Preoperative stereotactic radiosurgery for patients with 1-4 brain metastases: A single-arm phase 2 trial outcome analysis (NCT03398694).

Background: Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10-15% local failure. Targeting a resection cavity is imprecise, thus preoperative radiosurgery where the target is well-defined may be superior, however, the efficacy of preoperative SRS has not yet been tested in a clinical trial. Methods: We conducted a phase 2, single-arm trial of preoperative SRS followed by surgical resection in patients with 1-4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing a gamma knife or linear accelerator as per RTOG-9005 dosing criteria [Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291-298] based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results: The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, the primary endpoint of 6-month LC was 100% (95% CI: 0.891-1.000; P = .005). Secondary endpoints, presented as medians, were overall survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions: Our data confirms superior local control in patients who received preoperative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of preoperative SRS.

Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure.

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

Mycophenolate and methotrexate are better tolerated than azathioprine in myasthenia gravis.

Azathioprine is recommended as the first-line steroid-sparing immunosuppressive agent for myasthenia gravis. Mycophenolate and methotrexate are often considered as second-line choices despite widespread consensus on their efficacy. We aimed to gather real-world data comparing the tolerability and reasons for discontinuation for these agents, by performing a national United Kingdom survey of side effects and reasons for discontinuation of immunosuppressants in myasthenia gravis. Of 235 patients, 166 had taken azathioprine, 102 mycophenolate, and 40 methotrexate. The most common side effects for each agent were liver dysfunction for azathioprine (23 %), diarrhoea for mycophenolate (14 %), and fatigue for methotrexate (18 %). Women were generally more likely to experience side effects of immunosuppressants. Azathioprine was significantly more likely to be discontinued than mycophenolate and methotrexate due to side effects. There was no significant difference in treatment cessation due to lack of efficacy. This study highlights the significant side-effect burden of treatment for myasthenia gravis. Mechanisms to reduce azathioprine toxicity should be utilised, however mycophenolate and methotrexate appear to be good treatment choices if teratogenicity is not a concern. Women are disadvantaged due to higher frequency of side effects and considerations around pregnancy and breastfeeding. Treatments with improved tolerability are needed.

Increased arthroplasty surgeon energy consumption when performing primary total hip arthroplasty compared to total knee arthroplasty.

Introduction: Previously published studies have hypothesized that total hip arthroplasty (THA) requires the surgeon to expend more energy that total knee arthroplasty (TKA). However, techniques for performing these procedures have evolved. Therefore, we sought to compare if primary THA had increased energy expenditure compared to primary TKA. Methods: We prospectively recorded the heart rate, respiratory rate, minute ventilation, cadence, and energy expenditure of a single fellowship-trained arthroplasty surgeon while performing primary THA and TKA on 372 patients. Patient demographics and operative records were reviewed to evaluate differences in the physical demands of each surgical case. Age (64.3 versus 65.9 years, p = 0.1) and gender (54.8% versus 51.0% female, p = 0.5) were similar between THA and TKA, but TKAs had a higher body mass index (31.1 versus 28.7 kg/m2, p < 0.001). Chi-square and independent-samples t-tests were used to compare cohorts. Significance was set at p < 0.05. Results: THA tended to have 1.1 times longer operative time than TKA (102.2 versus 88.9 min, p < 0.001). THA had a statistically higher heart rate compared to TKA, although this is unlikely to be clinically significant (82.5 versus 80.7 beats/minute, p < 0.001). Respiratory Rate was 1.1 times higher (15.9 versus 14.9 respirations/minute, p < 0.001) and minute ventilation was 1.2 times higher (19.6 versus 16.9 L/min, p < 0.001) when performing THA. Cadence was 1.5 times higher when performing TKA (4.2 versus 2.8 steps/minute, p < 0.001). THA had a 1.2 times higher energy expenditure/patient (378.8 versus 312.0 Calories/patient, p < 0.001) and a 1.1 times higher energy expenditure/minute (3.7 versus 3.5 Calories/minute, p = 0.01) compared to TKA. Discussion: THA is associated with longer operative time and increased energy expenditure per compared to TKA. Despite THA and TKA procedures becoming more efficient, arthroplasty surgery continues to have heavy physical burden on the surgeon. Further research is needed to understand ways to decrease surgeon energy expenditure and promote career longevity.

