John Schoeneman Vorhies

All Publications

• The Utility of Intraoperative Arthrogram in the Management of Pediatric Lateral Condyle Fractures of the Humerus ORTHOPEDICS Vorhies, J., Funk, S., Elliott, M., Riccio, A., Ramo, B. 2020; 43 (1): 30–35

  Abstract

  Intraoperative arthrograms are commonly used in conjunction with closed reduction and percutaneous pinning (CRPP) of pediatric lateral condyle fractures of the humerus. The authors sought to determine how arthrograms affect management of these fractures. They reviewed all lateral condyle fractures treated surgically at a pediatric level I trauma center from 2008 to 2014. They stratified patients managed with and without an arthrogram as well as by timing of arthrogram. The authors compared injury parameters, initial and postoperative fracture displacement, and complications between groups. They identified 107 patients who were taken to the operating room for attempted closed reduction, which they classified as either CRPP without arthrogram or arthrogram first and then a decision to treat open or with CRPP. Fifty-eight (54.21%) underwent CRPP without arthrogram and 49 (45.79%) underwent arthrogram. Of those who had arthrograms, 27 (25.23%) were prior to fixation and 22 (20.56%) were after fixation. There was no difference in age, weight, or preoperative displacement among the groups. Mean postoperative displacement was significantly lower in the no arthrogram group vs the arthrogram group (0.91 mm vs 1.68 mm; P<.0001), but it did not differ based on timing of arthrogram (P=.836). Arthrograms changed management in 4 (8%) of 49 patients who had them. There was no statistical difference in the rate of changed management by timing of arthrogram (before vs after fixation, 14.8% vs 0%; P=.060). The authors demonstrated that arthrograms may be useful for assessing final fracture alignment after CRPP, but are unlikely to result in a treatment change and are not associated with improved postoperative alignment. [Orthopedics. 2020; 43(1):30-35.].

  View details for DOI 10.3928/01477447-20191031-01

  View details for Web of Science ID 000508434100015

  View details for PubMedID 31693741

• Posterior Sternoclavicular Dislocation: Do We Need "Cardiothoracic Backup"? Insights from a National Sample. Journal of orthopaedic trauma Leonard, D. A., Segovia, N., Kaur, J., Lucas, J., Bishop, J., Vorhies, J. S. 2019

  Abstract

  OBJECTIVES: To describe the incidence of and risk factors for vascular injury associated with P-SCD.METHODS: We used data from the HCUP-NIS from 2015-2016 and defined a cohort of patients with sternoclavicular dislocation (SCD) using ICD-10-CM diagnosis codes. We further isolated a subset with P-SCD. We describe the incidence of thoracic vascular injury, demographics and injury severity score (ISS) in this cohort.RESULTS: Of an estimated 550 patients who had SCD, 140 (25%) were identified as having a P-SCD. No vascular injuries occurred in the P-SCD cohort. Among all patients with SCD, < 2% of patients had a vascular injury, all of whom had an ISS ≥ 15, independent of the vascular injury itself (Figure 1). Among patients with an isolated P-SCD injury (55), overall length of stay was 1.8 days and total charges averaged $29,724.45. There was no mortality among patients with isolated P-SCD.CONCLUSION: Here we report no vascular injuries in the largest known series of P-SCD. Among all patients with SCD, vascular injury was rare, occurring only in severely polytraumatized patients. The recommendation for routine involvement of cardiothoracic surgeons in all cases of P-SCD should be re-examined.LEVEL OF EVIDENCE: Level III.

