Citations

ABSTRACT Alternative splicing generates functional diversity in higher organisms through alternative first and last exons, skipped and included exons, intron retentions and alternative donor, and acceptor sites. In large-scale microarray studies in humans and the mouse, emphasis so far has been placed on exon-skip events, leaving the prevalence and importance of other splice types largely unexplored. Using a new human splice variant database and a genome-wide microarray to probes thousands of splice events of each type, we measured differential expression of splice types across six pair of diverse cell lines and validated the database annotation process. Results suggest that splicing in humans is more complex than simple exon-skip events, which account for a minority of splicing differences. The relative frequency of differential expression of the splice types correlates with what is found by our annotation efforts. In conclusion, alternative splicing in human cells is considerably more complex than the canonical example of the exon skip. The complementary approaches of genome-wide annotation of alternative splicing in human and design of genome-wide splicing microarrays to measure differential splicing in biological samples provide a powerful high-throughput tool to study the role of alternative splicing in human biology.

Purpose To review the state of the science with respect to diagnostic imaging and locoregional therapy for patients with breast cancer receiving preoperative chemotherapy. Methods Published data relevant to clinical staging, monitoring of tumor response, and locoregional therapy for patients with breast cancer treated with preoperative chemotherapy were reviewed. Results High-quality data from prospective randomized trials are limited. Available data suggest that locoregional therapy decisions should be based on both the pretreatment clinical extent of disease and the pathologic extent of the disease after chemotherapy. Accordingly, physical examination and imaging studies that accurately define the initial extent of disease are required before treatment. Sentinel lymph node biopsy can be performed either before or after preoperative chemotherapy for patients with clinical N0 disease. The success of breast conservation after preoperative chemotherapy depends on careful patient selection and achieving negative surgical margins. Adjuvant breast radiation is indicated for all patients treated with breast conservation. For patients treated with mastectomy, chest-wall and regional nodal radiation should be considered for those who present with clinical stage III disease or have histologically positive lymph nodes after preoperative chemotherapy. Additional prospective studies are needed to determine the value of postmastectomy radiation for patients with stage II breast cancer who have negative lymph nodes after chemotherapy. Conclusion The increased use of preoperative chemotherapy has raised new questions concerning the optimal methods to stage and monitor disease response to treatment and how to optimize locoregional treatment. The available evidence suggests that a multidisciplinary approach improves outcomes.

After Alzheimer's disease, frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in persons less than 65 years of age. Up to 40% of FTLD cases have a positive family history. Research on these families has led to the discovery of four disease-causing genes: microtubule-associated protein tau ( MAPT), progranulin ( PGRN), valosin-containing protein ( VCP), and charged multivesicular body protein 2B ( CHMP2B). MAPT and PGRN are responsible for the largest number of familial cases. Each of these genes differs by disease mechanism. Moreover mutations in both genes are associated with significant interfamilial and intrafamilial phenotypic variation. Genetic counseling needs to address the differences between the PGRN and MAPT mutations as well as the variation in clinical symptoms. The aims of this article are to describe the genetics of the FTLD spectrum and aid in the genetic counseling of individuals who may carry genetic mutations.

Abstract Epidemiologic studies have shown the health risks of exposure to cigarette smoke and air pollution, with heavy metal composition implicated as contributing to both. Environmental exposure to cigarette smoke has been epidemiologically associated with pancreatic cancer, but the pathophysiologic basis for this is not yet clear. In the current work, we have used inductively coupled plasma mass spectrometry to quantify the metal composition of pancreatic juice collected in response to secretin stimulation in successive patients evaluated for abdominal pain (35 with pancreatic cancer, 30 with chronic pancreatitis, and 35 with normal pancreas). Indeed, metal composition of pancreatic juice was distinctive in patients with pancreatic cancer relative to those without such a cancer. The metal concentrations that were found to have the strongest association with pancreatic cancer were chromium, selenium, and molybdenum, with 1 SD increases in the concentrations of each associated with substantial increases in the odds of having pancreatic cancer relative to those in patients with normal pancreas (210%, 160%, and 76%, respectively). Of note, elevations in concentrations of chromium and selenium did not correlate in individuals, whereas those having a 1 SD increase in the sum of the concentrations of these two metals in their pancreatic juice had a 480% increase in the odds of having pancreatic cancer. Elevations of nickel and zinc correlated with elevated chromium in individuals, with each of these metals known to be present in cigarette smoke, whereas other recognized metal components of cigarette smoke were not elevated. An understanding of why these metals are elevated in pancreatic juice and what effects they might have on pancreatic cells may have important implications for the diagnosis, treatment, and even prevention of pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2656–63)

Object Enhancement of pathological entities in the central nervous system is a common finding when the blood–brain barrier has been compromised. In the brain, the presence or absence of gadolinium enhancement is often an indicator of tumor invasiveness and/or grade. In the spinal cord, however, contrast enhancement has been shown in all tumor types, regardless of grade. In this study the authors explore the incidence of nonenhancing tumors of the spinal cord and the clinical course of patients with these lesions. Methods A retrospective analysis was conducted in which investigators examined the patterns of enhancement of histologically proven intramedullary spinal cord tumors that had been evaluated at the Mayo Clinic between 1998 and 2002. The tumors that did not enhance were the subject of this report. Results A total of 130 patients with intramedullary tumors were evaluated. Of those, 11 patients (9%) had tumors that did not enhance. Histologically, a majority of tumors were astrocytomas (eight low-grade and two high-grade lesions); one tumor was a subependymoma. Morphologically, most of the tumors were diffuse and none had associated cysts. Tumors spanned from two to seven levels and were located throughout the spinal cord (four cervical, three cervicothoracic, one thoracic, and three thoracolumbar). Biopsy procedures were performed in eight patients, subtotal resection was performed in two, and gross-total resection in one. After a mean follow-up period of 19 months, tumors remained stable in eight patients but progressed in three, two of whom died. Conclusions A number of intramedullary spinal cord tumors will not enhance after addition of contrast agents. The absence of enhancement does not imply the absence of tumor.

Purpose The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. Patients and Methods Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. Results In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. Conclusion PFS is an acceptable surrogate for OS in advanced colorectal cancer.