Long-term Morbidity in Patients After Surgical Correction of Adult Spinal Deformity: Results From a Cohort With Minimum 5-year Follow-up.

STUDY DESIGN: Retrospective. OBJECTIVE: The objective of this study is to describe the rate of postoperative morbidity before and after two-year (2Y) follow-up for patients undergoing surgical correction of adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: Advances in modern surgical techniques for deformity surgery have shown promising short-term clinical results. However, the permanence of radiographic correction, mechanical complications, and revision surgery in ASD surgery remains a clinical challenge. Little information exists on the incidence of long-term morbidity beyond the acute postoperative window. METHODS: ASD patients with complete baseline and five-year (5Y) health-related quality of life and radiographic data were included. The rates of adverse events, including proximal junctional kyphosis (PJK), proximal junctional failure (PJF), and reoperations up to 5Y were documented. Primary and revision surgeries were compared. We used logistic regression analysis to adjust for demographic and surgical confounders. RESULTS: Of 118 patients eligible for 5Y follow-up, 99(83.9%) had complete follow-up data. The majority were female (83%), mean age 54.1 years and 10.4 levels fused and 14 undergoing three-column osteotomy. Thirty-three patients had a prior fusion and 66 were primary cases. By 5Y postop, the cohort had an adverse event rate of 70.7% with 25 (25.3%) sustaining a major complication and 26 (26.3%) receiving reoperation. Thirty-eight (38.4%) developed PJK by 5Y and 3 (4.0%) developed PJF. The cohort had a significantly higher rate of complications (63.6% vs. 19.2%), PJK (34.3% vs. 4.0%), and reoperations (21.2% vs. 5.1%) before 2Y, all P <0.01. The most common complications beyond 2Y were mechanical complications. CONCLUSIONS: Although the incidence of adverse events was high before 2Y, there was a substantial reduction in longer follow-up indicating complications after 2Y are less common. Complications beyond 2Y consisted mostly of mechanical issues.

Crossing the Bridge From Degeneration to Deformity: When Does Sagittal Correction Impact Outcomes in Adult Spinal Deformity Surgery?

BACKGROUND: Patients with less severe adult spinal deformity (ASD) undergo surgical correction and often achieve good clinical outcomes. However, it is not well understood how much clinical improvement is due to sagittal correction rather than treatment of the spondylotic process. PURPOSE: Determine baseline thresholds in radiographic parameters that, when exceeded, may result in substantive clinical improvement from surgical correction. STUDY DESIGN: Retrospective. MATERIALS AND METHODS: ASD patients with BL and two-year data were included. Parameters assessed: sagittal vertical axis, pelvic incidence-lumbar lordosis mismatch, pelvic tilt, T1 pelvic angle, L1 pelvic angle, L4-S1 lordosis, C2-C7 sagittal vertical axis, C2-T3, C2 slope. Outcomes: Good Outcome (GO) at two years: [meeting either: (1) Substantial Clinical Benefit for Oswestry Disability Index (change >18.8), or (2) Oswestry Disability Index <15 and Scoliosis Research Society Total>4.5]. Binary logistic regression assessed each parameter to determine if correction was more likely needed to achieve GO. Conditional inference tree run machine learning analysis generated baseline thresholds for each parameter, above which, correction was necessary to achieve GO. RESULTS: We included 431 ASD patients. There were 223 (50%) that achieved a GO by two years. Binary logistic regression analysis demonstrated, with increasing baseline severity in deformity, sagittal correction was more often seen in those achieving GO for each parameter(all P <0.001). Of patients with baseline T1 pelvic angle above the threshold, 95% required correction to meet GO (95% vs. 54%, P <0.001). A baseline pelvic incidence-lumbar lordosis >10° (74% of patients meeting GO) needed correction to achieve GO (odds ratio: 2.6, 95% confidence interval: 1.4-4.8). A baseline C2 slope >15° also necessitated correction to obtain clinical success (odds ratio: 7.7, 95% confidence interval: 3.7-15.7). CONCLUSIONS: Our study highlighted point may be present at which sagittal correction has an outsized influence on clinical improvement, reflecting the line where deformity becomes a significant contributor to disability. These new thresholds give us insight into which patients may be more suitable for sagittal correction, as opposed to intervention for the spondylotic process only, leading to a more efficient utility of surgical intervention for ASD.

