Metolazone vs chlorothiazide in acute heart failure patients with diuretic resistance and renal dysfunction: a retrospective cohort study.

Guidelines recommend intravenous (IV) loop diuretics as first-line therapy for patients hospitalized with acute heart failure (AHF) and volume overload. Additional agents can be utilized for augmentation but there is limited guidance on agent selection. The study objective was to determine if chlorothiazide or metolazone is associated with differences in diuretic efficacy or safety in loop diuretic-resistant patients with AHF and renal dysfunction. We conducted a multi-center, retrospective cohort study of patients hospitalized with AHF and renal dysfunction who received metolazone or chlorothiazide in addition to IV loop diuretics. The primary endpoint was a comparison of 24-hour urine output (UOP) between the 24 hours before and after thiazide administration. Secondary and safety endpoints included weight change, requirement for vasopressors or inotropes, electrolyte abnormalities, and changes in renal function. A total of 223 patients were included. The mean daily diuretic doses were chlorothiazide 632 mg and metolazone 7 mg. Mean 24-hour UOP increased more among chlorothiazide- (1668 to 3826 mL) versus metolazone-treated patients (1672 to 2834 mL) (p<0.001) after addition of the second diuretic. No statistically significant differences in weight or serum creatinine changes were observed. More hypomagnesemia was observed in the chlorothiazide group; no differences in other electrolytes or serum creatinine were observed. Chlorothiazide was associated with a greater increase in 24-hour UOP than metolazone without an excess of potassium or serum creatinine derangements. However, weight changes did not differ significantly between groups. Future prospective studies are needed to confirm potential differences in diuretic response and safety.

Estimated Time of Arrival: Impact of Healthcare Disparities on Access to and Outcomes of Multidisciplinary Cleft Lip and Palate Care.

OBJECTIVE: To determine the impact of sociodemographic and clinical factors on patient presentation into the cleft care pathway and determine how delayed interventions may affect post-surgical outcomes. DESIGN: Retrospective study. SETTING: Multidisciplinary craniofacial clinics of two university hospitals. PATIENTS, PARTICIPANT: 135 patients with cleft lip and/or palate. INTERVENTIONS: Primary cheiloplasty, primary palatoplasty. MAIN OUTCOME MEASURES: Age at initial presentation, age at first surgery, lag time, delayed surgery, rate of return to the emergency department (ED), readmission rate, reoperations, and oronasal fistula development. RESULTS: Patients referred by OBGYN who underwent cheiloplasty had an earlier age at initial presentation (p < 0.01), earlier age at first surgery (p = 0.01), and a shorter lag time (p < 0.01) compared to children from other referral pathways. African American children had an older age at first surgery (p = 0.01) and a longer lag time (p = 0.02) when compared to non-African American children. Children with syndromes had an older age at first surgery (p < 0.01) and a longer lag time (p < 0.01) than children without syndromes. Patient race, cleft type, and syndromic status increased the odds of receiving delayed surgery. Patients who received delayed palatoplasty returned to the ED at a higher rate than patients who received non-delayed palatoplasty (p = 0.02). CONCLUSIONS: Our data suggest that referral source, race, and syndromic status influence the timeliness of cleft care. Surgeons should develop strong referral networks with local OBGYNs and hospitals to allow for an early entry into the cleft care pathway.

Infection After Lower-Limb Osseointegration: A Single-Center Retrospective Evaluation of Pathogens, Management, and Outcomes.

PURPOSE: Osseointegration (OI) is a novel alternative to traditional socket-suspended prostheses for lower-limb amputees, eliminating the socket-skin interface and allowing for weight bearing directly on the skeletal system. However, the stoma through which the implant attaches to the external prosthesis creates an ingress route for bacteria, and infection rates as high as 66% have been reported. The aims of this study are to classify infection management and long-term outcomes in this patient population to maximize implant salvage. METHODS: An institutional review board-approved retrospective analysis was performed on all patients who underwent lower-limb OI at our institution between 2017 and 2022. Demographic, operative, and outcome data were collected for all patients. Patients were stratified by the presence and severity of infection. Chi-square and t tests were performed on categorical and continuous data, respectively, using an alpha of 0.05. RESULTS: One hundred two patients met our study criteria; 62 had transfemoral OI and 40 had transtibial OI. Patients were followed for 23.8 months on average (range, 3.5-63.7). Osteomyelitis was more likely than soft tissue infection to be polymicrobial in nature (71% vs 23%, P < 0.05). Infections at the stoma were mostly (96%) managed with oral antibiotics alone, whereas deeper soft tissue infections also required intravenous antibiotics (75%) or operative washout (19%). Osteomyelitis was managed with intravenous antibiotics and required operative attention; 5 (71%) underwent washout and 2 (29%) underwent explantation. Both implants were replaced an average of 3.5 months after explantation. There was no correlation between history of soft tissue infection and development of osteomyelitis (P > 0.05). The overall implant salvage rate after infection was 96%. CONCLUSIONS: This study describes our institution's experience managing infection after OI and soft tissue reconstruction. Although infections do occur, they are easily treatable and rarely require operative intervention. Explantation due to infection is rare and can be followed up with reimplantation, reaffirming that OI is a safe and effective treatment modality.