  View details for DOI 10.1097/BOT.0000000000001685

  View details for PubMedID 31764407

• Debridement, antibiotic pearls, and retention of the implant (DAPRI): A modified technique for implant retention in total knee arthroplasty PJI treatment. Journal of orthopaedic surgery (Hong Kong) Calanna, F., Chen, F., Risitano, S., Vorhies, J. S., Franceschini, M., Giori, N. J., Indelli, P. F. 2019; 27 (3): 2309499019874413

  Abstract

  We describe a modified surgical technique developed to enhance the classical irrigation and debridement procedure to improve the possibilities of retaining an infected total knee arthroplasty. This technique, debridement antibiotic pearls and retention of the implant (DAPRI), aims to remove the intra-articular biofilm allowing a higher and prolonged local antibiotic concentration using calcium sulfate beads. The combination of three different surgical techniques (methylene blue staining, argon beam electrical stimulation, and chlorhexidine gluconate brushing) might enhance the identification, disruption, and finally removal of the bacterial biofilm, which is the main responsible of antibiotics and antibodies resistance. The DAPRI technique might represent a safe and more conservative treatment for acute and early hematogenous periprosthetic joint infection.

  View details for DOI 10.1177/2309499019874413

  View details for PubMedID 31554470

• Moving toward patients being pain- and spasm-free after pediatric scoliosis surgery by using bilateral surgically-placed erector spinae plane catheters. Canadian journal of anaesthesia = Journal canadien d'anesthesie Tsui, B. C., Esfahanian, M. n., Lin, C. n., Policy, J. n., Vorhies, J. n. 2019

  View details for DOI 10.1007/s12630-019-01543-0

  View details for PubMedID 31776896

• Treatment in a Nonpediatric Hospital Is a Risk Factor for Open Reduction of Pediatric Supracondylar Humerus Fractures: A Population-Based Study. Journal of orthopaedic trauma Vorhies, J. S., Uzosike, O. B., Imrie, M. N., Rinsky, L. n., Hoffinger, S. n. 2019; 33 (9): e331–e338

  Abstract

  To describe the distribution of open versus closed treatment and its relationship with the location of care in pediatric specialty versus general hospitals.Patient data were extracted from the Healthcare Cost and Utilization Project's Kid's Inpatient Database for the years 2000-2012. ICD9-CM diagnosis and procedure codes were used to identify open versus closed treatment of closed supracondylar humerus fractures in children younger than 12 years. A multilevel logistic regression model to control for confounders and identify drivers of open treatment was used.An estimated 40,706 inpatient surgical fixation procedures met our inclusion criteria. Overall rate of open treatment was 13.65%. Fractures were less likely to be treated open at pediatric hospitals versus general hospitals 7.61% versus 16.13% (P < 0.0001). Over the study period, rates of open treatment have fallen at nonpediatric hospitals from 20.21% in 2000 to 17.42% in 2012 (P < 0.001) but have remained stable at pediatric hospitals: 7.8% in 2000 and 8.62% in 2012 (P = 0.4369). Mean hospital length of stay was higher for patients who had open treatment 1.63 versus 1.20 days (P < 0.0001), and mean hospital charges were higher for patients who had open treatment $21,465 versus $15,026 (P < 0.0001). After controlling for time trends as well as demographic and hospital characteristics with a logistic regression model, treatment at a nonpediatric hospital was the single most significant predictor of open treatment for an isolated closed supracondylar humerus fractures with an odds ratio of 1.96 (95% confidence interval 1.56-2.46; P < 0.001).In this comprehensive population-based study of risk factors for open treatment of supracondylar humerus fractures in the United States, we identified differences in practice patterns by hospital type. Pediatric supracondylar fractures of the elbow have almost twice the odds of open treatment at nonpediatric hospitals.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

  View details for DOI 10.1097/BOT.0000000000001502

  View details for PubMedID 31188255

• An Excellent Addition to Recent Studies in the US From Various Disciplines and Locations That Show Similar Results Response JOURNAL OF ORTHOPAEDIC TRAUMA Bishop, J., Vorhies, J., Paci, G. 2019; 33 (1): E38

  View details for Web of Science ID 000467798900013

• In response. Journal of orthopaedic trauma Bishop, J., Vorhies, J., Paci, G. 2019; 33 (1): e38

  View details for PubMedID 30562264

• Severity Adjusted Risk of Long-Term Adverse Sequelae Among Children with Osteomyelitis. The Pediatric infectious disease journal Vorhies, J. S., Lindsay, E. A., Tareen, N. G., Kellum, R. J., Jo, C. H., Copley, L. A. 2018