The Approach to Pseudarthrosis After Adult Spinal Deformity Surgery: Is a Multiple-Rod Construct Necessary?

STUDY DESIGN: Retrospective study. OBJECTIVES: Our goal was to evaluate the rate of rod fracture and persistent pseudarthrosis in cohorts of patients treated with a dual rod or multiple-rod construct in revision surgery for pseudarthrosis. METHODS: A dual rod construct was used in 23 patients, and a multiple rod construct in 24 patients, spanning the pseudarthrosis level. Two-year fusion grading, and rates of pseudarthrosis and implant failure, were assessed. RESULTS: There were no differences in patient or surgical characteristics between the groups: (2- rod construct: Age 60 ± 14, Levels 10 ± 5, 3-column osteotomy:17%; multiple-rod construct: Age: 62 ± 11, Levels 9 ± 4, 3-column osteotomy:30%). Patients in the multiple rod construct were transfused a greater volume of packed red blood cells (pRBCs) intraoperatively (2.6 ± 2.9 vs. 1.1 ± 1.5 U, p < 0.0001). At 2 year follow up there was no difference in fusion grades at the previous level of pseudarthrosis, the rate of rod fracture or pseudarthrosis between the 2 groups, or rate of reoperation for pseudarthrosis, rod fracture, wound infection, hardware prominence, or PJK/PJF. CONCLUSIONS: Our data demonstrate no difference in fusion grade, or rates of rod fracture and revision at 2 years, after utilizing a dual rod versus multiple rod construct in revision surgery for pseudarthrosis. The low complication rates seen with either configuration warrant further investigation of the optimal instrumentation configuration.

Assessing the Effects of Prior History of Vertebral Osteomyelitis on Peri-Operative Factors and Post-Operative Recovery in Adult Spinal Deformity Patients.

Vertebral osteomyelitis (VOM), which includes the clinical entities of spinal osteomyelitis, spondylodiscitis, or pyogenic spondylitis, describes a complex inflammatory reaction within the vertebral column in the setting of microbial infection [...].

Augmented Reality in Orthopedics History to Current Applications.

Orthopedic surgeons play a pivotal role in developing ways to practically and safely integrate new technology into their surgical workflow with the aim of improving safety, efficiency, and clinical outcomes. Interest in augmented reality applications to orthopedic surgery has grown significantly in the last decade due to a desire to limit complications and improve procedural efficiency. However, despite this technology remaining in its infancy, it is now emerging from proof of concept toward clinical use. This review provides a history and brief overview of the different applications of this technology in order to critically appraise its potential usefulness as its becomes more widespread.

Case Start Timing of Adult Spinal Deformity Surgeries: Does the Wait Matter?