Catastrophic complications following microvascular free tissue transfer: A 10-year review of NSQIP data.

INTRODUCTION: There is an absence of literature regarding the risks of catastrophic medical outcomes (CMOs) such as stroke, cardiac arrest, and pulmonary embolism in microvascular free tissue transfer. This study aims to determine the CMO and mortality rates, as well as risk factors, associated with microvascular reconstruction of the head and neck, extremity, and breast. METHODS: This study uses data from the American College of Surgeons National Surgical Quality Improvement Program. Cases of microvascular free tissue transfer from 2012 to 2021 were analyzed to assess the 30-day rates of CMOs, including death, as well as associated risk factors. RESULTS: Of the 22,839 included patients, 785 (3.44%) experienced 1043 CMOs, including 99 (0.43%) deaths. Pulmonary complications of prolonged respiratory failure and pulmonary embolism were the most common. Independent risk factors included age, male sex, underweight status, longer operation times, American Society of Anesthesiologists (ASA) class of III or above, wound classification other than clean, and underlying conditions such as diabetes, hypertension, chronic obstructive pulmonary disorder, dyspnea, metastatic cancer, and ventilator dependence. CMOs were associated with an average 10-day delay in hospital discharge. Multivariate regression analysis revealed that head and neck reconstructions were associated with increased risk of CMO (OR 4.96; p < 0.0001). CONCLUSION: This is the largest study to examine CMOs following microvascular free tissue transfer. Compared to previous literature spanning the period between 2006 and 2011, we observed a decreased rate of CMOs but a slight increase in 30-day mortality. Our data provide updated and comprehensive criteria for risk stratification and patient counseling. The modifiable risk factors reported in our study should be considered in elective, non-urgent cases of microvascular reconstruction.

Management of Total Frontal Bone Loss After Surgery for Craniosynostosis: The Modified Visor Bone Flap With Brain Cage.

Complications after craniosynostosis surgery occur in 11% to 36% of cases and may be precipitated by poor soft tissue coverage and concomitant exposure of non-sterile regions; sequelae may result in infection, osteomyelitis, and bone loss requiring complex reconstruction. In the pediatric population, autologous cranioplasty remains the gold standard due to growth potential and a more favorable complication profile than synthetic cranioplasty. Virtual surgery planning (VSP) and computer-assisted design (CAD)/computer-assisted manufacturing (CAM) technology can be utilized to create innovative, patient-specific autologous solutions, similar to the approach with synthetic cranioplasty. A novel surgical approach using VSP was used for an 18-month-old female with near total bifrontal bone loss. Surface area measurements were used to determine the amount of bone available to replace the infected frontal bone. VSP was utilized to determine the most efficient construct configuration possible to achieve maximal coverage via calculation of cranial bone surface area measurements. Surgical reconstruction of the defect was planned as a Modified Visor Bone Flap with Posterior Brain Cage. A construct was fashioned from available cranial bone struts to obtain widespread coverage. 3D Recon images from before and after surgery demonstrate almost complete re-ossification of the cranial vault with significant resulting clinical improvement. Reconstruction of total frontal bone loss is possible by utilizing this technique. VSP can improve the safety and efficiency of complex autologous cranial bone reconstructions. We propose a treatment algorithm to address the problem of near total frontal bone loss in young children for whom alloplastic implants are not suitable.

Targeted Nipple Reinnervation in Gender-affirming Mastectomy Using Autologous Nerve Graft.