  Abstract

  BACKGROUND: The purpose of this investigation is to evaluate the risk for long-term, adverse outcomes among children with osteomyelitis.METHODS: Children with osteomyelitis were prospectively enrolled from 2012-2014. Care was accomplished by a multidisciplinary team according to an institutional algorithm. Data was collected to define the severity of illness during the initial hospitalization and assess short, intermediate and long-term outcomes. Clinical examination, radiographic assessment, and functional outcome survey administration were performed at a minimum of 2 year follow-up. A comparison cohort analysis was performed according to initial severity of illness score (SIS) of mild (0-2), moderate (3-6), and severe (7-10).RESULTS: Of 195 children enrolled, 139 (71.3%) returned for follow-up at an average of 2.4 years (range 2.0 to 5.0 years). Children with severe illness were less likely to have normal radiographs (Severe - 4.0%; Moderate - 38.2%; Mild - 53.2%, p<0.0001), and more likely to have osteonecrosis, chondrolysis, or deformity (Severe - 32.0%; Moderate - 5.9%; Mild - 1.3%, p<0.0001). Functional outcome measures did not significantly differ between severity categories.By regression analysis SIS, plus age less than 3 years and MRSA predicted severe sequelae with an area under the curve of 0.8617 and an increasing odds ratio of 1.34 per point of increase in severity score.CONCLUSION: Long term severe adverse outcomes among children with osteomyelitis occurred in 11 of 139 (7.9%) children and were predicted by initial severity of illness. Other risks that diminished the likelihood of complete resolution or increased the risk of severe sequelae included MRSA etiology and young age. The majority of children with osteomyelitis do not require long term follow-up beyond the initial treatment period.LEVEL OF EVIDENCE: Level II, Prognostic, Prospective Cohort Comparison.

  View details for PubMedID 29742649

• Treatment of Degenerative Lumbar Spondylolisthesis With Fusion or Decompression Alone Results in Similar Rates of Reoperation at 5 Years. Clinical spine surgery Vorhies, J. S., Hernandez-Boussard, T. n., Alamin, T. n. 2018; 31 (1): E74–E79

  Abstract

  Population-based analysis of administrative discharge records from California, Florida, and New York inpatient, ambulatory, and emergency department settings between 2005 and 2011, utilizing Healthcare Cost and Utilization Project data.We aimed to compare, and characterize rates of reoperation and readmission among patients with degenerative spondylolisthesis treated with surgical decompression alone versus fusion.Degenerative lumbar spondylolisthesis with stenosis can be treated by decompression with or without fusion. Fusion has traditionally been preferred. We hypothesized that rates of reoperation after decompression alone would be higher than after fusion.We undertook a population-based analysis of administrative discharge records from California, Florida, and New York inpatient, ambulatory, and emergency department settings between 2005 and 2011, with Healthcare Cost and Utilization Project data. We identified all patients who had degenerative spondylolisthesis who were treated with decompression alone or with fusion and compared their rates of reoperation at 1, 3, and 5 years from the index operation. We used descriptive statistics and a hierarchical logistic regression model to generate risk-adjusted odds of all-cause readmissions.Our study consisted of 75,024 patients with spondylolisthesis; 6712 (8.95%) of them underwent decompression alone and 68,312 (91.05%) of them underwent fusion. Rates of reoperation were higher for decompression versus fusion at 1 year; 6.87% versus 5.53% (P≤0.001), but at 3 years; 13.86% versus 12.91% (P=0.18) and 5 years; 16.9% versus 17.7% (P=0.398) years rates of reoperation were not statistically different. Patients treated with decompression alone that had a second operation tended to have the operation sooner 512.6 versus 567.4 days (P=0.008).Our study suggests that treatment of degenerative spondylolisthesis with fusion or decompression alone results in similar rates of reoperation at 5 years. This medium term data indicate that decompression alone may be a viable treatment for some patients with degenerative spondylolisthesis.

