Stereotactic Body Radiation Therapy for Reirradiation of Localized Adenocarcinoma of the Pancreas

AbstractBackgroundLocal control rates are poor in the treatment of pancreatic cancer. We investigated the role of hypofractionated stereotactic body radiation therapy (SBRT) for salvage or boost treatment after conventional doses of external beam radiation therapy.MethodsAll patients treated with SBRT for pancreatic adenocarcinoma at Georgetown University from June 2002 through July 2007 were examined. Eligible patients had prior external beam radiation therapy to the pancreas. Treatment parameters and clinical and radiographic follow-up were evaluated.ResultsTwenty-eight patients were identified who received SBRT after a median prior external beam radiotherapy dose of 50.4 Gy. The median patient age was 63 years old and the median follow-up was 5.9 months. Twelve of fourteen (85.7%) evaluable patients were free from local progression, with three partial responses and nine patients with stable disease. Toxicity consisted of one case of acute Grade II nausea/vomiting, and two cases of Grade III late GI toxicity. The median overall survival was 5.9 months, with 18% survival and 70% freedom from local progression at one year.ConclusionsHypofractionated SBRT reirradiation of localized pancreatic cancer is a well-tolerated treatment. Most patients are free from local progression, albeit with limited follow-up, but overall survival remains poor.Peer Reviewe

Immunotherapy and radiation therapy for gastrointestinal malignancies: Hope or hype?

Immunotherapy represents the newest pillar in cancer care. Although there are increasing data showing the efficacy of immunotherapy there is a spectrum of response across unselected populations of cancer patients. In fact, response rates can be poor even among patients with immunogenic tumors for reasons that remain poorly understood. A promising clinical strategy to improve outcomes, which is supported by an abundance of preclinical data, is combining immunotherapy with radiation therapy. Here we review the existing evidence and future directions for combining immunotherapy and radiation therapy for patients with gastrointestinal cancers

Prevalence, incidence, and clearance of human papillomavirus types covered by current vaccines in men with human immunodeficiency virus in the SUN Study

BACKGROUND: High-risk anal human papillomavirus (HPV) infection is prevalent among men living with human immunodeficiency virus (HIV); the association between 9-valent (9v) high-risk HPV (HR-HPV) vaccine types and abnormal cytology has not been well characterized. METHODS: We followed a prospective cohort study of persons with HIV at 7 HIV clinics in 4 US cities from March 2004 through June 2012. Annually, providers collected separate anal swabs for HPV detection and cytopathologic examination. Among men, we examined prevalence, incidence, and clearance of 9v HR-HPV vaccine types, compared with other HR types, and associations with abnormal cytology to assess potential vaccine impact. RESULTS: Baseline prevalence of any anal 9v HR-HPV type among men who have sex with men (MSM) and men who have sex with women (MSW) was 74% and 25% (P \u3c .001), respectively. Among 299 MSM, abnormal cytology was detected in 161 (54%) MSM and was associated with the presence of any 9v HR-HPV (relative risk [RR], 1.8 [95% confidence interval {CI}, 1.3-2.6]; P \u3c .001). Among 61 MSW, abnormal anal cytology was detected in 12 (20%) and was associated with the presence of any 9v HR-HPV (RR, 4.3 [95% CI, 1.6-11.5]; P \u3c .001). CONCLUSIONS: Among men with HIV, the prevalence of the 7 HR-HPV types in the 9v vaccine was high and was associated with abnormal cytology. These findings indicate that men with HIV could benefit from prophylactic administration of the 9v HPV vaccine

Yttrium-90 Radioembolization in Patients with Hepatocellular Carcinoma Who have Previously Received Sorafenib

Purpose: Yttrium-90 radioembolization (RE) is a locoregional therapy option for hepatocellular carcinoma (HCC). Sorafenib is a multikinase inhibitor used in HCC that can potentially affect the efficacy of RE by altering tumor vascularity or suppressing post-irradiation angiogenesis. The safety and efficacy of sorafenib followed by RE has not been previously reported. Materials and Methods: Patients with HCC who received RE after sorafenib were included in this retrospective review. Overall survival, toxicity, and maximal radiographic response and necrosis criteria were examined. Results: Ten patients (15 RE administrations) fit the inclusion criteria. All were Barcelona Clinic Liver Cancer (BCLC) stage C. Median follow-up was 16.5 weeks. Median overall survival and radiographic progression-free survival were 30 and 28 weeks, respectively. Significant differences in overall survival were seen based on Child-Pugh class (p = 0.002) and radiographic response (p = 0.009). Three patients had partial response, six had stable disease, and one had progressive disease. Grade 1 or 2 acute fatigue, anorexia, and abdominal pain were common. Three patients had Grade 3 ascites in the setting of disease progression. Two patients had Grade 3 biochemical toxicity. One patient was sufficiently downstaged following RE and sorafenib to receive a partial hepatectomy. Conclusion: Yttrium-90 RE in patients with HCC who have received sorafenib demonstrate acceptable toxicity and rates of radiographic response. However, the overall survival is lower than that reported in the literature on RE alone or sorafenib alone. This may be due in part to more patients in this study having advanced disease compared to these other study populations. Larger prospective studies are needed to determine whether the combination of RE and sorafenib is superior to either therapy alone

Prevalence, incidence, and clearance of anal high-risk human papillomavirus infection among HIV-infected men in the SUN study