BACKGROUND: Adult spinal deformity (ASD) surgery can entail complex reconstructive procedures. It is unclear whether there is any effect of case start time on outcomes. We sought to evaluate the effects of case start time and day of the week on 90-day complication, readmission, and revision rates after ASD surgery. METHODS: This is a retrospective study of 1040 ASD patients from a single institution. We collected start times and day of the week for cases from 2011 to 2018. Early start was designated as any case starting either before or at 7:30 am or between 7:30 and 11 am; late start was designated as any case starting at 11 am or later. Outcome measures include 90-day complication, revision, and readmission rates. RESULTS: A total of 1040 ASD patients (age, 46 ± 23 years; body mass index, 25 ± 7; American Society of Anesthesiologists classification, 2.5 ± 0.6; levels fused, 10 ± 4; three column osteotomy (3CO), 13%) were included. There was no association between surgery day of the week and length of stay, 90-day complication, readmission, or reoperation rates in the adjusted analyses. Late start cases had higher rates of 90-day readmission (10.5% vs 6.0%, P = 0.02), reoperation (11.9% vs 6.6%, P = 0.008), and neurologic injury (5.2% vs 2.1%, P = 0.019). Subanalysis of neurologic complications demonstrated that there was a higher rate of postoperative radiculopathy (P = 0.007) and residual central or foraminal stenosis (P = 0.029) in late start cases. A late start time was predictive of increased risk for 90-day readmission (OR 1.8, P = 0.02), unplanned reoperation (OR 1.9, P = 0.009), and neurologic complication (OR 2.1, P = 0.046). CONCLUSIONS: A late OR start time was predictive of increased risk for neurologic complication, 90-day readmission, and unplanned reoperation. The well-established protocols for first start OR times for elective ASD surgery may decrease outcome risk and reduce variability in complication rates. CLINICAL RELEVANCE: Understanding the impact of start time on outcomes and complications after ASD surgery is helpful for surgeons in preoperative planning and for institutions and hospitals' allocation of operating room staff and resources.

Reducing Postoperative Opioid-prescribing Following Posterior Lumbar Fusion Does Not Significantly Change Patient Satisfaction.

STUDY DESIGN: Retrospective comparative; LOE-3. OBJECTIVE: The purpose of this study was to investigate what effect, if any, an institutional opioid reduction prescribing policy following one- or two-level lumbar fusion has on Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey results. SUMMARY OF BACKGROUND DATA: Previous research has demonstrated that high levels of opioid-prescribing may be related, in part, to a desire to produce superior patient satisfaction. METHODS: A retrospective review of prospectively collected data was conducted on patients who underwent one- or two-level lumbar fusions L3-S1 between October 2014 and October 2019 at a single institution. Patients with complete survey information were included in the analysis. Patients with a history of trauma, fracture, spinal deformity, fusions more than two levels, or prior lumbar fusion surgery L3-S1 were excluded. Cohorts were based on date of surgery relative to implementation of an institutional opioid reduction policy, which commenced in October 1, 2018. To better compare groups, opioid prescriptions were converted into milligram morphine equivalents (MME). RESULTS: A total of 330 patients met inclusion criteria: 259 pre-protocol, 71 post-protocol. There were 256 one-level fusions and 74 two-level fusions included. There were few statistically significant differences between groups with respect to patient demographics (P > 0.05) with the exception of number of patients who saw the pain management service, which increased from 36.7% (95) pre-protocol to 59.2% (42) post-protocol; P < 0.001. Estimated blood loss (EBL) decreased from 533 ±â€Š571 mL to 346 ±â€Š328 mL (P = 0.003). Percentage of patients who underwent concomitant laminectomy decreased from 71.8% to 49.3% (P < 0.001). Average opioids prescribed on discharge in the pre-protocol period was 534 ±â€Š425 MME, compared to after initiation of the protocol, that is 320 ±â€Š174 MME (P < 0.001). There was no statistically significant difference with respect to satisfaction with pain control, 4.49 ±â€Š0.85 pre-protocol versus 4.51 ±â€Š0.82 post-protocol (P = 0.986). CONCLUSION: A reduction in opioids prescribed at discharge after one- or two-level lumbar fusion is not associated with any statistically significant change in patient satisfaction with pain management, as measured by the HCAHPS survey.Level of Evidence: 3.

Pseudarthrosis and Rod Fracture Rates After Transforaminal Lumbar Interbody Fusion at the Caudal Levels of Long Constructs for Adult Spinal Deformity Surgery.