  View details for PubMedID 28671881

• Pediatric Supracondylar Humerus Fractures: Does After-Hours Treatment Influence Outcomes? Journal of orthopaedic trauma Paci, G. M., Tileston, K. R., Vorhies, J. S., Bishop, J. A. 2018; 32 (6): e215–e220

  Abstract

  To compare the outcomes of pediatric supracondylar humerus fractures treated during daytime hours to those treated after-hours.Retrospective.Academic Level I trauma center.Two hundred ninety-eight pediatric patients treated with surgical reduction and fixation of closed supracondylar fractures were included.Seventy-seven patients underwent surgery during daytime hours (06:00-15:59 on weekdays). One hundred eighty-six patients underwent surgery after-hours (16:00-05:59 on weekdays and any surgery on weekends or holidays).Surgeon subspecialty, operative duration, and radiographic and clinical outcomes, including range of motion and carrying angle, were extracted from the patient medical records.There were no patient-related demographic differences between the daytime hours and after-hours groups. Daytime surgery was more likely to be performed by a pediatric orthopaedic surgeon than after-hours surgery. Fractures treated after-hours had more severe injury patterns. After-hours surgery was not independently associated with rate of open reduction, operative times, complications, achievement of functional range of motion, or radiographic alignment. A late-night surgery subgroup analysis demonstrated an increased rate of malunion in patients undergoing surgery between the hours of 23:00 and 05:59.There is no difference in the operative duration or outcomes after surgical treatment of pediatric supracondylar humerus fractures performed after-hours when compared with daytime surgery. However, late-night surgery performed between 23:00 and 05:59 may be associated with a higher rate of malunion. Surgeons can use these data to make better-informed decisions about the timing of surgery in this patient population.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

  View details for PubMedID 29432316

• Does the Watson-Jones or Modified Smith-Petersen Approach Provide Superior Exposure for Femoral Neck Fracture Fixation? Clinical orthopaedics and related research Lichstein, P. M., Kleimeyer, J. P., Githens, M. n., Vorhies, J. S., Gardner, M. J., Bellino, M. n., Bishop, J. n. 2018