Our team recently described targeted nipple reinnervation (TNR) during female-to-male gender-affirming mastectomy with free nipple grafting using either direct nerve coaptation or nerve allograft. The goals of TNR are to improve sensation (including erogenous sensation) and prevent numbness, paresthesias, chronic pain, and phantom sensation. Here, we describe our modified technique, which has evolved to use autologous intercostal nerve branches as donor nerves for reinnervation if direct nerve coaptation cannot be achieved. During TNR, the T3-T5 sensory branches are preserved and coapted to the repositioned nipple-areolar complex (NAC). In patients with donor nerves that were not adequate in length to allow for direct coaptation, autologous intercostal nerve branches were not used for coaptation (branches present along the chest wall that would otherwise be lost) or one of the T3-T5 branches were harvested. An end-to-end nerve repair between the autograft and donor nerves was done, and the donor nerve/autograft complex was coapted to the NAC. Targeted muscle reinnervation was performed after autograft harvest to prevent neuroma formation. TNR with intercostal nerve autograft is technically feasible in female-to-male gender-affirming mastectomy with free nipple grafting when direct coaptation is not possible. Chest reinnervation using autologous intercostal nerve branches as donor nerves is another option for reinnervation when the nerves are too short for direct coaptation. Because the collection of long-term data is ongoing, the effectiveness of NAC reinnervation using our technique will be described in a future publication.

Utilization of Healthcare Resources by Vascular Anomaly Patients: An Assessment of Healthcare Burden by Lesion Complexity.

Background: Vascular anomalies (VAs) are heterogeneous lesions. Symptoms vary widely by lesion type and complexity. VA patients often require life-long interdisciplinary care; however, there is a paucity of data on the healthcare utilization of VA patients, and their burden on the healthcare system remains largely unquantified. We hypothesize that healthcare utilization by complex lymphatic malformation (LM) and venous malformation (VM) patients will be significantly higher compared with simple LM and VM patients. Methods: A retrospective, longitudinal study was performed of LM/VM patients seen through multidisciplinary VA clinics between January 1, 2019 and December 31, 2020. Data were collected from each patient's first presentation through December 31, 2021 and included number of office visits, imaging studies, specialists involved, procedures, hospitalization data, and approximate costs, normalized to per year utilization. Patients were divided into "simple" and "complex" LMs/VMs. Involvement of the airway, more than one anatomic area, and/or complex lymphatic anomalies were defined as "complex." Results: In total, 28 simple and 29 complex LM patients and 51 simple and 18 complex VM patients were identified. Complex LM and VM patients had significantly higher numbers of imaging studies, specialists involved, procedures and hospitalizations, and costs incurred. Complex LM patients also had significantly higher per year office visits. Conclusions: VA care is chronic and costly, especially for complex LM/VM patients. LM/VM complexity was a predictor for increased inpatient and outpatient healthcare utilization and higher costs. Better awareness of the healthcare utilization trends of LM/VM patients will allow for improved counseling for these patients regarding prognosis and expectations.

A cellular selection identifies elongated flavodoxins that support electron transfer to sulfite reductase.

Flavodoxins (Flds) mediate the flux of electrons between oxidoreductases in diverse metabolic pathways. To investigate whether Flds can support electron transfer to a sulfite reductase (SIR) that evolved to couple with a ferredoxin, we evaluated the ability of Flds to transfer electrons from a ferredoxin-NADP reductase (FNR) to a ferredoxin-dependent SIR using growth complementation of an Escherichia coli strain with a sulfur metabolism defect. We show that Flds from cyanobacteria complement this growth defect when coexpressed with an FNR and an SIR that evolved to couple with a plant ferredoxin. When we evaluated the effect of peptide insertion on Fld-mediated electron transfer, we observed a sensitivity to insertions within regions predicted to be proximal to the cofactor and partner binding sites, while a high insertion tolerance was detected within loops distal from the cofactor and within regions of helices and sheets that are proximal to those loops. Bioinformatic analysis showed that natural Fld sequence variability predicts a large fraction of the motifs that tolerate insertion of the octapeptide SGRPGSLS. These results represent the first evidence that Flds can support electron transfer to assimilatory SIRs, and they suggest that the pattern of insertion tolerance is influenced by interactions with oxidoreductase partners.

Noninferiority Clinical Trial of Adapted START NOW Psychotherapy for Outpatient Opioid Treatment.

