An assessment of perioperative outcomes for open, laparoscopic, and robot-assisted pancreaticoduodenectomy in New York State.

BACKGROUND: Minimally invasive techniques for pancreaticoduodenectomy (PD) are increasing in practice, however, data remains limited regarding perioperative outcomes. Our study sought to compare patients undergoing open pancreaticoduodenectomy (OPD) with those undergoing laparoscopic (LPD) or robot-assisted pancreaticoduodenectomy (RPD). METHODS: Patients who underwent PD during 2016-2018 were identified from the New York State Planning and Research Cooperative System database. RESULTS: Of the 1954 patients identified, 1708 (87.4%) underwent OPD, 165 (8.4%) underwent LPD, and 81 (4.2%) underwent RPD. The majority of patients were White (63.8%), males (53.3%) with a mean age of 65.4 years. RPD patients had a lower median Charlson Comorbidity Index (2) than OPD (3) or LPD (3, p = 0.01) and had a lower 30-day rate of complications (35.8% vs. 48.3% vs. 43.6% respectively, p = 0.05). After propensity-score matching, however, there were no differences between the groups regarding overall complications, surgical site infections, anastomotic leaks, or mortality (p = NS for all). OPD demonstrated a longer length of stay (median 8 days) compared to LPD (7 days) or RPD (7 days, p < 0.01). CONCLUSIONS: Patients undergoing LPD and RPD have a shorter length of hospital stay compared to OPD and there was no difference in overall morbidity or mortality when matched to similar patients.

Implications of Hyperthermic Intraperitoneal Chemotherapy Perfusion-Related Hyperglycemia.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) administration can be associated with hyperglycemia during perfusion. Little is known about this effect, and no previous studies have examined patient characteristics associated with perfusion-related hyperglycemia. METHODS: We retrospectively identified consecutive patients at a single institution treated with HIPEC from 8/2003 to 10/2016 who had intraoperative blood glucose measured. Hypertonic 1.5% dextrose-containing peritoneal dialysate was used as carrier solution in all patients. Comparisons were made using parametric [Student's t test, analysis of variance (ANOVA)], and nonparametric tests (χ 2, Kruskal-Wallis) where appropriate. RESULTS: There were 85 patients identified, with average age of 53 ± 12 years, 69 (81%) with appendiceal or colorectal peritoneal cancer. Most patients were perfused with mitomycin C (69%) or oxaliplatin (24%). Intraoperative hyperglycemia (> 180 mg/dL) affected the majority of patients (86%), with values up to 651 mg/dL. Insulin was required for treatment in 66% of patients. Peak hyperglycemia occurred within an hour of perfusion in 91%, and resolved by postoperative day one in 91% of patients. Glucose > 309 mg/dL (highest quartile) was associated with longer operating time (p = 0.03) and with use of oxaliplatin compared with mitomycin C (p = 0.01). No association was found with other comorbidities, peritoneal carcinomatosis index score, or postoperative outcomes. CONCLUSIONS: Most patients experience hyperglycemia during HIPEC. This is not clearly associated with patient factors, and may be due to use of dextrose-containing carrier solution. Since perioperative hyperglycemia has potential negative impact, use of dextrose-containing carrier solution should be questioned and is worth investigating further.

Laparoscopic pancreaticoduodenectomy: changing the management of ampullary neoplasms.