BACKGROUND: Interbody fusion at the caudal levels of long constructs for adult spinal deformity (ASD) surgery is used to promote fusion and secure a solid foundation for maintenance of deformity correction. We sought to evaluate long-term pseudarthrosis, rod fracture, and revision rates for TLIF performed at the base of a long construct for ASD. METHODS: We reviewed 316 patients who underwent TLIF as a component of ASD surgery for medical comorbidities, surgical characteristics, and rate of unplanned reoperation for pseudarthrosis or instrumentation failure at the TLIF level. Fusion grading was assessed after revision surgery for pseudarthrosis at the TLIF level. RESULTS: Rate of pseudarthrosis at the TLIF level was 9.8% (31/316), and rate of rod fractures was 7.9% (25/316). The rate of revision surgery at the TLIF level was 8.9% (28/316), and surgery was performed at a mean of 20.4 ± 16 months from the index procedure. Current smoking status (odds ratio 3.34, P = 0.037) was predictive of pseudarthrosis at the TLIF site. At a mean follow-up of 43 ± 12 months after revision surgery, all patients had achieved bony union at the TLIF site. CONCLUSIONS: At 3-year follow-up, the rate of pseudarthrosis after TLIF performed at the base of a long fusion for ASD was 9.8%, and the rate of revision surgery to address pseudarthrosis and/or rod fracture was 8.9%. All patients were successfully treated with revision interbody fusion or posterior augmentation of the fusion mass, without need for further revision procedures at the TLIF level.

Same Day Surgical Intervention Dramatically Minimizes Complication Occurrence and Optimizes Perioperative Outcomes for Central Cord Syndrome.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The aim of this study was to investigate associations between time to surgical intervention and outcomes for central cord syndrome (CCS) patients. BACKGROUND: As surgery is increasingly recommended for patients with neurological deterioration CCS, it is important to investigate the relationship between time to surgery and outcomes. MATERIALS AND METHODS: CCS patients were isolated in Nationwide Inpatient Sample database 2005-2013. Patients were grouped by time to surgery: same-day, 1-day delay, 2, 3, 4-7, 8-14, and >14 days. Means comparison tests compared patient factors, perioperative complications, and charges across patient groups. Controlling for age, comorbidities, length of stay, and concurrent traumatic fractures, binary logistic regression assessed surgical timing associated with increased odds of perioperative complication, using same-day as reference group. RESULTS: Included: 6734 CSS patients (64% underwent surgery). The most common injury mechanisms were falls (30%) and pedestrian accidents (7%). Of patients that underwent surgery, 52% underwent fusion, 30% discectomy, and 14% other decompression of the spinal canal. Breakdown by time to procedure was: 39% same-day, 16% 1-day, 10% 2 days, 8% 3 days, 16% 4-7 days, 8% 8-14 days, and 3% >14 days. Timing groups did not differ in trauma status at admission, although age varied: [minimum: 1 d (58±15 y), maximum: >14 d (63±13 y)]. Relative to other groups, same-day patients had the lowest hospital charges, highest rates of home discharge, and second lowest postoperative length of stay behind 2-day delay patients. Patients delayed >14 days to surgery had increased odds of perioperative cardiac and infection complications. Timing groups beyond 3 days showed increased odds of VTE and nonhome discharge. CONCLUSIONS: CCS patients undergoing surgery on the same day as admission had lower odds of complication, hospital charges, and higher rates of home discharge than patients that experienced a delay to operation. Patients delayed >14 days to surgery were associated with inferior outcomes, including increased odds of cardiac complication and infection.

Complications After Adult Spinal Deformity Surgeries: All Are Not Created Equal.