The Molecular Evolution of Melanoma Distant Metastases.

The evolution of primary melanoma to lymph node and distant metastasis is incompletely understood. We examined the genomic diversity in melanoma progression in matched primary melanomas and lymph node and distant metastases from 17 patients. FISH analysis revealed cancer cell fractions with monotonic copy number alterations, including PHIP gain and PTEN loss, in the metastatic cascade. By contrast, the cancer cell fraction with copy number alterations for BPTF and MITF was reduced in lymph node metastases but increased in distant metastases. Separately, the cancer cell fraction with NCOA3 copy number alteration was comparable between primary tumors and lymph node metastases yet increased in distant metastases. These results suggest enrichment of the phosphoinositide 3-kinase and MITF pathways in the transition through the metastatic cascade. By contrast, next-generation sequencing analysis did not identify a consistent pattern of changes in variant allele frequency while revealing several intriguing findings, including decreased variant allele frequency in distant metastases and distinct drivers in lymph node versus distant metastases. These results provide evidence that distant melanoma metastasis does not always emanate from lymph node metastasis. These results enhance our understanding of clonal patterns of melanoma metastasis, with possible implications for targeted therapy and metastasis competency.

Patient-Derived Tumor Xenograft Study with CDK4/6 Inhibitor Plus AKT Inhibitor for the Management of Metastatic Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

A xenotransplantation mouse model to study physiology of the mammary gland from large mammals.

Although highly conserved in structure and function, many (patho)physiological processes of the mammary gland vary drastically between mammals, with mechanisms regulating these differences not well understood. Large mammals display variable lactation strategies and mammary cancer incidence, however, research into these variations is often limited to in vitro analysis due to logistical limitations. Validating a model with functional mammary xenografts from cryopreserved tissue fragments would allow for in vivo comparative analysis of mammary glands from large and/or rare mammals and would improve our understanding of postnatal development, lactation, and premalignancy across mammals. To this end, we generated functional mammary xenografts using mammary tissue fragments containing mammary stroma and parenchyma isolated via an antibody-independent approach from healthy, nulliparous equine and canine donor tissues to study these species in vivo. Cryopreserved mammary tissue fragments were xenotransplanted into de-epithelialized fat pads of immunodeficient mice and resulting xenografts were structurally and functionally assessed. Preimplantation of mammary stromal fibroblasts was performed to promote ductal morphogenesis. Xenografts recapitulated mammary lobule architecture and contained donor-derived stromal components. Mammatropic hormone stimulation resulted in (i) upregulation of lactation-associated genes, (ii) altered proliferation index, and (iii) morphological changes, indicating functionality. Preimplantation of mammary stromal fibroblasts did not promote ductal morphogenesis. This model presents the opportunity to study novel mechanisms regulating unique lactation strategies and mammary cancer induction in vivo. Due to the universal applicability of this approach, this model serves as proof-of-concept for developing mammary xenografts for in vivo analysis of virtually any mammals, including large and rare mammals.

Pelvic floor injury during vaginal birth is life-altering and preventable: what can we do about it?

Pelvic floor disorders after childbirth have distressing lifelong consequences for women, requiring more than 300,000 women to have surgery annually. This represents approximately 10% of the 3 million women who give birth vaginally each year. Vaginal birth is the largest modifiable risk factor for prolapse, the pelvic floor disorder most strongly associated with birth, and is an important contributor to stress incontinence. These disorders require 10 times as many operations as anal sphincter injuries. Imaging shows that injuries of the levator ani muscle, perineal body, and membrane occur in up to 19% of primiparous women. During birth, the levator muscle and birth canal tissues must stretch to more than 3 times their original length; it is this overstretching that is responsible for the muscle tear visible on imaging rather than compression or neuropathy. The injury is present in 55% of women with prolapse later in life, with an odds ratio of 7.3, compared with women with normal support. In addition, levator damage can affect other aspects of hiatal closure, such as the perineal body and membrane. These injuries are associated with an enlarged urogenital hiatus, now known as antedate prolapse, and with prolapse surgery failure. Risk factors for levator injury are multifactorial and include forceps delivery, occiput posterior birth, older maternal age, long second stage of labor, and birthweight of >4000 g. Delivery with a vacuum device is associated with reduced levator damage. Other steps that might logically reduce injuries include manual rotation from occiput posterior to occiput anterior, slow gradual delivery, perineal massage or compresses, and early induction of labor, but these require study to document protection. In addition, teaching women to avoid pushing against a contracted levator muscle would likely decrease injury risk by decreasing tension on the vulnerable muscle origin. Providing care for women who have experienced difficult deliveries can be enhanced with early recognition, physical therapy, and attention to recovery. It is only right that women be made aware of these risks during pregnancy. Educating women on the long-term pelvic floor sequelae of childbirth should be performed antenatally so that they can be empowered to make informed decisions about management decisions during labor.