  Abstract

  A well-reduced femoral neck fracture is more likely to heal than a poorly reduced one, and increasing the quality of the surgical exposure makes it easier to achieve anatomic fracture reduction. Two open approaches are in common use for femoral neck fractures, the modified Smith-Petersen and Watson-Jones; however, to our knowledge, the quality of exposure of the femoral neck exposure provided by each approach has not been investigated.(1) What is the respective area of exposed femoral neck afforded by the Watson-Jones and modified Smith-Petersen approaches? (2) Is there a difference in the ability to visualize and/or palpate important anatomic landmarks provided by the Watson-Jones and modified Smith-Petersen approaches?Ten fresh-frozen human pelvi underwent both modified Smith-Petersen (utilizing the caudal extent of the standard Smith-Petersen interval distal to the anterosuperior iliac spine and parallel to the palpable interval between the tensor fascia lata and the sartorius) and Watson-Jones approaches. Dissections were performed by three fellowship-trained orthopaedic traumatologists with extensive experience in both approaches. Exposure (in cm) was quantified with calibrated digital photographs and specialized software. Modified Smith-Petersen approaches were analyzed before and after rectus femoris tenotomy. The ability to visualize and palpate seven clinically relevant anatomic structures (the labrum, femoral head, subcapital femoral neck, basicervical femoral neck, greater trochanter, lesser trochanter, and medial femoral neck) was also recorded. The quantified area of the exposed proximal femur was utilized to compare which approach afforded the largest field of view of the femoral neck and articular surface for assessment of femoral neck fracture and associated femoral head injury. The ability to visualize and palpate surrounding structures was assessed so that we could better understand which approach afforded the ability to assess structures that are relevant to femoral neck fracture reduction and fixation.After controlling for age, body mass index, height, and sex, we found the modified Smith-Petersen approach provided a mean of 2.36 cm (95% confidence interval [CI], 0.45-4.28 cm; p = 0.015) additional exposure without rectus femoris tenotomy (p = 0.015) and 3.33 cm (95% CI, 1.42-5.24 cm; p = 0.001) additional exposure with a tenotomy compared with the Watson-Jones approach. The labrum, femoral head, subcapital femoral neck, basicervical femoral neck, and greater trochanter were reliably visible and palpable in both approaches. The lesser trochanter was palpable in all of the modified Smith-Petersen and none of the Watson-Jones approaches (p < 0.001). All modified Smith-Petersen approaches (10 of 10) provided visualization and palpation of the medial femoral neck, whereas visualization of the medial femoral neck was only possible in one of 10 Watson-Jones approaches (p < 0.001) and palpation was possible in eight of 10 Watson-Jones versus all 10 modified Smith-Petersen approaches (p = 0.470).In the hands of surgeons experienced with both surgical approaches to the femoral neck, the modified Smith-Petersen approach, with or without rectus femoris tenotomy, provides superior exposure of the femoral neck and articular surface as well as visualization and palpation of clinically relevant proximal femoral anatomic landmarks compared with the Watson-Jones approach.Open reduction and internal fixation of a femoral neck fracture is typically performed in a young patient (< 60 years old) with the objective of obtaining anatomic reduction that would not be possible by closed manipulation, thus enhancing healing potential. In the hands of surgeons experienced in both approaches, the modified Smith-Petersen approach offers improved direct access for reduction and fixation. Higher quality reductions and fixation are expected to translate to improved healing potential and outcomes. Although our experimental results are promising, further clinical studies are needed to verify if this larger exposure area imparts increased quality of reduction, healing, and improved outcomes compared with other approaches. The learning curve for the exposure is unclear, but the approach has broad applications and is frequently used in other subspecialties such as for direct anterior THA and pediatric septic hip drainage. Surgeons treating femoral neck fractures with open reduction and fixation should familiarize themselves with the modified Smith-Petersen approach.

  View details for PubMedID 29698292

• Admission Through the Emergency Department Is an Independent Risk Factor for Lower Satisfaction With Physician Performance Among Orthopaedic Surgery Patients: A Multicenter Study JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS Vorhies, J. S., Weaver, M. J., Bishop, J. A. 2016; 24 (10): 735-742

  Abstract

  Patient experience data are increasingly used to guide performance improvement and to determine physician and hospital reimbursement. We studied the relationship between emergency department (ED) admission and patient satisfaction with physicians' performance, and identified other associated predictors.We evaluated 6,524 inpatient Press Ganey patient experience surveys from two academic level I trauma centers over 5 years. We stratified patients by ED admission or other admission and compared the proportions of patients in each group who were satisfied with physician performance. We used logistic regression to control for demographic differences and characteristics of hospitalizations.Among patients admitted through the ED, 85.18% were satisfied, compared with 89.44% of patients admitted through other pathways (P < 0.001). Admission through the ED predicted decreased satisfaction, with an odds ratio of 0.67 (P = 0.032) after controls were applied through logistic regression.Admission through the ED is an independent risk factor for lower satisfaction with physician performance. Understanding the determinants of patient satisfaction will help improve physician-patient interactions and guide quality improvement and value-based reimbursement initiatives.This retrospective survey-based analysis of satisfaction does not fall clearly under any of the Journal's established categories of level of evidence. The most closely aligned choice would be Level III Prognostic.

  View details for DOI 10.5435/JAAOS-D-16-00084

  View details for Web of Science ID 000385408400010

  View details for PubMedID 27579815

• Growth mechanisms and geochemistry of carbonate concretions from the Cambrian Wheeler Formation (Utah, USA) SEDIMENTOLOGY Gaines, R. R., Vorhies, J. S. 2016; 63 (3): 662-698

  View details for DOI 10.1111/sed.12234

  View details for Web of Science ID 000372342200007

• Legal restrictions and complications of abortion: Insights from data on complication rates in the United States JOURNAL OF PUBLIC HEALTH POLICY Rolnick, J. A., Vorhies, J. S. 2012; 33 (3): 348-362