BACKGROUND: Data on timing of complications are important for accurate quality assessments. We sought to better define pre- and postdischarge complications occurring within 90 days of adult spinal deformity (ASD) surgery and quantify the effect of multiple complications on recovery. METHODS: We performed a review of 1040 patients who underwent ASD surgery (age: 46 ± 23; body mass index: 25 ± 7, American Society of Anesthesiologists [ASA] score: 2.5 ± 0.6, levels: 10 ± 4, revision: 9%, 3-column osteotomy: 13%). We assessed pre- and postdischarge complications and risk factors for isolated versus multiple complications, as well as the impact of multiple complications. RESULTS: The 90-day complication rate was 17.7%. 85 patients (8.2%) developed a predischarge complication, most commonly ileus (12%), and pulmonary embolism (PE; 7.1%). The most common causes of predischarge unplanned reoperation were neurologic injury (12.9%) and surgical site drainage (8.2%). Predictors of a predischarge complication included smoking (odds ratio [OR]: 2.2, P = .02), higher ASA (OR: 1.8, P = .008), hypertension (HTN; OR: 2.0, P = .004), and iliac fixation (OR: 4.3, P < .001). Ninety-nine patients (9.5%) developed a postdischarge complication, most commonly infection (34%), instrumentation failure (13.4%), and proximal junctional failure (10.4%). Predictors of postdischarge complications included chronic obstructive pulmonary disease (OR: 3.6, P < .0001), congestive heart failure (OR: 4.4, P = .016), HTN (OR: 2.3, P < .0001), and multiple rod construct (OR: 1.8, P = .02). Patients who developed multiple complications (9.3%) had a longer length of stay, and increased risk for readmission and unplanned reoperation. CONCLUSIONS: Knowledge regarding timing of postoperative complications in relation to discharge may better inform quality improvement measures. PE and implant-related complications play a prominent role in perioperative complications and need for readmission, with several modifiable risk factors identified. LEVEL OF EVIDENCE: Level 3. CLINICAL RELEVANCE: Advances in surgical techniques and instrumentation have improved postoperative radiographic and clinical outcomes after ASD surgery. The rate of complications after complex ASD surgery remains high, both at early postoperative and long term follow-up. This study reviews complications within 90 days of surgery, with an assessment of patient and surgical risk factors. We found that modifiable risk factors for early complications after ASD surgery include COPD, and current smoking. The data presented in this study also provide surgeons with knowledge of the most common complications encountered after ASD surgery, to aid in preoperative patient discussion.

Multi-institution analysis of racial disparity among African-American men eligible for prostate cancer active surveillance.

There is a significant controversy on whether race should be a factor in considering active surveillance for low-risk prostate cancer. To address this question, we analyzed a multi-institution database to assess racial disparity between African-American and White-American men with low risk prostate cancer who were eligible for active surveillance but underwent radical prostatectomy. A retrospective analysis of prospectively collected clinical, pathologic and oncologic outcomes of men with low-risk prostate cancer from seven tertiary care institutions that underwent radical prostatectomy from 2003-2014 were used to assess potential racial disparity. Of the 333 (14.8%) African-American and 1923 (85.2%) White-American men meeting active surveillance criteria, African-American men were found to be slightly younger (57.5 vs 58.5 years old; p = 0.01) and have higher BMI (29.3 v 27.9; p < 0.01), pre-op PSA (5.2 v 4.7; p < 0.01), and maximum percentage cancer on biopsy (15.1% v 13.6%; p < 0.01) compared to White-American men. Univariate and multivariate analysis demonstrated similar rates of upgrading, upstaging, positive surgical margin, and biochemical recurrence between races. These results suggest that single institution studies recommending more stringent AS enrollment criteria for AA men with a low-risk prostate cancer may not capture the complete oncologic landscape due to institutional variability in cancer outcomes. Since all seven institutions demonstrated no significant racial disparity, current active surveillance eligibility should not be modified based upon race until a prospective study has been completed.

Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.

INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). MAIN OUTCOME MEASURES: Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. RESULTS: Sildenafil and rolipram significantly decreased cell death after exposure to H2O2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. CONCLUSION: Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI.

Safety of Robot-Assisted Radical Prostatectomy with Pneumoperitoneum of 20 mm Hg: A Study of 751 Patients.

