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1.  Angiosarcoma of the Seminal Vesicle: A Case Report of Long-Term Survival Following Multimodality Therapy 
Rare Tumors  2014;6(1):5202.
Angiosarcoma of the seminal vesicle is an extremely rare malignancy, with few published case reports in the literature. We present a case of primary angiosarcoma of the seminal vesicle in a 45-year-old male who was treated with multimodality therapy, consisting of neoadjuvant chemotherapy and chemoradiation followed by surgical resection and intraoperative radiation therapy. He has been free of cancer recurrence for more than six years after completion of therapy. To our knowledge, this represents the longest reported survival of a patient with this rare tumor, and one of the few cases reported using a multimodality therapy approach.
doi:10.4081/rt.2014.5202
PMCID: PMC3977171
angiosarcoma; seminal vesicle; prostate; neoadjuvant; surgery; chemoradiation; trimodality therapy
2.  Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism 
Summary
Background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia.
Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation.
Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease.
Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.
Learning points
HH is a cause of severe hypoglycaemia in the newborn period.Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease. 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions.Gallium-68 tetra-aza-cyclododecane-N N′N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions.The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear.Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.
doi:10.1530/EDM-13-0041
PMCID: PMC3922076  PMID: 24616771
3.  The impact of diphenhydramine and promethazine in patients undergoing advanced upper endoscopic procedures 
Background
Endoscopic retrograde cholangiopancreatography (ERCP ) and endoscopic ultrasound (EUS) procedures are more complex and longer duration than standard endoscopy, requiring deeper levels of sedation. While prior studies have compared standard sedation (meperidine and midazolam) to propofol, no randomized, controlled trials have evaluated the use of adjunct sedatives in these procedures.
Aims
To prospectively compare the use of promethazine and diphenhydramine as adjunct sedatives to standard sedation in patients undergoing advanced endoscopic procedures.
Methods
This was a prospective, randomized, placebo-controlled study in a single, tertiary-care referral center. Promethazine (P), diphenhydramine (B), or normal saline (NS) were given as adjunct sedatives along with meperidine and midazolam in adult patients undergoing upper EUS and/or ERCP procedures. The main outcome measurement was sedation failure.
Results
292 patients (P: 97, B: 93, NS: 102) were randomized over 36 months. No significant differences in sedation failures (P: 8, B: 13, NS: 11, p=0.449) or in the times needed to achieve adequate sedation (P: 11.8 minutes, B: 12.9 minutes, NS: 14.0 minutes, p=0.054) were seen between the groups. Sedation using P (43.7 minutes) was associated with a significantly longer recovery time compared to B (28.0 minutes) or NS (24.5 minutes).
Conclusions
The use of promethazine and diphenhydramine as adjunct sedatives did not improve sedation failure rates or reduce the time needed to achieve sedation in patients undergoing upper EUS or ERCP. Patients with anticipated sedation difficulties should proceed directly to propofol-based sedation.
doi:10.7178/jig.124
PMCID: PMC3896573  PMID: 24498528
promethazine; diphenhydramine; endoscopic retrograde cholangiopancreatography; endoscopic ultrasound; sedation
4.  EUS compared with endoscopy plus transabdominal US in the initial diagnostic evaluation of patients with upper abdominal pain 
Gastrointestinal endoscopy  2010;72(5):967-974.
Background
Primary upper endoscopy (EGD) and transabdominal US (TUS) are often performed in patients with upper abdominal pain.
Objective
Primary: Determine whether the combination of EGD and EUS was equivalent to EGD plus TUS in the diagnostic evaluation of upper abdominal pain. Secondary: Compare EUS versus TUS in detecting abdominal lesions, and compare EGD by using an oblique-viewing echoendoscope versus the standard, forward-viewing endoscope in detecting mucosal lesions.
Design
Prospective, paired design.
Setting
Six academic endoscopy centers.
Patients
This study involved patients with upper abdominal pain referred for endoscopy.
Intervention
All patients had EGD, EUS, and TUS. The EGD was done using both an oblique-viewing echoendoscope and the standard, forward-viewing endoscope (randomized order) by two separate endoscopists in a blinded fashion, followed by EUS. TUS was performed within 4 weeks of EGD/EUS, also in a blinded fashion. Follow-up: telephone interviews and chart reviews.
Main Outcome Measurements
Diagnose possible etiology of upper abdominal pain and detect clinically significant lesions.