Background: Medications for opioid use disorder (MOUD) such as buprenorphine is effective for treating opioid use disorder (OUD). START NOW (SN) is a manualized, skills-based group psychotherapy originally developed and validated for the correctional population and has been shown to result in reduced risk of disciplinary infractions and future psychiatric inpatient days with a dose response effect. We investigate whether adapted START NOW is effective for treating OUD in a MOUD office-based opioid treatment (OBOT) setting in this non-inferiority clinical trial. Methods: Patients enrolled in once weekly buprenorphine/suboxone MOUD OBOT were eligible for enrollment in this study. Participants were cluster-randomized, individually-randomized, or not randomized into either START NOW psychotherapy or treatment-as-usual (TAU) for 32 weeks of therapy. Treatment effectiveness was measured as the number of groups attended, treatment duration, intensity of attendance, and overall drug use as determined by drug screens. Results: 137 participants were quasi-randomized to participate in SN (n = 79) or TAU (n = 58). Participants receiving START NOW psychotherapy, when compared to TAU, had comparable number of groups attended (16.5 vs. 16.7, p = 0.80), treatment duration in weeks (24.1 vs. 23.8, p = 0.62), and intensity defined by number of groups attended divided by the number of weeks to last group (0.71 vs. 0.71, p = 0.90). SN compared to TAU also had similar rates of any positive drug screen result (81.0% vs. 91.4%, p = 0.16). This suggests that adapted START NOW is noninferior to TAU, or the standard of care at our institution, for treating opioid use disorder. Conclusion: Adapted START NOW is an effective psychotherapy for treating OUD when paired with buprenorphine/naloxone in the outpatient group therapy setting. Always free and publicly available, START NOW psychotherapy, along with its clinician manual and training materials, are easily accessible and distributable and may be especially useful for low-resource settings in need of evidence-based psychotherapy.

Curriculum mapping of accredited pharmacy programs in the United States.

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US). METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates. RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate. CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

Osseointegration for Lower Limb Amputation: Understanding the Risk Factors and Time Courses of Soft Tissue Complications.

PURPOSE: Lower-limb osseointegrated prostheses are a novel alternative to traditional socket-suspended prostheses, which are often associated with poor fit, soft tissue damage, and pain. Osseointegration eliminates the socket-skin interface and allows for weight-bearing directly on the skeletal system. However, these prostheses can also be complicated by postoperative issues that can negatively impact mobility and quality of life. Little is known about the incidence of or risk factors for these complications as few centers currently perform the procedure. METHODS: A retrospective analysis was performed on all patients who underwent single-stage lower limb osseointegration at our institution between 2017 and 2021. Patient demographics, medical history, operative data, and outcomes were collected. Fisher exact test and unpaired t tests were performed to identify risk factors for each adverse outcome, and time-to-event survival curves were generated. RESULTS: Sixty patients met our study criteria: 42 males and 18 females with 35 transfemoral and 25 transtibial amputations. The cohort had an average age of 48 years (range, 25-70 years) and follow-up period of 22 months (range, 6-47 months). Indications for amputation were trauma (50), prior surgical complication (5), cancer (4), and infection (1). Postoperatively, 25 patients developed soft tissue infections, 5 developed osteomyelitis, 6 had symptomatic neuromas, and 7 required soft tissue revisions. Soft tissue infections were positively correlated with obesity and female sex. Neuroma development was associated with increased age at osseointegration. Neuromas and osteomyelitis were both associated with decreased center experience. Subgroup analysis by amputation etiology and anatomic location did not show significant differences in outcomes. Notably, hypertension (15), tobacco use (27), and prior site infection (23) did not correlate with worse outcomes. Forty-seven percent of soft tissue infections occurred in the 1 month after implantation, and 76% occurred in the first 4 months. CONCLUSIONS: These data provide preliminary insights into risk factors for postoperative complications arising from lower limb osseointegration. These factors are both modifiable (body mass index, center experience), and unmodifiable (sex, age). As this procedure continues to expand in popularity, such results are necessary to inform best practice guidelines and optimize outcomes. Further prospective studies are needed to confirm the above trends.

Osseointegration for Lower-Extremity Amputees: Operative Considerations from the Plastic Surgeon's Perspective.