BACKGROUND AND PURPOSE: Early studies describing robot-assisted radical prostatectomy (RARP) reported the use of pneumoperitoneum at a pressure of 15 mm Hg. While higher insufflation pressures (20 mm Hg) may reduce venous oozing and improve visualization, the safety of this method has not been confirmed. This study evaluates the short-term perioperative outcomes of patients undergoing RARP with insufflation pressures of 20 mm Hg. PATIENTS AND METHODS: A single-surgeon, prospectively maintained database of patients undergoing RARP was retrospectively analyzed. Patients who underwent RARP with a pneumoperitoneum pressure of 15 and 20 mm Hg for the entire procedure were analyzed. Preoperative and postoperative hemoglobin levels and estimated glomerular filtration rate (eGFR) were compared. Complications, operative time, and estimated blood loss were also examined. RESULTS: The number of patients in the experimental (20 mm Hg) and control (15 mm Hg) groups were 550 and 201, respectively. The groups were well matched with respect to age and operative time. The experimental group had a significantly smaller decrease in mean hemoglobin levels after surgery (-1.18 vs-2.13 mg/dL, P<0.0001). There was no significant difference in the eGFR on the first day after surgery (postoperative day [POD]1) (88.4 vs 85.0 mL/min/1.73m(2), P=0.11) or in the change in eGFR from preoperative to POD1 levels (-0.49 vs 1.54 mL/min/1.73m(2), P=0.18). The complication rate in the experimental group was 8.55% vs 8.46% in the control group. CONCLUSION: Pneumoperitoneum using a pressure of 20 mm Hg for RARP is safe and has no significant short-term effects on renal function and hemoglobin. Increased insufflation pressure was not associated with a higher complication rate.

Inhibition of E2F1/CDK1 pathway attenuates neuronal apoptosis in vitro and confers neuroprotection after spinal cord injury in vivo.

Apoptosis of post-mitotic neurons plays a significant role in secondary tissue damage following traumatic spinal cord injury (SCI). Activation of E2F1-dependent transcription promotes expression of pro-apoptotic factors, including CDK1; this signal transduction pathway is believed to represent an important mechanism for the physiological or pathological neuronal cell death. However, a specific role for this pathway in neuronal apoptosis induced by SCI has not yet been reported. Here we demonstrate up-regulation of the E2F1/CDK1 pathway that is associated with neuronal apoptosis following impact SCI in rats. Expression of E2F1 and CDK1 were robustly up-regulated as early as 15 min after injury and sustained until 3 days post-injury. CDK1 activity and E2F1 downstream targets bim and c-Myb were significantly increased after SCI. Activation of E2F1/CDK1 signaling also was associated with death of neurons in vitro; this was attenuated by shRNA knockdown or pharmacological inhibition of the E2F1/CDK1 pathway. CR8, a novel and potent CDK1 inhibitor, blocked apoptosis of primary cortical neurons at low-micromolar concentrations. Moreover, SCI-induced up-regulation of E2F1/CDK1 and associated neuronal apoptosis was significantly attenuated by systemic injection of CR8 (1 mg/kg, i.p.) at 5 min after injury. CR8 significantly decreased posttraumatic elevation of biochemical markers of apoptosis, such as products of caspase-3 and α-fodrin cleavage, as well as neuronal cell death, as indicated by TUNEL staining. Importantly, CR8 treatment also increased the number of surviving neurons at 5 weeks after injury. Together, these findings indicate that activation of the E2F1/CDK1 pathway contributes to the pathophysiology of SCI and that selective inhibition of this signaling cascade may represent an attractive therapeutic strategy.

Impact of surgical margin status on prostate-cancer-specific mortality.

