurgery of larger meningiomas is poorly understood. Methods The authors performed a retrospective review of 116 patients who underwent SRS for meningiomas (WHO Grade I) > 10 cm3 between 1990 and 2007, with a minimum follow-up of 12 months. Patients with atypical or malignant meningiomas and those who received prior radiotherapy were excluded. The average tumor volume was 17.5 cm3 (range 10.1–48.6 cm3); the average tumor margin dose was 15.1 Gy (range 12–18 Gy); and the mean follow-up duration was 70.1 months (range 12–199 months). Results Tumor control was 99% at 3 years and 92% at 7 years after radiosurgery. Thirty complications after radiosurgery were noted in 27 patients (23%), including 7 cases of seizures, 6 cases of hemiparesis, 5 cases of trigeminal injury, 4 cases of headaches, 3 cases of diplopia, 2 cases each of cerebral infarction and ataxia, and 1 case of hearing loss. Patients with supratentorial tumors experienced a higher complication rate compared with patients with skull base tumors (44% compared with 18%) (hazard ratio 2.9, 95% CI 1.3–6.7, p = 0.01). Conclusions The morbidity associated with SRS for patients with benign meningiomas > 10 cm3 is greater for supratentorial tumors compared with skull base tumors. Whereas radiosurgery is relatively safe for patients with large-volume skull base meningiomas, resection should remain the primary disease management for the majority of patients with large-volume supratentorial meningiomas.

AbstractPurpose: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu–expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor.Experimental Design: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment.Results: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-γ enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting >48 weeks.Conclusions: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu–expressing breast, ovarian, and colorectal cancer are warranted. (Clin Cancer Res 2009;15(18):5937–44)

In recognition of the global problem posed by Alzheimer's disease and other dementias, an international think‐tank meeting was convened by Biocat, the Pasqual Maragall Foundation, and the Lou Ruvo Brain Institute in February 2009. The meeting initiated the planning of a European Union‐North American collaborative research enterprise to expedite the delay and ultimate prevention of dementing disorders. The key aim is to build parallel and complementary research infrastructure that will support international standardization and inter‐operability among researchers in both continents. The meeting identified major challenges, opportunities for research resources and support, integration with ongoing efforts, and identification of key domains to influence the design and administration of the enterprise.

Background— Recurrent functional mitral regurgitation (MR) has been reported after mitral valve repair with annuloplasty in patients with dilated cardiomyopathy, but the mechanism is not understood completely. The authors sought to identify abnormalities of the mitral valve and left ventricle that are associated with recurrent MR after mitral annuloplasty. Method and Results— In 104 patients with idiopathic dilated cardiomyopathy who underwent annuloplasty for functional MR, basal mitral anterior leaflet angle, distal mitral anterior leaflet angle (ALA tip ), posterior leaflet angle, coaptation depth, tenting area, mitral annular dimensions, left ventricular volumes, and MR severity were quantified by echocardiography before surgery and at 6-month intervals after it. Compared with patients without MR recurrence (n=79), patients with recurrent MR (defined as ≥2+) (n=25) had greater ALA tip ( P <0.001) and basal mitral anterior leaflet angle ( P <0.001), greater coaptation depth and tenting area ( P <0.001), larger left ventricular volumes ( P <0.001), and worse left ventricular ejection fraction ( P <0.05) but similar mitral annular dimensions and postoperative exaggeration in posterior leaflet angle. Multivariable analysis identified postoperative ALA tip as the major determinant of postoperative MR. Receiver operator characteristic curves identified preoperative ALA tip as the best predictor of MR recurrence (area under curve, 0.98). For ALA tip >25°, the sensitivity, specificity, and positive and negative predictive values in predicting recurrent MR were 88%, 94%, 82%, and 93%, respectively. Three distinct patterns of anterior leaflet tethering (minimal, basal, and distal) with an increasing risk of recurrent MR were identified. Conclusions— Posterior leaflet tethering is invariable after mitral annuloplasty, rendering postoperative mitral competence highly dependent on distal anterior leaflet mobility.

Once considered a rare and largely untreatable condition, obsessive-compulsive disorder (OCD) is now known to be the fourth most common psychiatric disorder. Obsessive thoughts are intrusive, repugnant, and distress and anxiety provoking, whereas compulsive rituals often lead to significant impairment in many areas of life. In this article, the authors present an empirically based review of the treatment outcome literature on cognitive-behavioral therapy for OCD. Specifically, treatment by exposure with response prevention (EX/RP) has been demonstrated to be effective in reducing OCD symptoms. The effectiveness of different variations of EX/RP and comparisons between this and other psychosocial therapies (e.g., cognitive therapy) are also discussed. Finally, the authors consider studies that have examined variables thought to influence the effectiveness of treatment.