  Abstract

  Although US federal law requires all American states to permit abortion within their borders, states retain authority to impose restrictions.We used hospital discharge data to study the rates of major abortion complications in 23 states from 2001 to 2008 and their relationship to two laws: (i) restrictions on Medicaid – the state insurance programs for the poor – funding, and (ii) mandatory delays before abortion. Of 131 000 000 discharges in the data set, 10 980 involved an abortion complication. The national rate for complications was 1.90 per 1000 abortions (95 per cent CI: 1.57–2.23). Eleven states required mandatory delays and 12 restricted funding for Medicaid participants. After controlling for socioeconomic characteristics and the pregnancy complication rate, legal restrictions were associated with lower complication rates: mandatory delays (OR 0.79(0.65–0.95)) and restricted Medicaid funding (OR 0.74 (0.61–0.90)). This result may reflect the fact that states without restrictions perform a higher percentage of second-trimester abortions. This study is the first to assess the association between legal restrictions on abortion and complication rates.

  View details for DOI 10.1057/jphp.2012.12

  View details for Web of Science ID 000307793800010

  View details for PubMedID 22622483

• Decreased Length of Stay After TKA Is Not Associated With Increased Readmission Rates in a National Medicare Sample CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Vorhies, J. S., Wang, Y., Herndon, J. H., Maloney, W. J., Huddleston, J. I. 2012; 470 (1): 166-171

  Abstract

  There is a trend toward decreasing length of hospital stay (LOS) after TKA although it is unclear whether this trend is detrimental to the overall postoperative course. Such information is important for future decisions related to cost containment.We determined whether decreases in LOS after TKA are associated with increases in readmission rates.We retrospectively reviewed the rates and reasons for readmission and LOS for 4057 Medicare TKA patients from 2002 to 2007. We abstracted data from the Medicare Patient Safety Monitoring System. Hierarchical generalized linear modeling was used to assess the odds of changing readmission rates and LOS over time, controlling for changes in patient demographic and clinical variables.The overall readmission rate in the 30 days after discharge was 228/4057 (5.6%). The 10 most common reasons for readmission were congestive heart failure (20.4%), chronic ischemic heart disease (13.9%), cardiac dysrhythmias (12.5%), pneumonia (10.8%), osteoarthrosis (9.4%), general symptoms (7.4%), acute myocardial infarction (7.0%), care involving other specified rehabilitation procedure (6.3%), diabetes mellitus (6.3%), and disorders of fluid, electrolyte, and acid-base balance (5.9%); the top 10 causes did not include venous thromboembolism syndromes. We found no difference in the readmission rate between the periods 2002-2004 (5.5%) and 2005-2007 (5.8%) but a reduction in LOS between the periods 2002-2004 (4.1 ± 2.0 days) and 2005-2007 (3.8 ± 1.7 days).The most common causes for readmission were cardiac-related. A reduction in LOS was not associated with an increase in the readmission rate in this sample. Optimization of cardiac status before discharge and routine primary care physician followup may lead to lower readmission rates.

  View details for DOI 10.1007/s11999-011-1957-0

  View details for Web of Science ID 000298103100021

  View details for PubMedID 21720934

  View details for PubMedCentralID PMC3237965

• Readmission and Length of Stay After Total Hip Arthroplasty in a National Medicare Sample JOURNAL OF ARTHROPLASTY Vorhies, J. S., Wang, Y., Herndon, J., Maloney, W., Huddleston, J. I. 2011; 26 (6): 119-123