➢: Osseointegration for lower-extremity amputees, while increasing in frequency, remains in its relative infancy compared with traditional socket-based prostheses. ➢: Ideal candidates for osseointegration have documented failure of a traditional prosthesis and should be skeletally mature, have adequate bone stock, demonstrate an ability to adhere to a longitudinal rehabilitation protocol, and be in an otherwise good state of health. ➢: Lowering the reoperation rate for soft-tissue complications depends heavily on surgical technique and on the implant device itself; the current gold standard involves a smooth implant surface for dermal contact as well as maximal skin resection to prevent skin breakdown against the prosthesis. This may include the need for thighplasty to optimize skin reduction. ➢: Interdisciplinary peripheral nerve management, such as targeted muscle reinnervation, performed in tandem with a plastic surgery team can treat existing and prevent future symptomatic neuromas, ultimately improving pain outcomes.

The Utility of Preoperative HbA1c as a Standardized Protocol in Elective Carpal Tunnel Release: A Retrospective Review of Clinical Outcomes.

Background: In an effort to reduce surgical complications, some institutions have implemented universal hemoglobin A1c (HbA1c) screening for all preoperative patients. However, the value of HbA1c screening for predicting clinically meaningful complications after elective carpal tunnel release (CTR) remains unclear. The purpose of this study was to investigate the clinically meaningful predicative value of HbA1c screening on postoperative complications following elective CTR. Methods: A retrospective cohort study of 790 patients who underwent CTR was performed. All patients had an HbA1c screening performed, regardless of whether they underwent the diagnosis for diabetes or not. Primary outcomes were overall complication rate, rates of major complications (readmission or reoperation), and rates of minor complications (surgical site infection and wound dehiscence). Patients were stratified into 3 groups based on HbA1c: HbA1c <7, HbA1c 7-8, and HbA1c >8. Results: The overall complication rate for all groups was 4.8%. Rates of major complications were 0.4% for readmission and 0.1% for reoperation. For minor complications, the odds ratio (OR) for the HbA1c 7-8 group was 0.6 (95% confidence interval [CI], 0.14-1.77), and for the HbA1c >8 group, the OR was 1.6 (95% CI, 0.66-3.60). All minor complications resolved with outpatient treatment. There were no statistically significant differences between the groups for any comparisons. Conclusions: Elective CTR has a low complication rate. Routine preoperative screening of HbA1c is of little value in predicting clinically meaningful complications.

Dislodgement of tissue expander ports in a patient without trauma or MRI history.

Tissue expansion is involved in the majority of breast reconstruction procedures in the United States. We describe a case of a 56-year-old woman who was found to have bilateral dislodged magnetic ports in her breast tissue expanders at her surgery to replace the expanders with permanent implants. An awareness that this can occur would be helpful for all plastic surgeons who perform breast reconstruction.

Systematic content analysis of patient evaluations of START NOW psychotherapy reveals practical strategies for improving the treatment of opioid use disorder.

BACKGROUND: Clinical trials provide consistent evidence for buprenorphine's efficacy in treating opioid use disorder (OUD). While the Drug Addiction Treatment Act of 2000 requires physicians to combine medication-assisted treatment (MAT) with behavioral intervention, there is no clear evidence for what form or elements of psychotherapy are most effective when coupled with MAT to treat OUD. This investigation involves focus groups designed to collect patient opinions about a specific psychotherapy, called START NOW, as well as general beliefs about various elements of psychotherapy for treating OUD. Our analysis reveals trends about patient preferences and strategies for improving OUD treatment. METHODS: Subjects included patients enrolled in buprenorphine/naloxone MAT at our institution's office-based opioid treatment program. All subjects participated in a single START NOW group session, which was led by a provider (physician or nurse practitioner trained and standardized in delivering START NOW). Consented subjects participated in satisfaction surveys and audio-recorded focus groups assessing individual beliefs about various elements of psychotherapy for treating OUD. RESULTS: Overall, 38 different focus groups, 92 participation events, and 44 unique subjects participated in 1-to-6 different START NOW session/audio-recorded focus group sessions led by a certified moderator. Demographic data from 36/44 subjects was collected. Seventy-five percent (33/44) completed the START NOW Assessment Protocol, which revealed self-reported behavioral trends. Analysis of all 92 START NOW Satisfaction Questionnaire results suggests that subjects' opinions about START NOW improved with increased participation. Our analysis of audio-recorded focus groups is divided into three subsections: content strategies for new psychotherapies, implementation strategies, and other observations. For example, participants request psychotherapies to target impulsivity and to teach future planning and build positive relationships. CONCLUSIONS: The results of this study may guide implementation of psychotherapy and improve the treatment of OUD, especially as it relates to improving the modified START NOW program for treating OUD. Our study also reveals a favorable outlook of START NOW with increased participation, suggesting that any initial reticence to this program can be overcome to allow for effective implementation.