BACKGROUND: The purpose of this study is to present the largest reported series comparing open pancreaticoduodenectomy (OPD) to total laparoscopic pancreaticoduodenectomy (TLPD) in patients with ampullary neoplasms. METHODS: Patients undergoing OPD or TLPD for ampullary neoplasms from June 2012 to August 2016 were retrospectively identified. Perioperative outcomes were compared using a Wilcoxon rank-sum test, Student's t test, and Chi square analysis where appropriate. Kaplan-Meier estimates for progression-free survival (PFS) and overall survival (OS) were compared between the groups using the log-rank test. RESULTS: We identified 47 patients with ampullary neoplasms (adenocarcinoma n = 36, neuroendocrine tumor n = 7, undifferentiated n = 1, adenoma n = 3) undergoing OPD (n = 25) and TLPD (n = 22). The proportion of patients being offered TLPD has progressively increased every year over 5 years: 0% (2012) to 50% (2015). There were no differences in baseline variables between the two groups. TLPD was associated with less blood loss (300 vs. 500 mL, p < 0.001) and shorter operative times (314 vs. 359 min, p = 0.024). No patient required conversion to an open procedure and there were no perioperative deaths in either group. TLPD was associated with lower rates of intra-abdominal abscess (0 vs. 16.0%, p = 0.049), but there were no differences in rates of pancreatic fistula, bile leak, delayed gastric emptying, wound infection, length of stay, and readmission (all p > 0.05). Among patients with adenocarcinoma, there was no difference in pathological features between the two groups (p > 0.05) and all patients had negative margins. At a median follow up of 25 months, there was no difference in PFS or OS between the two groups. CONCLUSIONS: TLPD in patients with ampullary neoplasms results in improved perioperative outcomes while having equivalent short and long-term oncologic outcomes compared to the traditional open approach.

SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway.

BACKGROUND: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. METHODS: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. RESULTS: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E-11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. CONCLUSION: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR).

INTRODUCTION: A common feature of neoplastic cells is that mutations in SMADs can contribute to the loss of sensitivity to the anti-tumor effects of transforming growth factor-ß (TGF-ß). However, germline mutation analysis of SMAD3 and SMAD4, the principle substrates of the TGF-ß signaling pathway, has not yet been conducted in breast cancer. Thus, it is currently unknown whether germline SMAD3 and SMAD4 mutations are involved in breast cancer predisposition. METHODS: We performed mutation analysis of the highly conserved mad-homology 2 (MH2) domains for both genes in genomic DNA from 408 non-BRCA1/BRCA2 breast cancer cases and 710 population controls recruited by the Ontario site of the breast cancer family registry (CFR) using denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing. The results were interpreted in several ways. First, we adapted nucleotide diversity analysis to quantitatively assess whether the frequency of alterations differ between the two genes. Next, in silico tools were used to predict variants' effect on domain function and mRNA splicing. Finally, 37 cases or controls harboring alterations were tested for aberrant splicing using reverse-transcription polymerase chain reaction (PCR) and real-time PCR statistical comparison of germline expressions by non-parametric Mann-Whitney test of independent samples. RESULTS: We identified 27 variants including 2 novel SMAD4 coding variants c.1350G > A (p.Gln450Gln), and c.1701A > G (p.Ile525Val). There were no inactivating mutations even though c.1350G > A was predicted to affect exonic splicing enhancers. However, several additional findings were of note: 1) nucleotide diversity estimate for SMAD3 but not SMAD4 indicated that coding variants of the MH2 domain were more infrequent than expected; 2) in breast cancer cases SMAD3 was significantly over-expressed relative to controls (P < 0.05) while the case harboring SMAD4 c.1350G > A was associated with elevated germline expression (> 5-fold); 3) separate analysis using tissue expression data showed statistically significant over-expression of SMAD3 and SMAD4 in breast carcinomas. CONCLUSIONS: This study shows that inactivating germline alterations in SMAD3 and SMAD4 are rare, suggesting a limited role in driving tumorigenesis. Nevertheless, aberrant germline expressions of SMAD3 and SMAD4 may be more common in breast cancer than previously suspected and offer novel insight into their roles in predisposition and/or progression of breast cancer.

Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine.

Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome-based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the genetic and drug response data of the NCI60 cell lines to discover potential candidate genetic variants associated with variable response to chemotherapy. As an example we have applied this strategy to discover single genetic markers and haplotypes from candidate genes previously implicated in the pharmacobiology of gemcitabine. Single-marker association analyses have implicated the association of four SNPs within the gene loci of CDC5L, EPC2, POLS, and PARP1. We have also investigated the combined effect of SNPs using haplotype-based analysis. Accordingly, we have shown modest association of haplotypes in six genes, whereas the most significant associations included a haplotype of the POLS gene. The hypothesis-generating tool presented in this study can be applied to drugs profiled in the NCI60 cell line screen and provides an effective means for the identification of genes associated with drug response. The results obtained using this novel methodology can be used to better design the clinical trials for effective study of the chemotherapeutic agents and thus provide a basis for individualized chemotherapy.