  Abstract

  Evaluation of hospital readmissions after total hip arthroplasty may help improve patient safety and cost reduction. This study investigates the rates and reasons for readmission as well as length of hospital stay (LOS) for 1802 total hip arthroplasty patients from 2002 to 2007. Data were abstracted from the Medicare Patient Safety Monitoring System. The overall 30-day rate of readmission was 6.8%. There was no difference in readmission rate from 2002 to 2004 (7.1%) to 2005 to 2007 (6.3%) (odds ratio, 0.90; 95% confidence interval, 0.63-1.30; P = .58). The overall mean LOS was 4.2 ± 2.2 days. There was a significant reduction in LOS from 2002 to 2004 (4.4 ± 2.5 days) to 2005 to 2007 (3.8 ± 1.7 days) (odds ratio, 1.28; 95% confidence interval, 1.25-1.31; P < .0001). The most common causes for readmission were cardiac related. A reduction in LOS was not associated with an increase in the rate of readmission in this sample. Efforts to optimize cardiac status before discharge may lead to lower rates of readmission in the future.

  View details for DOI 10.1016/j.arth.2011.04.036

  View details for Web of Science ID 000294393000023

  View details for PubMedID 21723700

• siRNA Versus shRNA for Personalized Cancer Therapy: Mechanisms and Applications GENE-BASED THERAPIES FOR CANCER Vorhies, J. S., Rao, D. D., Senzer, N., Nemunaitis, J., Roth, J. A. 2010: 51–62

  View details for DOI 10.1007/978-1-4419-6102-0_4

  View details for Web of Science ID 000280962600004

• siRNA vs. shRNA: Similarities and differences ADVANCED DRUG DELIVERY REVIEWS Rao, D. D., Vorhies, J. S., Senzer, N., Nemunaitis, J. 2009; 61 (9): 746-759

  Abstract

  RNA interference (RNAi) is a natural process through which expression of a targeted gene can be knocked down with high specificity and selectivity. Using available technology and bioinformatics investigators will soon be able to identify relevant bio molecular tumor network hubs as potential key targets for knockdown approaches. Methods of mediating the RNAi effect involve small interfering RNA (siRNA), short hairpin RNA (shRNA) and bi-functional shRNA. The simplicity of siRNA manufacturing and transient nature of the effect per dose are optimally suited for certain medical disorders (i.e. viral injections). However, using the endogenous processing machinery, optimized shRNA constructs allow for high potency and sustainable effects using low copy numbers resulting in less off-target effects, particularly if embedded in a miRNA scaffold. Bi-functional design may further enhance potency and safety of RNAi-based therapeutics. Remaining challenges include tumor selective delivery vehicles and more complete evaluation of the scope and scale of off-target effects. This review will compare siRNA, shRNA and bi-functional shRNA.

  View details for DOI 10.1016/j.addr.2009.04.004

  View details for Web of Science ID 000267476800008

  View details for PubMedID 19389436

• "Bifunctional" Short Hairpin RNA for Cancer Gene Therapy Rao, D. D., Wang, Z., Kumar, P., Yu, Y., Haddock, C., Vorhies, J., Tong, A. W., Maples, P. B., Senzer, N. N., Nemunaitis, J. NATURE PUBLISHING GROUP. 2009: S255

  View details for Web of Science ID 000278019801241

• Microbial dissolution of clay minerals as a source of iron and silica in marine sediments NATURE GEOSCIENCE Vorhies, J. S., Gaines, R. R. 2009; 2 (3): 221–25

  View details for DOI 10.1038/NGEO441

  View details for Web of Science ID 000264289900025

• Nucleic acid aptamers for targeting of shRNA-based cancer therapeutics. Biologics : targets & therapy Vorhies, J. S., Nemunaitis, J. J. 2007; 1 (4): 367-376

  Abstract

  Aptamers are nucleic acid ligands which have been validated to bind to epitopes with a specificity similar to that of monoclonal antibodies. Aptamers have been primarily investigated for their direct function in terms of inhibition of protein targets; however, recent evidence gives reason to actively explore aptamers as targeting moieties for delivery of anticancer therapeutics. Many aptamers have been developed to bind to extracellular membrane domains of proteins overexpressed on cancer cells and have the potential to be modified for use in targeting cancer therapeutics. The use of DNA vector-based short hairpin RNA (shRNA) for RNA interference (RNAi) is a precise means for the disruption of target gene expression but its clinical usage in cancer is limited by obstacles related to delivery into cancer cells. Nucleic acid aptamers are attractive candidates for targeting of shRNA therapies. Their small size, ease of production and modification, and high specificity are valued attributes in comparison to other targeting moieties currently being tested. Here we review the development of aptamers directed to PSMA, Nucleolin, HER-3, RET, TN-C, and MUC1 and focus on their potential for use in targeting of shRNA-based cancer therapeutics.