BACKGROUND: The natural history of anal human papilloma virus (HPV) infection among human immunodeficiency virus (HIV)-infected men is unknown. METHODS: Annually, from 2004 to 2012, we examined baseline prevalence, incidence, and clearance of anal HPV infection at 48 months, and associated factors among HIV-infected men. RESULTS: We examined 403 men who have sex with men (MSM) and 96 men who have sex with women (MSW) (median age 42 years for both, 78% versus 81% prescribed cART, median CD4+ T-lymphocyte cell count 454 versus 379 cells/mm3, and 74% versus 75% had undetectable viral load, respectively). Type 16 prevalence among MSM and MSW was 38% versus 14% (P \u3c .001), and incidence 24% versus 7% (P = .001). Type 18 prevalence was 24% versus 8% (P \u3c .001), and incidence 13% versus 4% (P = .027). Among MSM and MSW, clearance of prevalent HPV 16 and HPV 18 was 31% and 60% (P = .392), and 47% and 25% (P = .297), respectively. Among MSM, receptive anal sex (with or without a condom) was associated with persistent HPV 16 (OR 2.24, P \u3c .001). CONCLUSIONS: MSM had higher prevalence and incidence of HPV than MSW, but similar clearance. Receptive anal sex may predict cancer risk among HIV-infected MSM

Metabolomic biomarkers of pancreatic cancer: a meta-analysis study

Pancreatic cancer (PC) is an aggressive disease with high mortality rates, however, there is no blood test for early detection and diagnosis of this disease. Several research groups have reported on metabolomics based clinical investigations to identify biomarkers of PC, however there is a lack of a centralized metabolite biomarker repository that can be used for meta-analysis and biomarker validation. Furthermore, since the incidence of PC is associated with metabolic syndrome and Type 2 diabetes mellitus (T2DM), there is a need to uncouple these common metabolic dysregulations that may otherwise diminish the clinical utility of metabolomic biosignatures. Here, we attempted to externally replicate proposed metabolite biomarkers of PC reported by several other groups in an independent group of PC subjects. Our study design included a T2DM cohort that was used as a non-cancer control and a separate cohort diagnosed with colorectal cancer (CRC), as a cancer disease control to eliminate possible generic biomarkers of cancer. We used targeted mass spectrometry for quantitation of literature-curated metabolite markers and identified a biomarker panel that discriminates between normal controls (NC) and PC patients with high accuracy. Further evaluation of our model with CRC, however, showed a drop in specificity for the PC biomarker panel. Taken together, our study underscores the need for a more robust study design for cancer biomarker studies so as to maximize the translational value and clinical implementation.This work was supported by ACS IRG-92-152-17 pilot award number AWD4470404 to KU and AKC. The authors would like to acknowledge the Metabolomics Shared Resource in Georgetown University (Washington DC, USA) partially supported by NIH/NCI/CCSG grant P30-CA05100

High resolution array-CGH analysis of single cells

Heterogeneity in the genome copy number of tissues is of particular importance in solid tumor biology. Furthermore, many clinical applications such as pre-implantation and non-invasive prenatal diagnosis would benefit from the ability to characterize individual single cells. As the amount of DNA from single cells is so small, several PCR protocols have been developed in an attempt to achieve unbiased amplification. Many of these approaches are suitable for subsequent cytogenetic analyses using conventional methodologies such as comparative genomic hybridization (CGH) to metaphase spreads. However, attempts to harness array-CGH for single-cell analysis to provide improved resolution have been disappointing. Here we describe a strategy that combines single-cell amplification using GenomePlex library technology (GenomePlex(®) Single Cell Whole Genome Amplification Kit, Sigma-Aldrich, UK) and detailed analysis of genomic copy number changes by high-resolution array-CGH. We show that single copy changes as small as 8.3 Mb in single cells are detected reliably with single cells derived from various tumor cell lines as well as patients presenting with trisomy 21 and Prader–Willi syndrome. Our results demonstrate the potential of this technology for studies of tumor biology and for clinical diagnostics

Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease

BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non - vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger se - quencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFR P4 , the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4 , like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treat - ment of Sfrp4- deficient mice with a soluble Bmp2 receptor (RAP-661) or with anti - bodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical- bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss Na - tional Foundation and the National Institutes of Health.

Rapid “Open-Source” Engineering of Customized Zinc-Finger Nucleases for Highly Efficient Gene Modification

Summary—Custom-made zinc-finger nucleases (ZFNs) can induce targeted genome modifications with high efficiency in cell types including Drosophila, C. elegans, plants, and humans. A bottleneck in the application of ZFN technology has been the generation of highly specific engineered zincfinger arrays. Here we describe OPEN (Oligomerized Pool ENgineering), a rapid, publicly available strategy for constructing multi-finger arrays, which we show is more effective than the previously published modular assembly method. We used OPEN to construct 37 highly active ZFN pairs which induced targeted alterations with high efficiencies (1 to 50%) at 11 different target sites located within three endogenous human genes (VEGF-A, HoxB13, CFTR), an endogenous plant gene (tobacco SuRA), and a chromosomally-integrated EGFP reporter gene. In summary, OPEN provides an “opensource” method for rapidly engineering highly active zinc-finger arrays, thereby enabling broader practice, development, and application of ZFN technology for biological research and gene therapy

Gastric Adenocarcinoma: A Multimodal Approach

Despite its declining incidence, gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. A multimodal approach to GC is critical to ensure optimal patient outcomes. Pretherapy fine resolution contrast-enhanced cross-sectional imaging, endoscopic ultrasound and staging laparoscopy play an important role in patients with newly diagnosed ostensibly operable GC to avoid unnecessary non-therapeutic laparotomies. Currently, margin negative gastrectomy and adequate lymphadenectomy performed at high volume hospitals remain the backbone of GC treatment. Importantly, adequate GC surgery should be integrated in the setting of a multimodal treatment approach. Treatment for advanced GC continues to expand with the emergence of additional lines of systemic and targeted therapies