Metabolic signatures of thymomas: potential biomarkers and treatment targets.

OBJECTIVES: A study of tumour metabolic reprogramming has revealed disease biomarkers and avenues for therapeutic intervention. Metabolic reprogramming in thymoma is currently understudied and largely unknown. This study utilized metabolomics and isotope tracing with 13C-glucose to metabolically investigate thymomas, adjacent thymic tissue and benign thymic lesions. METHODS: From 2017 to 2021, 20 patients with a suspected thymoma were recruited to this prospective Institutional Review Board approved clinical trial. At the time of surgery, 11 patients were infused with 13C-glucose, a stable, non-radioactive tracer which reports the flow of carbon through metabolic pathways. Samples were analysed by mass spectrometry to measure the abundance of >200 metabolites.13C enrichment was measured in patients who received 13C-glucose infusions. RESULTS: Histological analysis showed that 9 patients had thymomas of diverse subtypes and 11 patients had benign cysts. In our metabolomic analysis, thymomas could be distinguished from both adjacent thymus tissue and benign lesions by metabolite abundances. Metabolites in pyrimidine biosynthesis and glycerophospholipid metabolism were differentially expressed across these tissues.13C-glucose infusions revealed differential labelling patterns in thymoma compared to benign cysts and normal thymus tissue. The lactate/3PG labelling ratio, a metabolic marker in aggressive lung tumours correlated with lactate uptake, was increased in thymomas (1.579) compared to normal thymus (0.945) and benign masses (0.807) (thymic tissue versus tumour P = 0.021, tumour versus benign P = 0.013). CONCLUSIONS: We report metabolic biomarkers, including differential 13C labelling of metabolites from central metabolism, that distinguish thymomas from benign tissues. Altered glucose and lactate metabolism warrant further investigation and may provide novel therapeutic targets for thymoma.

Routine chest radiography after thoracostomy tube removal and during postoperative follow-up is not necessary after lung resection.

OBJECTIVES: The need for routine chest radiography following chest tube removal after elective pulmonary resection may be unnecessary in most patients. The purpose of this study was to determine the safety of eliminating routine chest radiography in these patients. METHODS: Patients who underwent elective pulmonary resection, excluding pneumonectomy, for benign or malignant indications between 2007 and 2013 were reviewed. Patients with in-hospital mortality or without routine follow-up were excluded. During this interval, our practice transitioned from ordering routine chest radiography after chest tube removal and at the first postoperative clinic visit to obtaining imaging based on symptomatology. The primary outcome was changes in management from results of chest radiography obtained routinely versus for symptoms. Characteristics and outcomes were compared using the Student t test and chi-square analyses. RESULTS: A total of 322 patients met inclusion criteria. Ninety-three patients underwent a routine same-day post-pull chest radiography, and 229 patients did not. Thirty-three patients (14.4%) in the nonroutine chest radiography cohort received imaging for symptoms, in whom 8 (24.2%) resulted in management changes. Only 3.2% of routine post-pull chest radiography resulted in management changes versus 3.5% of unplanned chest radiography with no adverse outcomes (P = .905). At outpatient postoperative follow-up, 146 patients received routine chest radiography; none resulted in a change in management. Of the 176 patients who did not have planned chest radiography at follow-up, 12 (6.8%) underwent chest radiography for symptoms. Two of these patients required readmission and chest tube reinsertion. CONCLUSIONS: Reserving imaging for patients with symptoms after chest tube removal and follow-up after elective lung resections resulted in a higher percentage of meaningful changes in clinical management.