  View details for PubMedID 19707307

  View details for PubMedCentralID PMC2721292

• Proof concept for clinical justification of network mapping for personalized cancer therapeutics CANCER GENE THERAPY Nemunaitis, J., Senzer, N., Khalil, I., Shen, Y., Kumar, P., Tong, A., Kuhn, J., LaMont, J., Nemunaitis, M., Rao, D., Zhang, Y., Zhou, Y., Vorhies, J., Maples, P., Hill, C., Shanahan, D. 2007; 14 (8): 686-695

  Abstract

  To identify signature targets associated with patient-specific cancer lesions based on tumor versus normal tissue differential protein and mRNA coexpression patterns for the purpose of synthesizing cancer-specific customized RNA interference knockdown therapeutics. Analysis of biopsied tissue involved two-dimensional difference in-gel electrophoresis (2D-DIGE) analysis coupled with MALDI-TOF/TOF mass spectrometry for proteomic assessment. Standard microarray techniques were utilized for mRNA analysis. Priority was assigned to overexpressed protein targets with co-overexpressed genes with a high likelihood of functional nodal centrality in the cancer network as defined by the interactive databases BIND, HPRD and ResNet. HPLC-grade small interfering RNA (siRNA) duplexes were utilized to assess knockdown of target proteins in expressive cell lines as measured by western blot. Seven patients with metastatic cancer underwent biopsy. One patient (RW001) had biopsies from two disease sites 10 months apart. Seven priority proteins were identified, one for each patient (RACK 1, Ras related nuclear protein, heat-shock 27 kDa protein 1, superoxide dismutase, enolase1, stathmin1 and cofilin1). Prioritized proteins in RW001 from the two disease sites over time were the same. We demonstrated >80% siRNA inhibition of RACK 1 and stathmin1 of inexpressive malignant cell lines with correlated cell kill. Identification of functionally relevant target gene fingerprints, unique to an individual's cancer, is feasible 'at the bedside' and can be utilized to synthesize siRNA knockdown therapeutics. Further animal safety testing followed by clinical study is recommended.

  View details for DOI 10.1038/sj.cgt.7701057

  View details for Web of Science ID 000248146500002

  View details for PubMedID 17541424

• 10-year follow-up of gene-modified adenoviral-based therapy in 146 non-small-cell lung cancer patients CANCER GENE THERAPY Nemunaitis, J., Vorhies, J. S., Pappen, B., Senzer, N. 2007; 14 (8): 762-763

  View details for DOI 10.1038/sj.cgt.7701048

  View details for Web of Science ID 000248146500010

  View details for PubMedID 17514194

• Nonviral delivery vehicles for use in short hairpin RNA-based cancer therapies EXPERT REVIEW OF ANTICANCER THERAPY Vorhies, J. S., Nemunaitis, J. 2007; 7 (3): 373-382

  Abstract

  The use of DNA vector-based short hairpin (sh)RNA for RNA interference shows promise as a precise means for the disruption of gene expression to achieve a therapeutic effect. The in vivo usage of shRNA therapeutics in cancer is limited by obstacles related to effective delivery into the nuclei of target cancer cells. Nonviral delivery vehicles that are relevant for shRNA delivery into humans belong to a group of substances about which significant preclinical data has been amassed to show an acceptable safety profile, resistance to immune defenses and good transfection efficiency. Here, we review the most promising current nonviral gene delivery vehicles with a focus on their potential use in cancer shRNA therapeutics.

  View details for DOI 10.1586/14737140.7.3.373

  View details for Web of Science ID 000245134900015

  View details for PubMedID 17338656