Results
A diagnosis of the etiology of upper abdominal pain was made in 66 of 172 patients (38%). The diagnostic rate was 42 of 66 patients (64%) for EGD plus EUS versus 41 of 66 patients (62%) for EGD plus TUS, which was statistically equivalent (McNemar test; P = .27). One hundred ninety-eight lesions were diagnosed with either EUS or TUS. EUS was superior to TUS for visualizing the pancreas (P < .0001) and for diagnosing chronic pancreatitis (P = .03). Two biliary stones were detected only by EUS. Two hundred fifty-one mucosal lesions were similarly diagnosed with EGD with either the standard, forward-viewing endoscope or the oblique-viewing echoendoscope (kappa = 0.48 [95% CI, .43-.54]). EGD with the standard, forward-viewing endoscope was preferred for biopsies.
Limitations
No cost analysis.
Conclusion
The combination of EGD with EUS is equivalent to EGD plus TUS for diagnosing a potential etiology of upper abdominal pain. EUS is superior to TUS for detecting chronic pancreatitis. EGD combined with EUS should be considered in the first-line diagnostic evaluation of patients with upper abdominal pain.
doi:10.1016/j.gie.2010.04.007
PMCID: PMC3775486  PMID: 20650452
5.  Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer 
Carcinogenesis  2012;33(7):1384-1390.
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
doi:10.1093/carcin/bgs151
PMCID: PMC3405651  PMID: 22523087
6.  FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR 
Nature  2011;471(7339):523-526.
Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFRtyrosine kinase inhibitors(TKIs),butthe magnitude of tumour regression is variable and transient1,2. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.
doi:10.1038/nature09870
PMCID: PMC3541675  PMID: 21430781
7.  RNAi in Cultured Mammalian Cells Using Synthetic siRNAs 
Cold Spring Harbor protocols  2012;2012(9):957-961.
RNA interference (RNAi) enables sequence-specific, experimentally induced silencing of almost any gene by tapping into innate regulatory mechanisms that are conserved among virtually all eukaryotes. In a typical RNAi experiment, an artificial silencing trigger directs the RNAi pathway toward a target that it would not normally recognize. This is most often an endogenous protein-coding gene, although some noncoding RNAs can also be silenced effectively. The artificial silencing trigger varies; this protocol uses synthetic small interfering RNAs (siRNAs). Lipofectamine 2000 is used to deliver the siRNAs into HEK293 cells. This lipid reagent has proven to be effective for many different cultured mammalian cell lines.
doi:10.1101/pdb.prot071076
PMCID: PMC3541682  PMID: 22949722
8.  The Rare Cancer Network: achievements from 1993 to 2012. 
Rare Tumors  2012;4(3):e35.
The Rare Cancer Network (RCN), founded in 1993, performs research involving rare tumors that are not common enough to be the focus of prospective study. Over 55 studies have either been completed or are in progress.
The aim of the paper is to present an overview of the 30 studies done through the RCN to date, organized by disease site. Five studies focus on breast pathology, including sarcoma, lymphoma, phyllodes tumor, adenoid cystic carcinoma, and ductal carcinoma in situ in young women. Three studies on prostate cancer address prostatic small cell carcinoma and adenocarcinoma of young and elderly patients. Six studies on head and neck cancers include orbital and intraocular lymphoma, mucosal melanoma, pediatric nasopharyngeal carcinoma, olfactory neuroblastoma, and mucosa-associated lymphoid tissue lymphoma of the salivary glands. There were 4 central nervous system studies on patients with cerebellar glioblastoma multiforme, atypical and malignant meningioma, spinal epidural lymphoma and myxopapillary ependymoma. Outside of these disease sites, there is a wide variety of other studies on tumors ranging from uterine leiomyosarcoma to giant cell tumors of the bone. The studies done by the RCN represent a wide range of rare pathologies that were previously only studied in small series or case reports. With further growth of the RCN and collaboration between members our ability to analyze rare tumors will increase and result in better understanding of their behavior and ultimately help direct research that may improve patient outcomes.
doi:10.4081/rt.2012.e35
PMCID: PMC3475942  PMID: 23087791
oncology; rare; tumors; radiotherapy.
9.  Durability of Radiofrequency Ablation in Barrett’s Esophagus with Dysplasia 
Gastroenterology  2011;141(2):460-468.
Background & Aims
Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett’s esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE.
Methods
We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events.
Results
After 2 years, 101/106 patients had complete eradication of all dysplasia (95%) and 99/106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51/52 (98%) and intestinal metaplasia was eradicated in 51/52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50/54 (93%) and intestinal metaplasia was eradicated in 48/54 (89%). After 3 years, dysplasia was eradicated in 55/56 of subjects (98%) and intestinal metaplasia was eradicated in 51/56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4/119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1/181 pt-yrs (0.55%/pt-yr); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1/73 pt-yrs (1.37%/pt-yr).
Conclusion
In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.
doi:10.1053/j.gastro.2011.04.061
PMCID: PMC3152658  PMID: 21679712
esophagus; cancer; prevention; endoscopic therapy
10.  Modulators of Prostate Cancer Cell Proliferation and Viability Identified by Short-Hairpin RNA Library Screening 
PLoS ONE  2012;7(4):e34414.
There is significant need to identify novel prostate cancer drug targets because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castration-resistant prostate cancer. To functionally identify genes that, when silenced, decrease prostate cancer cell proliferation or induce cell death in combination with antiandrogens, we employed an RNA interference-based short hairpin RNA barcode screen in LNCaP human prostate cancer cells. We identified and validated four candidate genes (AKT1, PSMC1, STRADA, and TTK) that impaired growth when silenced in androgen receptor positive prostate cancer cells and enhanced the antiproliferative effects of antiandrogens. Inhibition of AKT with a pharmacologic inhibitor also induced apoptosis when combined with antiandrogens, consistent with recent evidence for PI3K and AR pathway crosstalk in prostate cancer cells. Recovery of hairpins targeting a known prostate cancer pathway validates the utility of shRNA library screening in prostate cancer as a broad strategy to identify new candidate drug targets.
doi:10.1371/journal.pone.0034414
PMCID: PMC3324507  PMID: 22509301
11.  Recurrent invasive lobular carcinoma presenting as a ruptured breast implant 
Radiology and Oncology  2011;46(1):23-27.
Background
For years, the treatment for invasive lobular carcinoma (ILC) has been mastectomy secondary to the lack of studies investigating the efficacy of breast conservation therapy on patients afflicted with ILC and due to the lack of long-term follow up investigating locoregional recurrence in this patient population. In this article we report the clinical course of a patient diagnosed with ILC.
Case report
We describe the case of a 50-year-old woman with stage IIB (T2N1M0) ER/PR positive right breast ILC who underwent a right modified radical mastectomy, postoperative chemotherapy, a prophylactic left simple mastectomy with bilateral breast reconstruction and tamoxifen. Approximately 12 years later, she presented with a deflated breast implant and recurrent breast cancer with metastatic spread. She received palliative radiotherapy then palliative chemotherapy. Unfortunately, she succumbed to the cancer less than a year after being diagnosed with metastatic disease.
Conclusions
This may be the first case report of a ruptured breast implant presenting at the same time as the diagnosis of recurrent breast cancer.
doi:10.2478/v10019-011-0032-5
PMCID: PMC3423769  PMID: 22933976
breast cancer; invasive lobular carcinoma; breast implant; rupture
12.  Pooled shRNA screen for sensitizers to inhibition of the mitotic regulator polo-like kinase (PLK1) 
Oncotarget  2011;2(12):1254-1264.
RNAi screening holds the promise of systemizing the search for combination therapeutic strategies. Here we performed a pooled shRNA library screen to look for promising targets to inhibit in combination with inhibition of the mitotic regulator polo-like kinase (PLK1). The library contained ~4,500 shRNAs targeting various signaling and cancer-related genes and was screened in four lung cancer cell lines using both high (IC80) and low (IC20) amounts of the PLK1 inhibitor GSK461364. The relative abundance of cells containing individual shRNAs following drug treatment was determined by microarray analysis, using the mock treatment replicates as the normalizing reference. Overall, the inferred influences of individual shRNAs in both high and low drug treatment were remarkably similar in all four cell lines and involved a large percentage of the library. To investigate which functional categories of shRNAs were most prominent in influencing drug response, we used statistical analysis of microarrays (SAM) in combination with a filter for genes that had two or more concordant shRNAs. The most significant functional categories that came out of this analysis included receptor tyrosine kinases and nuclear hormone receptors. Through individual validation experiments, we determined that the two shRNAs from the library targeting the nuclear retinoic acid receptor gene RARA did indeed silence RARA expression and as predicted conferred resistance to GSK461364. This led us to test whether activation of RARA receptor with retinoids could sensitize cells to GSK461364. We found that retinoids did increase the drug sensitivity and enhanced the ability of PLK1 inhibition to induce mitotic arrest and apoptosis. These results suggest that retinoids could be used to enhance the effectiveness of GSK461364 and provide further evidence that RNAi screens can be effective tools to identify combination target strategies.
PMCID: PMC3282082  PMID: 22248814
Polo-like kinase 1; shRNA library screening; retinoids; combination therapy strategies
13.  Functional identification of optimized RNAi triggers using a massively parallel Sensor assay 
Molecular cell  2011;41(6):733-746.
Summary
Short hairpin RNAs (shRNAs) provide powerful experimental tools by enabling stable and regulated gene silencing through programming of endogenous microRNA pathways. Since requirements for efficient shRNA biogenesis and target suppression are largely unknown, many predicted shRNAs fail to efficiently suppress their target. To overcome this barrier, we developed a “Sensor assay” that enables the biological identification of effective shRNAs at large scale. By constructing and evaluating 20,000 RNAi reporters covering every possible target site in 9 mammalian transcripts, we show that our assay reliably identifies potent shRNAs that are surprisingly rare and predominantly missed by existing algorithms. Our unbiased analyses reveal that potent shRNAs share various predicted and previously unknown features associated with specific microRNA processing steps, and suggest a new model for competitive strand selection. Together, our study establishes a powerful tool for large-scale identification of highly potent shRNAs and provides new insights into sequence requirements of effective RNAi.
doi:10.1016/j.molcel.2011.02.008
PMCID: PMC3130540  PMID: 21353615
15.  Profiling Essential Genes in Human Mammary Cells by Multiplex RNAi Screening 
Science (New York, N.Y.)  2008;319(5863):617-620.
By virtue of their accumulated genetic alterations, tumor cells may acquire vulnerabilities that create opportunities for therapeutic intervention. We have devised a massively parallel strategy for screening short hairpin RNA (shRNA) collections for stable loss-of-function phenotypes. We assayed from 6000 to 20,000 shRNAs simultaneously to identify genes important for the proliferation and survival of five cell lines derived from human mammary tissue. Lethal shRNAs common to these cell lines targeted many known cell-cycle regulatory networks. Cell line–specific sensitivities to suppression of protein complexes and biological pathways also emerged, and these could be validated by RNA interference (RNAi) and pharmacologically. These studies establish a practical platform for genome-scale screening of complex phenotypes in mammalian cells and demonstrate that RNAi can be used to expose genotype-specific sensitivities.
doi:10.1126/science.1149185
PMCID: PMC2981861  PMID: 18239125
16.  Cancer Proliferation Gene Discovery Through Functional Genomics 
Science (New York, N.Y.)  2008;319(5863):620-624.
Retroviral short hairpin RNA (shRNA)–mediated genetic screens in mammalian cells are powerful tools for discovering loss-of-function phenotypes. We describe a highly parallel multiplex methodology for screening large pools of shRNAs using half-hairpin barcodes for microarray deconvolution. We carried out dropout screens for shRNAs that affect cell proliferation and viability in cancer cells and normal cells. We identified many shRNAs to be antiproliferative that target core cellular processes, such as the cell cycle and protein translation, in all cells examined. Moreover, we identified genes that are selectively required for proliferation and survival in different cell lines. Our platform enables rapid and cost-effective genome-wide screens to identify cancer proliferation and survival genes for target discovery. Such efforts are complementary to the Cancer Genome Atlas and provide an alternative functional view of cancer cells.
doi:10.1126/science.1149200
PMCID: PMC2981870  PMID: 18239126
17.  Diabetes mellitus as a risk factor for gastrointestinal cancer among American veterans 
AIM: To assess the risk of biliary and pancreatic cancers in a large cohort of patients with type 2 diabetes mellitus (DM).
METHODS: Eligibility for this study included patients with type 2 DM (ICD-9 code 250.0) who were discharged from Department of Veteran Affairs hospitals between 1990 and 2000. Non-matched control patients without DM were selected from the same patient treatment files during the same period. Demographic information included age, sex and race. Secondary diagnoses included known risk factors based on their ICD-9 codes. By multivariate logistic regression, the occurrence of biliary and pancreatic cancer was compared between case subjects with DM and controls without DM.
RESULTS: A total of 1 172 496 case and control subjects were analyzed. The mean age for study and control subjects was 65.8 ± 11.3 and 64.8 ± 12.6 years, respectively. The frequency of pancreatic cancer in subjects with DM was increased (0.9%) in comparison to control subjects (0.3%) with an OR of 3.22 (95% CI: 3.03-3.42). The incidence of gallbladder and extrahepatic biliary cancers was increased by twofold in diabetic patients when compared to controls. The OR and 95% CI were 2.20 (1.56-3.00) and 2.10 (1.61-2.53), respectively.
CONCLUSION: Our study demonstrated that patients with DM have a threefold increased risk for developing pancreatic cancer and a twofold risk for developing biliary cancer.
doi:10.3748/wjg.15.5274
PMCID: PMC2776853  PMID: 19908334
Diabetes mellitus; Pancreatic neoplasms; Adenocarcinoma; Gallbladder neoplasms

Results 1-17 (17)