Developing an Algorithm for Optimizing Care of Elderly Patients With Glioblastoma.

BACKGROUND: Elderly patients with glioblastoma have an especially poor prognosis; optimizing their medical and surgical care remains of paramount importance. OBJECTIVE: To investigate patient and treatment characteristics of elderly vs nonelderly patients and develop an algorithm to predict elderly patients' survival. METHODS: Retrospective analysis of 554 patients (mean age = 60.8; 42.0% female) undergoing first glioblastoma resection or biopsy at our institution (2005-2011). RESULTS: Of the 554 patients, 218 (39%) were elderly (≥65 yr). Compared with nonelderly, elderly patients were more likely to receive biopsy only (26% vs 16%), have ≥1 medical comorbidity (40% vs 20%), and develop postresection morbidity (eg, seizure, delirium; 25% vs 14%), and were less likely to receive temozolomide (TMZ) (78% vs 90%) and gross total resection (31% vs 45%). To predict benefit of resection in elderly patients (n = 161), we identified 5 factors known in the preoperative period that predicted survival in a multivariate analysis. We then assigned points to each (1 point: Charlson comorbidity score >0, subtotal resection, tumor >3 cm; 2 points: preoperative weakness, Charlson comorbidity score >1, tumor >5 cm, age >75 yr; 4 points: age >85 yr). Having 3 to 5 points (n = 78, 56%) was associated with decreased survival compared to 0 to 2 points (n = 41, 29%, 8.5 vs 16.9 mo; P = .001) and increased survival compared to 6 to 9 points (n = 20, 14%, 8.5 vs 4.5 mo; P < .001). Patients with 6 to 9 points did not survive significantly longer than elderly patients receiving biopsy only (n = 57, 4.5 vs 2.7 mo; P = .58). CONCLUSION: Further optimization of the medical and surgical care of elderly glioblastoma patients may be achieved by providing more beneficial therapies while avoiding unnecessary resection in those not likely to receive benefit from this intervention.

Improved Survival with Decreased Wait Time to Surgery in Glioblastoma Patients Presenting with Seizure.

BACKGROUND: Preoperative seizure is reported to confer favorable prognosis in glioblastoma patients, but studies to date have not investigated how broadly applicable seizure is as a prognostic factor. OBJECTIVE: To investigate if prompter surgical intervention affects the relationship between preoperative seizure and prognosis in glioblastoma patients, focusing on the development of tumor growth and/or additional preoperative symptoms after seizure. METHODS: Retrospective analysis of 443 patients (mean age = 60.2; 60% male) undergoing first glioblastoma resection at our institution (2005-2011). RESULTS: Preoperative seizure(s) occurred in 28% of patients (n = 124), of which 63 (51%) had only seizure at presentation. Patients experiencing seizure as their only preoperative symptom ("seizure-only"; n = 45) survived over twice as long as patients who presented with seizure and then later developed additional preoperative symptoms (n = 18; "other symptoms postseizure"; 26.8 vs 10.2 months, P < .001) and patients without preoperative seizure ("no seizure"; 26.8 vs 13.1 months, P < .001). Multivariate stepwise analysis revealed preoperative seizures only (hazard ratio 0.54 [0.37-0.75]; P < .001) to be independently associated with increased survival. Longer wait time from presentation (ie, diagnostic magnetic resonance imaging) to surgery was a risk factor for developing additional symptoms. Eleven "other symptoms postseizure" patients (69%) vs 6 of the "seizure-only" patients (15%) had wait times >45 days (P < .001). CONCLUSION: Seizure as the only preoperative symptom independently improved survival, however, when patients developed additional preoperative symptoms, typically due to surgical delay, no prognostic benefit was observed. Prompt diagnosis and neurosurgical intervention is warranted in patients with seizures without other preoperative symptoms to preserve their favorable prognosis.

A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.

Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1.

Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.

Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma.