Use of navigation for anterior and posterior instrumentation in the surgical management of pediatric pathologic lumbosacral deformity.

We report the use of computerized tomography (CT)-guided navigation for complex spinal deformity correction (anterior and posterior) in an 8-year-old patient with neurofibromatosis complicated by dystrophic pedicles, dural ectasia, and extensive vertebral scalloping. A retrospective review was conducted of the patient's medical records for the past 3 years, including the patient's office visit notes, operative reports, pre- and 2-year postoperative imaging studies. The patient successfully underwent anterior lumbar interbody fusion from L3-S1 using CT-guided navigation to negotiate the challenges posed by dural ectasia and vertebral body scalloping. One week after the anterior procedure, she underwent navigation-guided T10-to-pelvis posterior instrumented fusion. There were no perioperative or postoperative complications at 2 years. In patients with complex deformities of the spine, including dural ectasia, scalloped vertebral bodies, and decreased pedicle integrity, the use of intraoperative CT-guided navigation can benefit surgeons by facilitating the safe placement of interbody spacers and pedicle screws.

Role of Topical Tranexamic Acid on Blood Loss and Transfusion Requirements in Spinal Fusion for Neuromuscular and Syndromic Scoliosis.

STUDY DESIGN: Retrospective case control study. OBJECTIVES: To determine the role of TXA when used as topical soaked sponges (tTXA) on peri-operative blood loss and changes in hemoglobin following posterior spinal fusion (PSF) for neuromuscular and syndromic scoliosis (NMS). METHODS: A single center review of NMS patients who underwent PSF was conducted. The initial set of patients where no tTXA (control) was used were compared to consecutive NMS patients in whom tTXA was used. In the tTXA group, sponges soaked in 1g TXA in 500 mL normal saline were packed in the wound instead of dry sponges. Estimated blood loss (EBL) was calculated intraoperatively using a standard way. Pre-operative, intra-operative and immediate post-operative variables were collected and compared between the 2 groups. RESULTS: 33 patients were included (mean age- 13.5 yrs., BMI- 21, 17 patients in tTXA and 16 patients in control group). Pre-op demographic and radiographic variables were similar between the 2 groups. EBL, EBL per level, EBVL, operative time and number of levels fused were similar in both groups. tTXA group received less intra-operative pRBC transfusion as compared to the control group (150 ± 214 vs 363 ± 186 cc, P = .004). No difference was noted in post-op blood transfusion and drain output for 3 days in both the groups. tTXA group had lesser hospital (5.1 vs 8.9 days) and ICU length of stay (2 vs 4.2 days) and fewer immediate post-operative complications (23.5 vs 52.9%) compared to the control group but not statistically significant (P > .05). CONCLUSION: Administration of tTXA-soaked sponges is an effective and safe method to reduce intraoperative blood transfusion requirements in the correction of spinal deformity in patients with NMS.

Congenital duodenal obstruction repair with and without transanastomotic tube feeding: a systematic review and meta-analysis.

OBJECTIVE: To determine the impact of transanastomotic tube (TAT) feeding in congenital duodenal obstruction (CDO). DESIGN: Systematic review with meta-analysis. PATIENTS: Infants with CDO requiring surgical repair. INTERVENTIONS: TAT feeding following CDO repair versus no TAT feeding. MAIN OUTCOME MEASURES: The main outcome was time to full enteral feeds. Additional outcomes included use of parenteral nutrition (PN), cost and complications from either TAT or central venous catheter. Meta-analyses were undertaken using random-effects models (mean difference (MD) and risk difference (RD)), and risk of bias was assessed using the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. RESULTS: Twelve out of 373 articles screened met the inclusion criteria. All studies were observational and two were prospective. Nine studies, containing 469 infants, were available for meta-analysis; however, four were excluded due to serious or critical risk of bias. TAT feeding was associated with reduced time to full enteral feeds (-3.34; 95% CI -4.48 to -2.20 days), reduced duration of PN (-6.32; 95% CI -7.93 to -4.71 days) and reduction in nutrition cost of £867.36 (95% CI £304.72 to £1430.00). Other outcomes were similar between those with and without a TAT including inpatient length of stay (MD -0.97 (-5.03 to 3.09) days), mortality (RD -0.01 (-0.04 to 0.01)) and requirement for repeat surgery (RD 0.01 (-0.03 to 0.05)). CONCLUSION: TAT feeding following CDO repair appears beneficial, without increased risk of adverse events; however, certainty of available evidence is low. Earlier enteral feeding and reduced PN use are known to decrease central venous catheter-associated risks while significantly reducing cost of care. PROSPERO REGISTRATION NUMBER: CRD42022328381.