Second primary malignancy risk in thyroid cancer survivors: a systematic review and meta-analysis.

OBJECTIVE: To determine the risk of second primary malignancies (SPMs) in thyroid cancer survivors. DESIGN: We performed a systematic review and meta-analysis examining the standardized incidence ratios (SIRs) of SPMs in thyroid cancer survivors (compared to individuals without thyroid cancer). Two independent reviewers screened citations and reviewed all full-text papers deemed potentially relevant. Final consensus was reached on inclusion of papers in the review. Data were pooled using fixed effects models. MAIN OUTCOMES: Thirteen full-text papers were included. The incidence of SPMs in thyroid cancer survivors was increased with an SIR of 1.20 (95% confidence interval 1.17, 1.24) (based on pooled data from six studies of 70,844 thyroid cancer survivors). The SIR of the following SPMs was significantly increased: salivary gland, stomach, colon/colorectal, breast, prostate, kidney, brain/central nervous system, soft tissue sarcoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, bone/joints, and adrenal. A significantly reduced risk of lung and cervical cancers was observed. CONCLUSIONS: Thyroid cancer survivors are at increased risk of SPMs, which may be related to disease-specific treatments or genetic predisposition.

Overuse of helicopter transport in the minimally injured: A health care system problem that should be corrected.

BACKGROUND: Mortality benefit has been demonstrated for trauma patients transported via helicopter but at great cost. This study identified patients who did not benefit from helicopter transport to our facility and demonstrates potential cost savings when transported instead by ground. METHODS: We performed a 6-year (2007-2013) retrospective analysis of all trauma patients presenting to our center. Patients with a known mode of transfer were included in the study. Patients with missing data and those who were dead on arrival were excluded from the study. Patients were then dichotomized into helicopter transfer and ground transfer groups. A subanalysis was performed between minimally injured patients (ISS < 5) in both the groups after propensity score matching for demographics, injury severity parameters, and admission vital parameters. Groups were then compared for hospital and emergency department length of stay, early discharge, and mortality. RESULTS: Of 5,202 transferred patients, 18.9% (981) were transferred via helicopter and 76.7% (3,992) were transferred via ground transport. Helicopter-transferred patients had longer hospital (p = 0.001) and intensive care unit (p = 0.001) stays. There was no difference in mortality between the groups (p = 0.6).On subanalysis of minimally injured patients there was no difference in hospital length of stay (p = 0.1) and early discharge (p = 0.6) between the helicopter transfer and ground transfer group. Average helicopter transfer cost at our center was $18,000, totaling $4,860,000 for 270 minimally injured helicopter-transferred patients. CONCLUSION: Nearly one third of patients transported by helicopter were minimally injured. Policies to identify patients who do not benefit from helicopter transport should be developed. Significant reduction in transport cost can be made by judicious selection of patients. Education to physicians calling for transport and identification of alternate means of transportation would be both safe and financially beneficial to our system. LEVEL OF EVIDENCE: Epidemiologic study, level III. Therapeutic study, level IV.

A multi-institutional analysis of prehospital tourniquet use.

BACKGROUND: Recent military studies demonstrated an association between prehospital tourniquet use and increased survival. The benefits of this prehospital intervention in a civilian population remain unclear. The aims of our study were to evaluate tourniquet use in the civilian population and to compare outcomes to previously published military experience. We hypothesized that incorporation of tourniquet use in the civilian population will result in an overall improvement in mortality. METHODS: This is a preliminary multi-institutional retrospective analysis of prehospital tourniquet (MIA-T) use of patients admitted to nine urban Level 1 trauma centers from January 2010 to December 2013. Patient demographics and mortality from a previous military experience by Kragh et al. (Ann Surg. 2009;249:1-7) were used for comparison. Patients younger than 18 years or with nontraumatic bleeding requiring tourniquet application were excluded. Data were analyzed using a two-tailed unpaired Student's t test with p < 0.05 as significant. RESULTS: A total of 197 patients were included. Tourniquets were applied effectively in 175 (88.8%) of 197 patients. The average Injury Severity Score (ISS) for MIA-T versus military was 11 ± 12.5 versus 14 ± 10.5, respectively (p = 0.02). The overall mortality and limb amputation rates for the MIA-T group were significantly lower than previously seen in the military population at 6 (3.0%) of 197 versus 22 (11.3%) of 194 (p = 0.002) and 37 (18.8%) of 197 versus 97 (41.8%) of 232 (p = 0.0001), respectively. CONCLUSION: Our study is the largest evaluation of prehospital tourniquet use in a civilian population to date. We found that tourniquets were applied safely and effectively in the civilian population. Adaptation of this prehospital intervention may convey a survival benefit in the civilian population. LEVEL OF EVIDENCE: Epidemiologic study, level V.