Lowering Cranioplasty Infection Incidence with Novel Bone Flap Storage Protocol: A Retrospective Cohort Study.

BACKGROUND: After craniectomy, autologous bone flaps may be stored using wet or dry cryopreservation. After brain edema subsides, they are replaced during an operation termed cranioplasty. Cranioplasty is associated with 15% infection incidence. METHODS: We conducted a retrospective comparison of infection outcomes between wet and dry cryopreservation of cranioplasty bone flaps. Historically, bone flaps were stored utilizing wet cryopreservation-bone flap storage in 1 L of lactated Ringer's solution containing 80 mg gentamicin and 2 g nafcillin in a sterile plastic container secured in an unsterile plastic bag. Our newer dry cryopreservation protocol involved storage in gauze soaked in 80 mg gentamicin and 2 g nafcillin within a 3-layer sterile bag system. RESULTS: A total of 119 autologous bone flaps were included, with median follow-up of 3.9 months from cranioplasty. Overall, 10.9% became infected, requiring subsequent surgery; 18.4% of 49 bone flaps stored using wet cryopreservation became infected compared with only 5.7% of 70 dry cryopreservation bone flaps (P = 0.038; relative risk [RR] 0.311; absolute risk reduction 12.7%). Tobacco use (P = 0.076; RR 3.17) was not associated with increased infection risk. Infection incidence was similar for traumatic craniectomy indications compared to the other indications (12.0% trauma vs. 10.1% other; P = 0.750). On average, infected cranioplasty patients spent 8.5 more days hospitalized and faced increased risk of additional complications. CONCLUSIONS: Dry cryopreservation significantly decreases infection after cranioplasty when compared with wet cryopreservation, and this mitigates additional morbidity, mortality, and costs attributable to cranioplasty infection. Other nonmodifiable risk factors for cranioplasty infection were identified.

Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

Improving Selection for Sentinel Lymph Node Biopsy Among Patients With Melanoma.

Importance: Refining eligibility guidelines may identify more appropriate patients to undergo useful medical procedures. Objective: To improve cost-effectiveness in selecting patients with melanoma for sentinel lymph node biopsy (SLNB). Design, Setting, and Participants: This hybrid prognostic study/decision analytical model was conducted among patients with melanoma who were eligible for SLNB at 2 melanoma centers from Australia and the US from 2000 to 2014. Participants consisted of 2 cohorts of patients with melanoma undergoing SLNB and a cohort of eligible patients without SLNB. Individualized probabilities of SLNB positivity generated by a patient-centered methodology (PCM) were compared with those generated by conventional multiple logistic regression analysis investigating 12 prognostic factors. Prognostic accuracy was assessed by the area under the receiver operating characteristic curve (AUROC) for each methodology and by matched-pair analyses. Interventions: Triaging appropriate patients to undergo SLNB. Main Outcomes and Measures: Total number of SLNBs performed (giving total cost) vs number of SLNB-positive outcomes (a measure of effectiveness) was evaluated. Improved cost-effectiveness through judicious patient selection was interpreted as increased numbers of SLNB-positive outcomes achieved, decreased numbers of SLNBs performed, or both outcomes simultaneously. Results: Among 7331 patients with melanoma, SLNB outcomes were assessed in 3640 Australian patients (2212 males [60.8%]; 2447 aged >50 years [67.2%]) and 1342 US patients (774 males [57.7%]; 885 aged >50 years [66.0%]); 2349 patients eligible for SLNB who did not undergo the procedure were included in the simulation. PCM-generated probabilities achieved an AUROC of 0.803 in predicting SLNB positivity in the Australian cohort and 0.826 in the US cohort, higher than corresponding AUROCs generated by conventional logistic regression analysis. In simulation, adopting many SLNB-positive probabilities as minimally acceptable patient-selection criteria resulted in fewer procedures performed or increased the expected numbers of positive SLNBs. A minimally acceptable PCM-generated probability of 8.7% elicited the same number of SLNBs as historically performed (3640 SLNBs), with 1066 positive SLNBs (29.3%), constituting an improvement of 287 additional positive SLNBs compared with 779 actual positive SLNBs (36.8% improvement). In contrast, adopting a 23.7% PCM-generated minimum cutoff probability resulted in performing 1825 SLNBs, or 1815 fewer SLNBs than the actual experience (49.9%). It resulted in the same expected number of positive results (779 SLNBs), for a 42.7% positivity rate. Conclusions and Relevance: This prognostic study/decision analytical model found that the PCM approach outperformed conventional multiple logistic regression analysis in predicting which patients would have positive results on SLNB. These findings suggest that systematically producing and exploiting more accurate SLNB-positivity probabilities could improve the selection of patients with melanoma for SLNB compared with using established guidelines, thus improving the cost-effectiveness of the selection process. Eligibility guidelines to undergo SLNB should include a context-tailored minimum cutoff probability.

Primary Malignant Melanoma of the Gastroesophageal Junction Treated With Immunotherapy: A Case Report.

INTRODUCTION: Primary malignant melanoma of the esophagus constitutes 0.1% to 0.5% of all primary malignant esophageal neoplasms. Melanocytes are present within the squamous epithelium of the esophagus in the stratum basale layer with melanocytosis rare within the esophagus. Primary esophageal melanoma is aggressive and has a poor survival rate; 80% of patients have metastatic disease at diagnosis. Resection surgery is usually first-line treatment for localized primary malignant esophageal melanoma, but recurrence rates remain high. Tumor-specific immunotherapy has shown promising results. We report a case of primary malignant esophageal melanoma with metastasis to the liver treated with immunotherapy. CASE PRESENTATION: A 66-year-old woman presented with 2 months of progressive dysphagia and 3 episodes of hematemesis the previous night. Endoscopic examination showed a hypervascular distal esophageal mass. Biopsy was positive for S-100, SOX-10, and HMB-45 and showed rare mitotic figures with scattered pigment, consistent with melanoma. She was scheduled for esophagectomy initially, but instead pursued immunotherapy after liver metastasis was diagnosed during preop magnetic resonance imaging. Immunotherapy consisted of 8 cycles of pembrolizumab, followed by 4 months nivolumab and ipilimumab. The patient remains in remission 3 years after completing immunotherapy. DISCUSSION/CONCLUSIONS: Our patient was diagnosed with primary malignant esophageal melanoma of the distal esophagus with metastasis to the liver, a presentation that typically has a poor prognosis. Despite this, remission was achieved with immunotherapy without surgical intervention. Only a small number of cases of primary esophageal melanoma treated with immunotherapy have been reported-one showcasing tumor stabilization following several cycles of therapy with eventual metastasis, while our patient had a stable response to treatment. Further exploration of medical management with immunotherapy should be conducted, as it represents an alternative treatment for patients who do not have the option of surgical management.

Comparison of in vivo visco-hyperelastic properties of uterine suspensory tissue in women with and without pelvic organ prolapse.

The uterine suspensory tissue (UST) complex includes the cardinal (CL) and uterosacral "ligaments" (USL), which are mesentery-like structures that play a role in resisting pelvic organ prolapse (POP). Since there is no information on the time-dependent material properties of the whole structure in situ and in vivo, we developed and tested an intraoperative technique to quantify in vivo whether there is a significant difference in visco-hyperelastic behavior of the CL and USL between women with and without POP. Thirteen women with POP (cases) and four controls scheduled for surgery were selected from an ongoing POP study. Immediately prior to surgery, a computer-controlled linear servo-actuator with a series force transducer applied a continuous, caudally directed traction force while simultaneously recording the resulting cervical displacement in the same direction. After applying an initial 1.1 N preload, a ramp rate of 4 mm/s was used to apply a maximum force of 17.8 N in three "ramp-and-hold" test trials. A simplified bilateral four-cable biomechanical model was used to identify the material behavior of each ligament. For this, the initial cross-section areas of the CL and USL were measured on 3-T magnetic resonance image-based 3D models from each subject. The time-dependent strain energy function of CL/USL was defined with a three-parameter hyperelastic Mooney-Rivlin material model and a two-term Prony series in relaxation form. When cases were compared with controls, the estimated time-dependent material constants of CL and USL did not differ significantly. These are the first measurements that compare the in vivo and in situ visco-hyperelastic response of the tissues comprising the CL and USL to loading in women with and without prolapse. Larger sample sizes would help improve the precision of intergroup differences.

Hiatal failure: effects of pregnancy, delivery, and pelvic floor disorders on level III factors.

INTRODUCTION AND HYPOTHESIS: The failure of the levator hiatus (LH) and urogenital hiatus (UGH) to remain closed is not only associated with pelvic floor disorders, but also contributes to recurrence after surgical repair. Pregnancy and vaginal birth are key events affecting this closure. An understanding of normal and failed hiatal closure is necessary to understand, manage, and prevent pelvic floor disorders. METHODS: This narrative review was conducted by applying the keywords "levator hiatus" OR "genital hiatus" OR "urogenital hiatus" in PubMed. Articles that reported hiatal size related to pelvic floor disorders and pregnancy were chosen. Weighted averages for hiatal size were calculated for each clinical situation. RESULTS: Women with prolapse have a 22% and 30% larger LH area measured by ultrasound at rest and during Valsalva than parous women with normal support. Women with persistently enlarged UGH have 2-3 times higher postoperative failure rates after surgery for prolapse. During pregnancy, the LH area at Valsalva increases by 29% from the first to the third trimester in preparation for childbirth. The enlarged postpartum hiatus recovers over time, but does not return to nulliparous size after vaginal birth. Levator muscle injury during vaginal birth, especially forceps-assisted, is associated with increases in hiatal size; however, it only explains a portion of hiatus variation-the rest can be explained by pelvic muscle function and possibly injury to other level III structures. CONCLUSIONS: Failed hiatal closure is strongly related to pelvic floor disorders. Vaginal birth and levator injury are primary factors affecting this important mechanism.

Intrathecal Baclofen and Opioid Therapy: Cerebrospinal Fluid Leak and Infection Incidence, Risk Factors, and Outcomes.

BACKGROUND: Intrathecal drug therapy treats medically refractory spasticity and pain. cerebrospinal fluid (CSF) leak or infection can limit efficacy and increase morbidity. We aim to evaluate risk factors and outcomes after CSF leaks and infections requiring reoperation. MATERIALS AND METHODS: We retrospectively analyzed our 7-year experience of intrathecal baclofen and opioid operations using a protocol designed to limit CSF leakage and infections. Postoperative complication incidence and risk factors for reoperation were compared with published reports. We assessed outcomes after these complications. RESULTS: We analyzed 282 intrathecal baclofen (ITB) and intrathecal opioid (ITO) therapy operations (mean 2.27-year follow-up). 21% developed CSF leaks overall with similar incidences in ITB and ITO patients (19% vs. 25%, p0.3). Overall, 5% of patients developed deep infections with similar incidences between ITB and ITO cohorts (6% vs. 4%, p0.6). Tobacco use and age <50 years were significantly associated with CSF leak in ITO operations. Underweight body mass index, immunosuppression, tobacco use, and primary implantation were associated with infection. When CSF leak or infection occurred, patients suffered more perioperative adverse events and had elevated 90-day readmission rate compared with those without these complications. CONCLUSIONS: Our 7-year ITB and ITO therapy using the 8781 Ascenda intrathecal catheter highlights a higher reoperation rate for CSF leak and similar infection incidence to reports using traditional catheters. Multiple modifiable risk factors for CSF leak include recent tobacco use among ITO patients. Body mass index optimization and immunosuppressant elimination may reduce reoperation for infection.

Cauda equina syndrome.

Cauda equina syndrome is an uncommon but serious cause of lower back pain resulting from compression of the cauda equina nerve roots, most commonly by lumbar disc herniation. Red flag symptoms, such as bladder dysfunction, saddle anaesthesia and sciatica, should lead to high clinical suspicion of cauda equina syndrome. The British Association of Spinal Surgeons has published an updated standard of care for these patients because of the potentially debilitating effects of missed cases of cauda equina syndrome. This review summarises these standards and provides a framework to support quick triage of at-risk patients. Immediate magnetic resonance imaging, within 1 hour of presentation to the emergency department, is crucial in patients with suspected cauda equina syndrome to allow prompt diagnosis and treatment. Urgent decompressive surgery is usually recommended for the best outcomes, to reduce morbidity and complication rates.