SRS-22r Self-Image After Surgery for Adolescent Idiopathic Scoliosis at 10-year Follow-up.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To examine SRS-Self Image scores at up to 10 years after surgery for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Self-image is complex with implications for surgical and patient-reported outcomes after AIS surgery. Surgically modifiable factors that impact self-image are inconsistently reported in the literature with few longer-term reports. We examined the rate and durability of self-image improvement. MATERIALS AND METHODS: An AIS registry was queried for patients with up to 10 years of follow-up after AIS surgery. A mixed effects model estimated change in SRS-22 Self Image from baseline to 6 weeks, 1 year, 2 years, 5 years, and 10 years. All enrolled patients contributed data to the mixed effects models. A sub-analysis of patients with 1-year and 10-year follow-up evaluated worsening/static/improved SRS-22 Self Image scores examined stability of scores over that timeline. Baseline demographic data and 1-year deformity magnitude data were compared between groups using parametric and nonparametric tests as appropriate. RESULTS: Data from 4608 patients contributed data to the longitudinal model; 162 had 1-year and 10-year data. Mean SRS-Self Image improvement at 10-year follow-up was 1.0 (95% CI: 0.9-1.1) point. No significant changes in Self-Image domain scores were estimated from 1-year to 10-year (all P >0.05) postoperative. Forty (25%) patients had SRS-Self Image worsening from 1 year to 10 years, 36 (22%) improved, and 86 (53%) were unchanged. Patients who worsened over 10 years had lower SRS-Self Image at baseline than those unchanged at enrollment (3.3 vs. 3.7, P =0.007). Neither radiographic parameters nor SRS-Mental Health were different at baseline for the enrolled patients. CONCLUSION: Ten years after surgery, 75% of patients reported similar or better SRS-Self Image scores than one year after surgery. Nearly 25% of patients reported worsening self-image at 10 years. Patients who worsened had lower baseline SRS-Self Image scores, without radiographic or mental health differences at baseline or follow-up.

Liquid biopsy in head neck cancer: ready for clinical routine diagnostics?

PURPOSE OF REVIEW: The bodily fluids of patients with solid cancers representing a minimally-invasive source of clinically exploitable biomarkers have attracted an increasing amount of attention in recent years. In patients with head and neck squamous cell carcinoma (HNSCC), cell-free tumour DNA (ctDNA) belongs to the most promising liquid biomarkers for monitoring disease burden and identifying patients at high risk of recurrence. In this review, we highlight recent studies, evaluating the analytical validity and clinical utility of ctDNA as a dynamic biomarker in HNSCC, especially as it relates to risk stratification and contrasting human papilloma virus (HPV+ and HPV-) and carcinomas. RECENT FINDINGS: The clinical potential of minimal residual disease monitoring through viral ctDNA in identifying HPV+ oropharyngeal carcinoma patients at higher risk of recurrence has recently been demonstrated. Furthermore, accumulating evidence supports a potential diagnostic value of ctDNA dynamics in HPV-negative HNSCC. Altogether, recent data suggest that ctDNA analysis may be a valuable tool in guiding (de)escalation of surgical interventions as well as adaptation in radiotherapy dosage, both in the definitive and adjuvant settings. SUMMARY: Rigorous clinical trials with patient-relevant endpoints are critical in order to demonstrate that treatment decisions based on ctDNA dynamics result in better outcomes in HNSCC.

Pedicle Screw Plowing in Adolescent Idiopathic Scoliosis: How Common Is It and Is It a Problem?

STUDY DESIGN: Multicenter retrospective review. OBJECTIVE: To calculate overall incidence of pedicle screw "plowing" in adolescent idiopathic scoliosis (AIS) patients who underwent posterior spinal fusion (PSF). To identify risk factors for pedicle screw plowing and associated postoperative outcomes, including loss of correction and revision rate. SUMMARY OF BACKGROUND DATA: Curve correction of AIS generates perpendicular stresses that can cause pedicle screws to lose alignment and "plow" through pedicles craniocaudally. METHODS: We reviewed records of 1057 patients who underwent PSF for AIS from 2002 to 2015. Preoperative and first postoperative erect radiographs were evaluated by two observers to determine (1) presence of plowing and (2) subsequent loss of correction (LOC). Plowing was defined as more than 25° sagittal angulation compared with pedicle axis or entry of the most dorsal part of the screw outside the pedicle projection. LOC was defined as postoperative change in focal angulation of an instrumented spinal level, when in consensus of both reviewers. Bivariate analyses were performed (alpha = 0.05). RESULTS: Nineteen thousand five hundred sixty nine screws were assessed across our cohort of 1057 patients. Both observers agreed that 48 patients (4.5%) demonstrated plowing of more than or equal to one pedicle screw. For 72 screws (0.4%), both observers noted plowing, most commonly through the cranial cortex of the pedicle (65/72 screws) and at the lowest instrument vertebra (LIV) (17/72 screws). Factors associated with plowing included larger curves (P = 0.02); lower mean pedicle screw density (P = 0.0003); skeletal immaturity as measured by open triradiate cartilage (P = 0.04); and younger chronological age at time of surgery (P = 0.04). LOC occurred in 13 patients, most commonly at LIV (P < 0.0001). Revision rate for loss of screw fixation was higher in the plowing group (P = 0.003). CONCLUSION: Pedicle screw plowing occurred in 4.5% of AIS patients, especially in those skeletally immature and with decreased implant density. Plowing commonly occurred in the cranial direction and was associated with LOC, particularly at the LIV.Level of Evidence: 3.

A Signature Enrichment Design with Bayesian Adaptive Randomization.

Clinical trials in the era of precision cancer medicine aim to identify and validate biomarker signatures which can guide the assignment of individually optimal treatments to patients. In this article, we propose a group sequential randomized phase II design, which updates the biomarker signature as the trial goes on, utilizes enrichment strategies for patient selection, and uses Bayesian response-adaptive randomization for treatment assignment. To evaluate the performance of the new design, in addition to the commonly considered criteria of type I error and power, we propose four new criteria measuring the benefits and losses for individuals both inside and outside of the clinical trial. Compared with designs with equal randomization, the proposed design gives trial participants a better chance to receive their personalized optimal treatments and thus results in a higher response rate on the trial. This design increases the chance to discover a successful new drug by an adaptive enrichment strategy, i.e., identification and selective enrollment of a subset of patients who are sensitive to the experimental therapies. Simulation studies demonstrate these advantages of the proposed design. It is illustrated by an example based on an actual clinical trial in non-small-cell lung cancer.

Topical tranexemic acid reduces intra-operative blood loss and transfusion requirements in spinal deformity correction in patients with adolescent idiopathic scoliosis.

PURPOSE: To evaluate the effectiveness of the use of topical tranexamic acid (tTXA) in spinal deformity correction in AIS patients METHODS: Sixty consecutive operative AIS patients were reviewed from a single institution and divided into two groups with similar demographics. Standardized peri-operative blood salvage techniques were utilized in all 60 patients. In the latter 30 patients, tTXA soaked sponges (1 g mixed in 500 ml Normal Saline) was utilised for wound packing during the entire surgical procedure compared to dry sponges as used in the former 30 patients. Both the groups were compared for the magnitude of deformity corrected, EBL per level fused, total EBL, blood transfused, drain output and peri-operative events. RESULTS: Sixty AIS patients (mean age 14.4 yrs, 43 females, mean BMI 21.5, mean levels 10.7) were included. Both groups achieved similar change in Coronal Cobb correction. The EBVL (Estimated blood volume loss) % lost in the topical TXA group was 38% less than the control group (11.2 vs. 18.3%, p = 0.006). Similarly, the EBL/level was significantly lower in the topical TXA group (41 ± 30 ml vs. 57 ± 26 ml, p = 0.03). Three of 30 patients in the control group required at least 1 unit of blood transfusion, whereas only 1 patient in the topical TXA group required transfusion (10 vs. 3.3%, p = 0.001). No differences were noted in post-operative drain output, change in hemoglobin levels, and peri-operative complication rates. CONCLUSION: When used as an adjunct to the conventional blood salvage techniques in spinal deformity correction procedures, the use of tTXA resulted in reduced operative blood loss, and blood transfusion requirements.

Safe and effective performance of pediatric spinal deformity surgery in patients unwilling to accept blood transfusion: a clinical study and review of literature.

BACKGROUND: Pediatric deformity surgery traditionally involves major blood loss. Patients refusing blood transfusion add extra clinical and medicolegal challenges; specifically the Jehovah's witnesses population. The objective of this study is to review the safety and effectiveness of blood conservation techniques in patients undergoing pediatric spine deformity surgery who refuse blood transfusion. METHODS: After obtaining institutional review board approval, we retrospectively reviewed 20 consecutive patients who underwent spinal deformity surgery and refused blood transfusion at a single institution between 2014 and 2018. We collected pertinent preoperative, intraoperative and most recent clinical and radiological data with latest follow-up (minimum two-year follow-up). RESULTS: Twenty patients (13 females) with a mean age of 14.1 years were identified. The type of scoliotic deformities were adolescent idiopathic (14), juvenile idiopathic (1), neuromuscular (3) and congenital (2). The major coronal Cobb angle was corrected from 55.4° to 11.2° (80% correction, p <  0.001) at the latest follow-up. A mean of 11.4 levels were fused and 5.6 levels of Pontes osteotomies were performed. One patient underwent L1 hemivertebra resection and three patients had fusion to pelvis. Estimated blood loss, percent estimated blood volume loss, and cell saver returned averaged 307.9 mL, 8.5%, and 80 mL, respectively. Average operative time was 214 min. The average drop in hemoglobin after surgery was 2.9 g/dL. The length of hospital stay averaged 5.1 days. There were no intraoperative complications. Three postoperative complications were identified, none related to their refusal of transfusion. One patient had in-hospital respiratory complication, one patient developed a late infection, and one patient developed asymptomatic radiographic distal junctional kyphosis. CONCLUSIONS: Blood conservation techniques allow for safe and effective spine deformity surgery in pediatric patients refusing blood transfusion without major anesthetic or medical complications, when performed by an experienced multidisciplinary team. LEVEL OF EVIDENCE: Level IV.

Late spinal infections following posterior spinal fusion in pediatric deformities: treatment using single-stage titanium implant exchange.

PURPOSE: Late infection following posterior spinal fusion (PSF) for deformity is a leading cause of revision. The purpose of this study is to evaluate clinical and radiographic outcomes following a single-stage debridement and exchange of spinal implants with titanium in adolescent patients with late-onset infections following PSF METHODS: A retrospective review of prospectively collected data of adolescent patients with spinal deformity, who were surgically treated with PSF was collected. Patients were included for the study if they developed late arising infection (> 1 year after index posterior fusion for the deformity) from 2006-2019. Treatment consisted of irrigation, debridement, implant exchange with titanium screws and rods, and antibiotics. Parameters evaluated include radiographic Cobb angles, operative data, and clinical data, all at minimum 2-year follow-up. RESULTS: 31 patients (29 with AIS and 2 with Scheuermann's kyphosis) developed late spinal infections. Mean age was 11.4 ± 2.3 years, 84% female, mean time from index surgery was 52.5 months. 25 had all stainless steel implants and 6 had cobalt chrome during the index procedure. Positive cultures were obtained in 5 patients (2 Staphylococcus Aureus, 1 Staphylococcus epidermidis, 1 Peptostreptococcus, 1 Pseudomonas aeruginosa) with cultures followed till 7 days post-operatively. At 2-years following the exchange, there was no change in coronal and sagittal alignment. Three (9%) patients developed subsequent infection necessitating implant removal. CONCLUSION: A single-stage procedure consisting of implant removal, irrigation, and debridement, and replacement with all titanium implants is an effective treatment strategy in patients developing late wound infection following PSF with regards to maintenance of curve correction and minimizing recurrent infections.

Mandibular slope: a reproducible and simple measure of horizontal gaze.

STUDY DESIGN: This study is a single-center retrospective radiographic review. OBJECTIVES: The objective of this study is to evaluate a novel measurement parameter, mandibular slope (MS), as a measure of horizontal gaze. INTRODUCTION: Assessment of sagittal spinal alignment is essential in the evaluation of spinal deformity patients. Ability to achieve a horizontal gaze, a parameter of sagittal alignment, is needed for the performance of daily activities. Standard measures of horizontal gaze, including the gold-standard chin-brow to vertical angle (CBVA) and the surrogate measures McGregor's line (McGS) and Chamberlain's line (CS), require high-quality imaging, precise head positioning, and reliance on difficult to view visual landmarks. A novel measurement parameter, MS, utilizing the caudal margin of the mandible on standard lateral spine radiographs is proposed. METHODS: 90 radiographs from spine deformity patients with or without spinal implants from a single center were evaluated. Three spine surgery fellows independently measured CBVA, McGS, CS, and MS at two timepoints at least one week apart to assess accuracy and reliability. MS was measured as the angle created by the inferior edge of the mandibular body and the horizontal. Formulas for calculating CBVA based on the above parameters were derived and compared to the actual CBVA. RESULTS: Mean age was 49.7 years, 76 females and 14 males. CBVA correlated with CS, McGS, and MS, r = 0.85, 0.81, and 0.80, respectively (p < 0.001). Standard error between real CBVA and calculated CBVA using CS (0.4 ± 4.79) and McGS (0.4 ± 3.9) was higher than that calculated using MS (- 0.2 ± 4.3). ICC demonstrated the highest inter-observer reliability with MS (0.999). MS had the highest intra-observer reliabilities 0.975, 0.981, and 0.988 (p < 0.001); CS and McGS also demonstrated high intra-observer reliability. CONCLUSIONS: MS is a promising measure of horizontal gaze that correlates highly with CBVA, has excellent intra- and inter-observer reliability with CBVA, and is easily measured using standard lateral spine radiographs.

Congenital duodenal obstruction in the UK: a population-based study.

OBJECTIVE: Congenital duodenal obstruction (CDO) comprising duodenal atresia or stenosis is a rare congenital anomaly requiring surgical correction in early life. Identification of variation in surgical and postoperative practice in previous studies has been limited by small sample sizes. This study aimed to prospectively estimate the incidence of CDO in the UK, and report current management strategies and short-term outcomes. DESIGN: Prospective population-based, observational study for 12 months from March 2016. SETTING: Specialist neonatal surgical units in the UK. MAIN OUTCOME MEASURES: Incidence of CDO, associated anomalies and short-term outcomes. RESULTS: In total, 110 cases were identified and data forms were returned for 103 infants giving an estimated incidence of 1.22 cases per 10 000 (95% CI 1.01 to 1.49) live births. Overall, 59% of cases were suspected antenatally and associated anomalies were seen in 69%. Operative repair was carried out mostly by duodenoduodenostomy (76%) followed by duodenojejunostomy (15%). Postoperative feeding practice varied with 42% having a trans-anastomotic tube placed and 88% receiving parenteral nutrition. Re-operation rate related to the initial procedure was 3% within 28 days. Two infants died within 28 days of operation from unrelated causes. CONCLUSION: This population-based study of CDO has shown that the majority of infants have associated anomalies. There is variation in postoperative feeding strategies which represent opportunities to explore the effects of these on outcome and potentially standardise approach. Short-term outcomes are generally good.

Bias-adjusted Kaplan-Meier survival curves for marginal treatment effect in observational studies.