Inhibition of sepsis-induced inflammatory response by ß1-adrenergic antagonists.

BACKGROUND: Although previous studies have described potential benefits of nonselective ß-adrenergic antagonist therapy in sepsis, there is a paucity of data on the use of ß1-selective antagonists (B1AA). The purposes of this study were to describe the effects of B1AA on survival in septic animals and to explore for molecular mechanisms of potential treatment benefit. METHODS: C57BL/6 male mice received intraperitoneal injection of lipopolysaccharide. Continuous infusion of a B1AA (esmolol) or an equal volume of saline (control) was initiated at 4 hours after injection. Kaplan-Meier survival analysis at 120 hours was used to explore for mortality differences. A subgroup of animals was sacrificed for microarray expression analysis. Top candidate genes were validated in vitro and in silico. Expression of our candidate genes in a human microarray database (GSE28750) was explored. RESULTS: B1AA infusion resulted in increased survival (p = 0.001) at 120 hours. Mean survival difference was 23.6 hours (p = 0.002). Hazard ratio for mortality with B1AA is 0.43 (95% confidence interval, 0.26-0.72). Immunologic disease (p = 0.0003-0.036) and cell death/survival (p = 0.0001-0.042) were significantly associated with improved survival in septic mice treated with B1AA. Further analysis of the gene structure revealed that eight genes shared common promoter activating sequence for NFKB and/or BRCA1 motifs. Analysis of a human sepsis database identified the up-regulation of CAMP (p = 0.032) and TNFSF10 (p = 0.001) genes in septic patients compared with healthy controls. CONCLUSION: Continuous infusion of a B1AA initiated after septic insult improves survival at 5 days in a murine model. Benefits may be caused by modulation of gene expression in immunologic pathways leading to an increase in CAMP and TNFSF10 expression. This observed effect may be explained by the activation of NFKB and BRCA1 genes involved in immune response and cell repair pathways. Our findings support further investigation of the use of B1AA in the treatment of sepsis.

Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis.

BACKGROUND: The rate of mortality and factors predicting worst outcomes in the geriatric population presenting with trauma are not well established. This study aimed to examine mortality rates in severe and extremely severe injured individuals 65 years or older and to identify the predictors of mortality based on available evidence in the literature. METHODS: We performed a systematic literature search on studies reporting mortality and severity of injury in geriatric trauma patients using MEDLINE, PubMed, and Web of Science. RESULTS: An overall mortality rate of 14.8% (95% confidence interval [CI], 9.8-21.7%) in geriatric trauma patients was observed. Increasing age and severity of injury were found to be associated with higher mortality rates in this patient population. Combined odds of dying in those older than 74 years was 1.67 (95% CI, 1.34-2.08) compared with the elderly population aged 65 years to 74 years. However, the odds of dying in patients 85 years and older compared with those of 75 years to 84 years was not different (odds ratio, 1.23; 95% CI, 0.99-1.52). A pooled mortality rate of 26.5% (95% CI, 23.4-29.8%) was observed in the severely injured (Injury Severity Score [ISS] ≥ 16) geriatric trauma patients. Compared with those with mild or moderate injury, the odds of mortality in severe and extremely severe injuries were 9.5 (95% CI, 6.3-14.5) and 52.3 (95% CI, 32.0-85.5; p ≤ 0.0001), respectively. Low systolic blood pressure had a pooled odds of 2.16 (95% CI, 1.59-2.94) for mortality. CONCLUSION: Overall mortality rate among the geriatric population presenting with trauma is higher than among the adult trauma population. Patients older than 74 years experiencing traumatic injuries are at a higher risk for mortality than the younger geriatric group. However, the trauma-related mortality sustains the same rate after the age of 74 years without any further increase. Moreover, severe and extremely severe injuries and low systolic blood pressure at the presentation among geriatric trauma patients are significant risk factors for mortality. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level IV.

Preoperative axillary ultrasound in breast cancer: safely avoiding frozen section of sentinel lymph nodes in breast-conserving surgery.

BACKGROUND: The American College of Surgeons Oncology Group Z0011 trial results provided convincing evidence that completion axillary lymph node dissection (CALND) was unnecessary in selected patients with 1 to 2 positive sentinel lymph nodes (SLNs). We hypothesized that preoperative axillary ultrasound (AUS) with fine-needle aspiration is sufficiently sensitive to detect worrisome macrometastasis to preclude the need for frozen-section pathology of SLNs. STUDY DESIGN: We conducted a retrospective single-institution study at a tertiary academic referral center. A total of 1,140 T1 to 2 breast cancer patients who underwent SLN biopsy with or without CALND from January 1, 2007 to December 31, 2010 were reviewed. All patients had negative preoperative AUS with or without fine-needle aspiration. RESULTS: One hundred forty-four (13%) patients were node positive at surgery. Mean age, tumor size, histology, and estrogen receptor and progesterone receptor status were similar comparing 996 SLN-negative with 144 (13%) SLN-positive patients. Of the SLN-positive patients, 25% were premenopausal, 9% were estrogen receptor-negative, and 19% had additional lymph nodes at CALND. Only 19 (2%) patients had SLN metastasis ≥6 mm, 10 (1%) had metastasis >7 mm, and only 1 patient had ≥3 positive SLNs. CONCLUSIONS: The addition of preoperative AUS with or without fine-needle aspiration to management of patients who meet American College of Surgeons Oncology Group Z0011 trial eligibility criteria reduced the risk of macrometastasis measuring ≥6 mm to only 2%; very few of these patients would be premenopausal, have estrogen receptor-negative tumors, or ≥3 positive SLNs. With the addition of AUS with or without fine-needle aspiration, we endorse the conclusions of the American College of Surgeons Oncology Group Z0011 trial to avoid CALND, and see marginal gain in frozen-section analysis of SLNs.

Mild and moderate pediatric traumatic brain injury: replace routine repeat head computed tomography with neurologic examination.

BACKGROUND: Opinion is divided on the role of routine repeat head computed tomography (RHCT) for guiding clinical management in pediatric patients with blunt head trauma. We hypothesize that routine RHCT does not lead to change in management in mild and moderate traumatic brain injury (TBI). METHODS: This is a 3-year retrospective study of all patients of age 2 years to 18 years with blunt TBI admitted to our Level 1 trauma center with an abnormal head CT. Indications for RHCT (routine vs. neurologic deterioration) and their findings (progression or improvement) were recorded. Neurosurgical intervention was defined as extraventricular drain placement, craniectomy, or craniotomy. Primary outcome was a change in management after RHCT. RESULTS: A total of 291 pediatric patients were identified; of which 191 patients received an RHCT. Routine RHCT did not lead to neurosurgical intervention in the mild and moderate TBI group. In patients who received RHCT due to neurologic decline (n = 7), radiographic progression was seen on 85% of the patients (n = 6), with subsequent neurosurgical interventions in three patients. Two of these patients had a Glasgow Coma Scale (GCS) score of less than 8 at admission. CONCLUSION: Our study showed that the neurologic examination can be trusted and is reliable in pediatric blunt TBI patients in determining when an RHCT scan is necessary. We recommend that RHCT is required routinely in patients with intracranial hemorrhage with GCS score of 8 or less and in patients with GCS greater than 8 and that RHCT be performed only when there are clinical indications. LEVEL OF EVIDENCE: Diagnostic/therapeutic study, level IV.

Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines.

BACKGROUND: Paclitaxel is a microtubule-stabilizing drug that has been commonly used in treating cancer. Due to genetic heterogeneity within patient populations, therapeutic response rates often vary. Here we used the NCI60 panel to identify SNPs associated with paclitaxel sensitivity. Using the panel's GI50 response data available from Developmental Therapeutics Program, cell lines were categorized as either sensitive or resistant. PLINK software was used to perform a genome-wide association analysis of the cellular response to paclitaxel with the panel's SNP-genotype data on the Affymetrix 125 k SNP array. FastSNP software helped predict each SNP's potential impact on their gene product. mRNA expression differences between sensitive and resistant cell lines was examined using data from BioGPS. Using Haploview software, we investigated for haplotypes that were more strongly associated with the cellular response to paclitaxel. Ingenuity Pathway Analysis software helped us understand how our identified genes may alter the cellular response to paclitaxel. RESULTS: 43 SNPs were found significantly associated (FDR<0.005) with paclitaxel response, with 10 belonging to protein-coding genes (CFTR, ROBO1, PTPRD, BTBD12, DCT, SNTG1, SGCD, LPHN2, GRIK1, ZNF607). SNPs in GRIK1, DCT, SGCD and CFTR were predicted to be intronic enhancers, altering gene expression, while SNPs in ZNF607 and BTBD12 cause conservative missense mutations. mRNA expression analysis supported these findings as GRIK1, DCT, SNTG1, SGCD and CFTR showed significantly (p<0.05) increased expression among sensitive cell lines. Haplotypes found in GRIK1, SGCD, ROBO1, LPHN2, and PTPRD were more strongly associated with response than their individual SNPs. CONCLUSIONS: Our study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel.

NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells.

Simvastatin and lovastatin are statins traditionally used for lowering serum cholesterol levels. However, there exists evidence indicating their potential chemotherapeutic characteristics in cancer. In this study, we used bioinformatic analysis of publicly available data in order to systematically identify the genes involved in resistance to cytotoxic effects of these two drugs in the NCI60 cell line panel. We used the pharmacological data available for all the NCI60 cell lines to classify simvastatin or lovastatin resistant and sensitive cell lines, respectively. Next, we performed whole-genome single marker case-control association tests for the lovastatin and simvastatin resistant and sensitive cells using their publicly available Affymetrix 125K SNP genomic data. The results were then evaluated using RNAi methodology. After correction of the p-values for multiple testing using False Discovery Rate, our results identified three genes (NRP1, COL13A1, MRPS31) and six genes (EAF2, ANK2, AKAP7, STEAP2, LPIN2, PARVB) associated with resistance to simvastatin and lovastatin, respectively. Functional validation using RNAi confirmed that silencing of EAF2 expression modulated the response of HCT-116 colon cancer cells to both statins. In summary, we have successfully utilized the publicly available data on the NCI60 cell lines to perform whole-genome association studies for simvastatin and lovastatin. Our results indicated genes involved in the cellular response to these statins and siRNA studies confirmed the role of the EAF2 in response to these drugs in HCT-116 colon cancer cells.

Dietary iodine restriction in preparation for radioactive iodine treatment or scanning in well-differentiated thyroid cancer: a systematic review.

BACKGROUND: Dietary iodine is often restricted before radioactive iodine (RAI) scanning or treatment of well-differentiated thyroid cancer. Our objective was to examine the impact of a low-iodine diet (LID) before RAI treatment or scanning on the following outcomes: (i) the efficacy of thyroid remnant ablation (or residual disease elimination), (ii) urinary iodine measurements, (iii) RAI kinetics, and (iv) long-term thyroid cancer outcomes. METHODS: We performed a systematic review of the English literature. We searched four electronic databases and conducted a hand search. Two reviewers independently screened citations and reviewed full-text articles and reached consensus on included articles. Two reviewers independently abstracted data. RESULTS: We reviewed 76 abstracts or citations and 26 full-text articles. Eight studies were included in the review. The most commonly studied diets allowed ≤ 50 µg/day of iodine for 1-2 weeks. In one study, 6-month successful remnant ablation rates were higher in patients following an LID than in controls. However, in another study, there was no significant benefit of an LID. LIDs reduce urinary iodine measurements and appear to increase I-131 uptake or lesional radiation compared to regular diets. No studies have examined long-term recurrence or mortality rates. CONCLUSIONS: Given that LIDs reduce urinary iodine measurements, increase I-131 uptake, and possibly improve efficacy of I-131 treatment, we currently favor the use of a 1-2-week LID before I-131 therapy or scanning. However, more research is needed to clarify the role of this dietary intervention.