UNLABELLED: Study Type--Diagnostic (exploratory cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Surgical margin status at radical prostatectomy (RP) has been shown to be a predictor of disease progression and the strongest predictor of benefit from adjuvant therapy, but the impact of a positive surgical margin (PSM) on long-term prostate-cancer-specific survival is unknown. The PSM rate is dependent on the pathological stage of the cancer. In a recent multicentre nomogram for 15-year prostate-cancer-specific mortality (PCSM) after RP, PSM was not significantly associated with PCSM, while Gleason score and pathological stage were the only significant predictors. This has not been validated in a single centre, and PSM has been shown to vary greatly with surgical technique. This is the first study on the impact of PSM on PCSM in a single surgeon's cohort. In other centres, the decision to administer adjuvant therapy may be influenced by surgical margin status. In this cohort, men routinely did not receive adjuvant therapy, affording the unique opportunity to study the long-term implications of a PSM. OBJECTIVE: • To examine the relative impact of a positive surgical margin (PSM) and other clinicopathological variables on prostate-cancer-specific mortality (PCSM) in a large retrospective cohort of patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS: • Between 1982 and 2011, 4569 men underwent RP performed by a single surgeon. • Of the patient population, 4461 (97.6%) met all the inclusion criteria. • The median (range) age was 58 (33-75) years and the median prostate-specific antigen (PSA) was 5.4 ng/mL; RP Gleason score was ≤ 6 in 2834 (63.7%), 7 in 1351 (30.3%), and 8-10 in 260 (6.0%) patients; PSMs were found in 462 (10.4%) patients. • Cox proportional hazards models were used to determine the impact of a PSM on PCSM. RESULTS: • At a median (range) follow-up of 10 years (1-29), 187 men (4.3%) had died from prostate cancer. • The 20-year prostate-cancer-specific survival rate was 75% for those with a PSM and 93% for those without. • Compared with those with a negative surgical margin, men with a PSM were more likely to be older (median age 60 vs 58 years) and to have undergone RP in the pre-PSA era (36.6% vs 11.8%). Additionally, they were more likely to have a higher PSA level (median 7.6 vs 5.2 ng/mL), a Gleason score of ≥ 7 (58.7% vs 33.7%), and a non-organ-confined tumour (90.9% vs 30.6% [P < 0.001 for all]). • In a univariate model for PCSM, PSM was highly significant (hazard ratio [HR] 5.0, 95% confidence interval [CI] 3.7-6.7, P < 0.001). • In a multivariable model, adjusting for pathological variables and RP year, PSM remained an independent predictor of PCSM (HR 1.4, 95% CI 1.0-1.9, P = 0.036) with a modest effect relative to RP Gleason score (HR 5.7-12.6) and pathological stage (HR 2.2-11.0 [P < 0.001]). CONCLUSION: • Although a PSM has a statistically significant adverse effect on prostate-cancer-specific survival in multivariable analysis, Gleason grade and pathological stage were stronger predictors.

Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion.

BACKGROUND: Traumatic spinal cord injury (SCI) induces secondary tissue damage that is associated with astrogliosis and inflammation. We previously reported that acute upregulation of a cluster of cell-cycle-related genes contributes to post-mitotic cell death and secondary damage after SCI. However, it remains unclear whether cell cycle activation continues more chronically and contributes to more delayed glial change. Here we examined expression of cell cycle-related proteins up to 4 months following SCI, as well as the effects of the selective cyclin-dependent kinase (CDKs) inhibitor CR8, on astrogliosis and microglial activation in a rat SCI contusion model. METHODS: Adult male rats were subjected to moderate spinal cord contusion injury at T8 using a well-characterized weight-drop model. Tissue from the lesion epicenter was obtained 4 weeks or 4 months post-injury, and processed for protein expression and lesion volume. Functional recovery was assessed over the 4 months after injury. RESULTS: Immunoblot analysis demonstrated a marked continued upregulation of cell cycle-related proteins - including cyclin D1 and E, CDK4, E2F5 and PCNA - for 4 months post-injury that were highly expressed by GFAP+ astrocytes and microglia, and co-localized with inflammatory-related proteins. CR8 administrated systemically 3 h post-injury and continued for 7 days limited the sustained elevation of cell cycle proteins and immunoreactivity of GFAP, Iba-1 and p22PHOX - a key component of NADPH oxidase - up to 4 months after SCI. CR8 treatment significantly reduced lesion volume, which typically progressed in untreated animals between 1 and 4 months after trauma. Functional recovery was also significantly improved by CR8 treatment after SCI from week 2 through week 16. CONCLUSIONS: These data demonstrate that cell cycle-related proteins are chronically upregulated after SCI and may contribute to astroglial scar formation, chronic inflammation and further tissue loss.

Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury.

Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1(+) microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1(+) oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI.