Citations

Abstract Background Outcomes for patients with hepatocellular carcinoma (HCC) without cirrhosis and factors associated with disease progression remain unclear. The goals of this single-institution study were to define the outcomes for such patients, and to determine factors associated with survival and disease progression. Methods This was a retrospective review of consecutive patients with HCC without cirrhosis who underwent hepatic resection between 1985 and 2003. Survival was estimated by the Kaplan–Meier method and risk factors were identified by Cox proportional hazards models. Results A total of 143 patients were enrolled, of whom 29·4 per cent had identifiable risk factors for chronic liver disease. Major resection (at least three segments) was undertaken in 63·6 per cent of patients. The operative mortality rate was 3·5 per cent. Median disease-free survival was 2·4 years. Multivariable analysis revealed presence of multiple tumours as the only independent predictor of tumour recurrence. Median overall survival was 3·3 years. Factors independently associated with decreased overall survival were multiple tumours, high histological grade, perioperative transfusion, male sex and age at least 66 years. Conclusion Patients with HCC but without cirrhosis have acceptable outcomes after resection. Specific risk factors for the development of HCC in these patients have yet to be defined.

Abstract A personalized approach to breast cancer management is increasingly possible with state of the art diagnostics and treatments. However, many challenges still exist in choosing the right therapeutic strategy and the right dosing for a specific patient population. Biomarkers such as estrogen receptor, progesterone receptor, and HER-2 status are used to tailor therapy, but success rates with targeted therapy suggest that appropriate patient populations still require greater definition. The introduction of the genomic era has likewise advanced the ability to offer a tailored approach to breast cancer management, but much work is still needed in this area as well. Microarray-based gene expression profiles have demonstrated initial promise, but we need a better understanding of more complex tumor signaling pathways. Strategies include annotated tumor specimens, next-generation gene sequencing, proteomics, and metabolomics. An individualized approach to breast cancer management has the potential to offer clear clinical benefits and the ability to bring more tailored, cost-effective strategies to the market. The current issues facing the delivery of individualized breast cancer care will be the focus of this discussion.

Abstract Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00–2.24, P = 0.052). Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Clin Cancer Res; 17(6); 1591–602. ©2011 AACR.

Object Little information is available on follow-up MR imaging after treatment of spinal dural arteriovenous fistulas (DAVFs). The authors studied MR imaging findings in treated spinal DAVFs in relation to clinical outcomes. Methods A retrospective review of patients with spinal DAVFs who had undergone both pre- and postoperative spinal MR imaging was conducted. Postoperative MR images were obtained as routine follow-up studies or because of subjective or objective clinical deterioration. Several pre- and posttreatment MR imaging characteristics were evaluated by 2 neuroradiologists blinded to the clinical outcome. Clinical outcomes of motor, sensory, and urinary function (in relation to the patient's preoperative status) at the time of the postoperative MR imaging were obtained from the clinical record. The chi-square, Fisher exact, and rank-sum tests were performed to correlate imaging findings and changes with clinical outcomes. Results Thirty-four patients met inclusion criteria. Treatment was surgical in 33 patients and endovascular in 1 patient. Follow-up MR imaging was performed at a mean 168 ± 107 days after treatment. Twenty-seven patients (79.4%) were either clinically stable or improved, and 7 (20.6%) experienced worsening in one or more clinical outcomes. Most patients were found to have improvement of MR imaging changes. However, some degree of persistent spinal cord signal abnormality, enhancement, and swelling was observed in 31 (91.2%), 29 (85.3%), and 18 (52.3%) patients, respectively. Changes in these MR imaging characteristics compared with preoperative MR imaging did not correlate with clinical outcomes (p > 0.05), with the one exception of a significant correlation between change in urinary function and extent of spinal cord contrast enhancement (p = 0.026), a correlation of uncertain importance. Ten of the 34 patients underwent posttreatment digital subtraction angiography, and 3 of these patients had recurrent/residual DAVFs. Worsening of motor function significantly correlated with recurrent/residual DAVF (p = 0.053). Conclusions Spinal cord abnormalities persist on postoperative MR imaging studies in patients with treated spinal DAVFs, and although they tend to mildly improve with time, these changes may not correlate with clinical outcomes. However, regardless of imaging findings, worsening motor function may correlate with a recurrent or residual DAVF.

Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions’ experience with resectable pancreatic SCC. Six patients with pancreatic SCC treated at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data were analyzed, and the literature on pancreatic SCC was reviewed. Median age at diagnosis was 50 years (range 27–60). All six tumors arose in the head of the pancreas. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There were no perioperative deaths and three patients had at least one postoperative complication. All six patients received adjuvant therapy, five of whom were given combined modality treatment with radiation, cisplatin, and etoposide. Median survival was 20 months with a range of 9–173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed favorable survival rates when compared to prior reports of both resected and unresectable SCC. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation.

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency—dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.

BackgroundTo better understand the status of frontotemporal dementia (FTD) research, and identify opportunities to accelerate translational research, we analyzed international funding for FTD and related dementias between 1998 and 2008.MethodsSearch terms were compiled to define the clinical spectrum of FTD and all known mechanisms. Funders were asked to return grants that contained these search terms in the title or abstract. Grants were classified according to the most reasonably achieved stated aim using a classification scheme of research activities that was developed to map grants along the continuum from basic research to clinical trials of treatments.ResultsThis analysis captured 613 grants ($432,167,275), from 19 private and public funders from 7 countries and the European Union. National Institutes of Health contributed $360 million (MM), 53% of grants and 83% of total funding. Foundations contributed $43 MM, 35% of grants and 10% of total funding, an increase in recent years. A total of $319 MM (74%, funding) went toward basic research, of which 10% was dedicated to preclinical treatment development, clinical treatment evaluation, and developing detection, diagnostic, and imaging technologies and reagents.ConclusionsFTD received moderate funding over the past decade, which has decreased almost five‐fold during this period. A sizable proportion of FTD funding supported mechanisms shared with Alzheimer's disease. Few programs advanced past validating target models and into drug discovery and preclinical development, indicating that the knowledge gained from recent research has still not advanced into treatment development. Quantitative analysis of funding highlighted under‐resourced areas as well as redundant efforts, enabling a more strategic approach toward advancing FTD drug discovery and development.

AbstractContext:Insulin resistance has been reported to be associated with development of atherogenic dyslipidemia. However, the confounding effects that obesity and low levels of cardiorespiratory fitness have on the relationship between insulin resistance and the development of atherogenic dyslipidemia remain to be adequately addressed.Objective:This study sought to examine the independent and combined effects of insulin sensitivity, body composition, and cardiorespiratory fitness on lipoprotein particle sizes and concentrations.Methods:Eight-four healthy, nondiabetic men (n = 43) and women (n = 41) were studied. The participants had a wide range of ages (18–30 and 65–80 yr), body composition (7.2–52.8% fat), and cardiorespiratory fitness (VO2 peak, 13.5–66.2 ml/kg·min). Body composition, cardiorespiratory fitness, insulin sensitivity, and lipoprotein particle profiles were assessed using dual-energy x-ray absorptiometry, cardiopulmonary exercise testing, a hyperinsulinemic-euglycemic clamp, and nuclear magnetic resonance spectroscopy, respectively.Results:Low levels of insulin sensitivity and cardiorespiratory fitness and higher levels of adiposity were associated with the accumulation of small, dense, low-density lipoprotein particles; small high-density lipoprotein particles; triglycerides; and very low-density lipoprotein particles. Multivariate forward-stepwise regression revealed that higher levels of adiposity, in particular truncal fat, were the strongest predictor of the lipoprotein particle size and concentration data, followed by insulin sensitivity.Conclusions:As expected, the accumulation of atherogenic lipoprotein particles (e.g. small, dense, low-density lipoprotein particles and small, high-density lipoprotein particles) was associated with low levels of insulin sensitivity, cardiorespiratory fitness, and higher levels of adiposity. However, multivariate forward-stepwise regression revealed that triglycerides, followed by truncal fat mass, were the strongest predictors of the lipoprotein particle size and concentration data.

ABSTRACT Target cell overexpression of the integrase binding domain (IBD) of LEDGF/p75 (LEDGF) inhibits HIV-1 replication. The mechanism and protein structure requirements for this dominant interference are unclear. More generally, how and when HIV-1 uncoating occurs postentry is poorly defined, and it is unknown whether integrase within the evolving viral core becomes accessible to cellular proteins prior to nuclear entry. We used LEDGF dominant interference to address the latter question while characterizing determinants of IBD antiviral activity. Fusions of green fluorescent protein (GFP) with multiple C-terminal segments of LEDGF inhibited HIV-1 replication substantially, but minimal chimeras of either polarity (GFP-IBD or IBD-GFP) were most effective. Combining GFP-IBD expression with LEDGF depletion was profoundly antiviral. CD4 + T cell lines were rendered virtually uninfectable, with single-cycle HIV-1 infectivity reduced 4 logs and high-input (multiplicity of infection = 5.0) replication completely blocked. We restricted GFP-IBD to specific intracellular locations and found that antiviral activity was preserved when the protein was confined to the cytoplasm or directed to the nuclear envelope. The life cycle block triggered by the cytoplasm-restricted protein manifested after nuclear entry, at the level of integration. We conclude that integrase within the viral core becomes accessible to host cell protein interaction in the cytoplasm. LEDGF dominant interference and depletion impair HIV-1 integration at distinct postentry stages. GFP-IBD may trigger premature or improper integrase oligomerization.