For time-to-event outcomes, the Kaplan-Meier estimator is commonly used to estimate survival functions of treatment groups and to compute marginal treatment effects, such as the difference in survival rates between treatments at a landmark time. The derived estimates of the marginal treatment effect are uniformly consistent under general conditions when data are from randomized clinical trials. For data from observational studies, however, these statistical quantities are often biased due to treatment-selection bias. Propensity score-based methods estimate the survival function by adjusting for the disparity of propensity scores between treatment groups. Unfortunately, misspecification of the regression model can lead to biased estimates. Using an empirical likelihood (EL) method in which the moments of the covariate distribution of treatment groups are constrained to equality, we obtain consistent estimates of the survival functions and the marginal treatment effect. Equating moments of the covariate distribution between treatment groups simulate the covariate distribution that would have been obtained if the patients had been randomized to these treatment groups. We establish the consistency and the asymptotic limiting distribution of the proposed EL estimators. We demonstrate that the proposed estimator is robust to model misspecification. Simulation is used to study the finite sample properties of the proposed estimator. The proposed estimator is applied to a lung cancer observational study to compare two surgical procedures in treating early-stage lung cancer patients.

An Observational Study of Elderly Veterans With Initially Asymptomatic Severe Aortic Stenosis.

BACKGROUND: The optimal timing of aortic valve replacement (AVR) among patients with asymptomatic severe aortic stenosis (AS) remains uncertain and controversial. METHODS: We conducted a cohort study of consecutive patients with severe AS (mean gradient, 40 mm Hg; aortic valve area <1 cm², or peak velocity ≥4 m/s) who were asymptomatic at the time of echocardiography (2005-2015). Outcomes included mortality, AVR, or AS symptoms. Kaplan-Meier curves and the log-rank test were used to compare the outcomes of patients treated with AVR compared with conservative management. Cox proportional-hazards regression analysis was performed to identify predictors of long-term mortality. RESULTS: Of 1181 echocardiograms and medical records reviewed, a total of 324 patients met inclusion criteria. The mean age of the study cohort was 78 ± 10 years and 97% were male. The median follow-up time was 8 years (interquartile range [IQR], 7-10 years), during which 147 patients (51%) underwent AVR and 94 patients (29%) died. The median survival for patients treated with AVR was 10 years (IQR, 9-10 years) and for patients managed conservatively was 4.8 years (IQR, 3.7-5.7 years; P<.001). A total of 47 patients (14% of the cohort and 48% of deaths) expired before AS symptoms were documented in their medical records. Independent predictors of mortality were age (hazard ratio [HR] per increase in decile, 1.14; 95% CI, 1.05-1.24; P<.01) and performance of AVR during follow-up (HR, 0.15; 95% CI, 0.9-0.28; P<.01). CONCLUSION: A significant proportion of elderly patients with initially asymptomatic severe AS died before symptoms were identified. Our study highlights the difficulty of relying on symptoms alone for timely referral to AVR surgery.

Anatomic Trajectory for Iliac Screw Placement in Pediatric Scoliosis and Spondylolisthesis: An Alternative to S2-Alar Iliac Portal.

STUDY DESIGN: Single-center retrospective study. OBJECTIVE: To analyze two-year postoperative outcomes following spinopelvic fixation in pediatric patients using the anatomic trajectory (AT) portal for iliac screws. SUMMARY: Iliac fixation is crucial in situations requiring fusion to sacrum. Challenges include complex anatomy, pelvic deformation, severe deformity, and previous surgery. The PSIS portal requires significant dissection, rod connectors, and complex bends. The SAI portal requires navigating the screw across the SI joint to the ilium. The anatomic trajectory (AT), first reported in 2009, is between the PSIS and SAI portal, without prominence, connectors, or complex bends. METHODS: Fifty-four patients aged ≤18 years requiring instrumentation to the Ilium with minimum follow-up of two years (mean 44 months) were clinically and radiographically evaluated. Changes in coronal curve magnitude and pelvic obliquity were assessed using paired t test for patients with cerebral palsy. Spondylolisthesis reduction was assessed in patients with moderate- to high-grade spondylolisthesis (Meyerding grade 3 and 4). RESULTS: A total of 108 iliac screws were inserted using AT portal in 54 patients. Twenty-eight neuromuscular and syndromic patients had an initial mean coronal curve of 85° corrected to 23° at two years (p < .001) and a pelvic obliquity of 22° corrected to 4° (p < .001). Twenty patients with moderate- to high-grade spondylolisthesis treated with reduction and interbody fixation improved significantly with respect to their slip angles (7° ± 14.7° to -7.9° ± 6.1°, p = .003). In the neuromuscular group, two surgical site infections occurred, two had implant fractures, and 12 had asymptomatic iliac screw loosening, none requiring revision. In the spondylolisthesis group, there were no neurologic complications and one had prominent screw requiring removal. Of 108 iliac screws, 2 rod connectors were employed. CONCLUSION: Iliac screw insertion using the AT portal is a safe and effective method of pelvic fixation in pediatric patients with satisfactory radiographic correction and minimal complications. LEVEL OF EVIDENCE: Level 4.

Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway.

Electrical stimulation of the vagus nerve (VNS) is a novel strategy used to treat inflammatory conditions. Therapeutic VNS activates both efferent and afferent fibers; however, the effects attributable to vagal afferent stimulation are unclear. Here, we tested if selective activation of afferent fibers in the abdominal vagus suppresses systemic inflammation. In urethane-anesthetized rats challenged with lipopolysaccharide (LPS, 60 µg/kg, i.v.), abdominal afferent VNS (2 Hz for 20 min) reduced plasma tumor necrosis factor alpha (TNF) levels 90 min later by 88% compared with unmanipulated animals. Pre-cutting the cervical vagi blocked this anti-inflammatory action. Interestingly, the surgical procedure to expose and prepare the abdominal vagus for afferent stimulation ('vagal manipulation') also had an anti-inflammatory action. Levels of the anti-inflammatory cytokine IL-10 were inversely related to those of TNF. Prior bilateral section of the splanchnic sympathetic nerves reversed the anti-inflammatory actions of afferent VNS and vagal manipulation. Sympathetic efferent activity in the splanchnic nerve was shown to respond reflexly to abdominal vagal afferent stimulation. These data demonstrate that experimentally activating abdominal vagal afferent fibers suppresses systemic inflammation, and that the efferent neural pathway for this action is in the splanchnic sympathetic nerves.

Percutaneous and open iliac screw safety and accuracy using a tactile technique with adjunctive anteroposterior fluoroscopy.

BACKGROUND CONTEXT: All currently described percutaneous iliac screw placement methods are entirely dependent on fluoroscopy. PURPOSE: The purpose of this study was to determine the safety and the accuracy of percutaneous and open iliac screw placement using a primarily tactile technique with adjunctive anteroposterior (AP) fluoroscopy. STUDY DESIGN/CONTEXT: All patients who underwent open and percutaneous iliac screw placement over a 5-year period were identified. Charts were reviewed to assess for any instances of neurologic or vascular injury associated with iliac screw placement. Screw accuracy was judged with postoperative computed tomography (CT) scans. PATIENT SAMPLE: A total of 133 patients were identified who underwent open or percutaneous iliac screw placement. Computed tomography scans were available for 57 patients, and all of these patients were included in the study, with a total of 115 iliac screws. OUTCOME MEASURES: Radiographic measurements were performed, consisting of the distance of the iliac screw to the sciatic notch on postoperative radiographs and CT scans. Computed tomography scans were used to determine iliac screw accuracy. METHODS: Charts were reviewed to assess for any neurologic or vascular injuries related to screw placement. The distance of the iliac screw to the sciatic notch was measured and compared on AP radiography and CT scans. Computed tomography scans were assessed for any screw violation of the iliac cortex or the sciatic notch. The accuracy of open iliac screw placement was compared with minimally invasive percutaneous placement. RESULTS: There were no neurologic or vascular injuries related to screw placement in the 133 patients. Computed tomography scans were available for 115 iliac screws, with 3 cortical breaches, all by less than 2 mm. All 112 other screws were accurately intraosseous. There was a strong correlation between the iliac screw to the sciatic notch distance when measured by CT scan compared with AP radiography (r=0.9), thus validating the accuracy of AP fluoroscopy in guiding iliac screw placement with respect to the sciatic notch. Iliac screw accuracy was equal with the open and percutaneous insertion techniques. CONCLUSIONS: The described surgical technique represents a safe and reliable surgical option for iliac screw placement. Intraoperative AP fluoroscopy accurately reflects the distance of the iliac screw to the sciatic notch. Percutaneous iliac screws placed with this technique are as accurate as open iliac screws.

On Enrichment Strategies for Biomarker Stratified Clinical Trials.

In the era of precision medicine, drugs are increasingly developed to target subgroups of patients with certain biomarkers. In large all-comer trials using a biomarker stratified design, the cost of treating and following patients for clinical outcomes may be prohibitive. With a fixed number of randomized patients, the efficiency of testing certain treatments parameters, including the treatment effect among biomarker-positive patients and the interaction between treatment and biomarker, can be improved by increasing the proportion of biomarker positives on study, especially when the prevalence rate of biomarker positives is low in the underlying patient population. When the cost of assessing the true biomarker is prohibitive, one can further improve the study efficiency by oversampling biomarker positives with a cheaper auxiliary variable or a surrogate biomarker that correlates with the true biomarker. To improve efficiency and reduce cost, we can adopt an enrichment strategy for both scenarios by concentrating on testing and treating patient subgroups that contain more information about specific treatment parameters of primary interest to the investigators. In the first scenario, an enriched biomarker stratified design enriches the cohort of randomized patients by directly oversampling the relevant patients with the true biomarker, while in the second scenario, an auxiliary-variable-enriched biomarker stratified design enriches the randomized cohort based on an inexpensive auxiliary variable, thereby avoiding testing the true biomarker on all screened patients and reducing treatment waiting time. For both designs, we discuss how to choose the optimal enrichment proportion when testing a single hypothesis or two hypotheses simultaneously. At a requisite power, we compare the two new designs with the BSD design in terms of the number of randomized patients and the cost of trial under scenarios mimicking real biomarker stratified trials. The new designs are illustrated with hypothetical examples for designing biomarker-driven cancer trials.

Sagittal Pelvic Orientation A Comparison of Two Methods of Measurement.

Pelvic tilt is an essential parameter in spinal deformity surgery and in acetabular positioning for total hip arthroplasty. However, the measurement of tilt varies between the hip and spine literature. Hip surgeons measure the anterior pelvic plane tilt, whereas spine surgeons measure the spinopelvic tilt. This study uses stereoradiography (EOS imaging SA, Paris, France) to assess the relationship and the inter-observer and intra-observer reliability of measuring these two common references for pelvic tilt. Retrospective analysis of full-body, standing stereoradiographic studies of 100 patients with varying degrees of spinal deformity was performed at a single institution. Assessment of anterior pelvic plane and spinopelvic tilt were undertaken by two orthopaedic surgeons and two orthopaedic residents using validated software. The pelvic incidence and sacral slope were also measured. The mean difference between anterior pelvic plane and spinopelvic tilt was 13.98° ± 7.04°, and the values were linearly inversely related. Both measures of tilt were strongly correlated with each other. Spinopelvic tilt has greater inter- and intra-user reliability and was a more precise measurement than anterior pelvic plane. Spinopelvic tilt is a more precise and reliable measurement than the anterior pelvic plane tilt; however, both measurements are strongly correlated. The clinical implications of this are not completely understood; however, it may be important for hip surgeons when placing acetabular components with precision. Further investigation is needed to assess which is a more accurate reference for the placement of acetabular components in hip arthroplasty.

A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent.

BACKGROUND: Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base. OBJECTIVE: To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent. DESIGN: Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (n = 301), (2) CEA testing only (n = 300), (3) computerised tomography (CT) only (n = 299) or (4) CEA testing and CT (n = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata). SETTING: Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence. PARTICIPANTS: A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l. MAIN OUTCOME MEASURES: Primary outcome Surgical treatment of recurrence with curative intent. Secondary outcomes Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained. RESULTS: Detection of recurrence During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%; p = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%; p = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. Survival A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank p = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%. Cost-effectiveness The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy. LIMITATIONS: Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality. CONCLUSIONS: Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41458548. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.