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OBJECTIVE The direct lateral approach is an alternative to the transoral or endonasal approaches to ventral epidural lesions at the lower craniocervical junction. In this study, the authors performed, to their knowledge, the first in vitro biomechanical evaluation of the craniovertebral junction after sequential unilateral C1 lateral mass resection. The authors hypothesized that partial resection of the lateral mass would not result in a significant increase in range of motion (ROM) and may not require internal stabilization. METHODS The authors performed multidirectional in vitro ROM testing using a robotic spine testing system on 8 fresh cadaveric specimens. We evaluated ROM in 3 primary movements (axial rotation [AR], flexion/extension [FE], and lateral bending [LB]) and 4 coupled movements (AR+E, AR+F, LB + left AR, and LB + right AR). Testing was performed in the intact state, after C1 hemilaminectomy, and after sequential 25%, 50%, 75%, and 100% C1 lateral mass resection. RESULTS There were no significant increases in occipital bone (Oc)–C1, C1–2, or Oc–C2 ROM after C1 hemilaminectomy and 25% lateral mass resection. After 50% resection, Oc–C1 AR ROM increased by 54.4% (p = 0.002), Oc LB ROM increased by 47.8% (p = 0.010), and Oc–C1 AR+E ROM increased by 65.8% (p < 0.001). Oc–C2 FE ROM increased by 7.2% (p = 0.016) after 50% resection; 75% and 100% lateral mass resection resulted in further increases in ROM. CONCLUSIONS In this cadaveric biomechanical study, the authors found that unilateral C1 hemilaminectomy and 25% resection of the C1 lateral mass did not result in significant biomechanical instability at the occipitocervical junction, and 50% resection led to significant increases in Oc–C2 ROM. This is the first biomechanical study of lateral mass resection, and future studies can serve to validate these findings.

Background Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. Methods We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age >50 and ≤75 years and lymphopenia and/or high D-dimers (group 3) or age >75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation ≤94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Results Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18; HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32; HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. Conclusion CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. Funding BMBF FKZ 01KI20152; EudraCT 2020-001632-10. Disclosures Uta Merle, MD, Gilead: Sponsored congress travel and accommodation Markus Weigand, MD, Bbraun: Speakers fee/ad boards fee|Biotest: Speakers fee/ad boards fee|Eumedica: Speakers fee/ad boards fee|Gilead: Speakers fee/ad boards fee|MSD: Speakers fee/ad boards fee|Pfizer: Speakers fee/ad boards fee|Shionogi: Speakers fee/ad boards fee|SOBI: Speakers fee/ad boards fee Martin Bornhäuser, MD, Alexion: Honoraria|Jazz Pharmaceuticals: Honoraria|MSD: Honoraria|Novartis: Honoraria Nael Alakel, MD, Amgen: personal fee, travel grant|Gilead: personal fee, travel grant|MSD Sharp and Dohme GmbH: personal fee, travel grant|Pfizer: personal fee, travel grant Timo Wolf, MD, Gilead Sciences: Lecture fee, travel grant|Janssen Pharmaceuticals: Lecture fee, travel grant|Merck Sharp Dome: Lecture fee, travel grant Maria Vehreschild, Prof. Dr., 3M: speaker fee|Astellas: Advisor/Consultant|Astellas: speaker fee|biologische heilmittel heel gmbh: Grant/Research Support|BioNtech: Grant/Research Support|EUMEDICA: Advisor/Consultant|Farmak International Holding: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Speaker fee|Gilead Sciences: Advisor/Consultant|Immunic AG: Advisor/Consultant|MaaT: Advisor/Consultant|Merck: Advisor/Consultant|Merck: speaker fee|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: speaker fees|Pfizer: speaker fee|Roche Molecular Systems: Grant/Research Support|Roche Molecular Systems: speaker fees|SocraRTec R&D GmbH: Advisor/Consultant|Takeda California: Grant/Research Support Hanns-Martin Lorenz, MD, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Actelion: Advisor/Consultant|Actelion: Honoraria|Alexion: Advisor/Consultant|Alexion: Honoraria|Amgen: Advisor/Consultant|Amgen: Grant/Research Support|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Baxter: Advisor/Consultant|Baxter: Advisor/Consultant|Baxter: Honoraria|Baxter: Honoraria|Bayer Vital: Advisor/Consultant|Bayer Vital: Honoraria|Biogen: Advisor/Consultant|Biogen: Honoraria|BMS: Advisor/Consultant|BMS: Honoraria|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Celgene: Advisor/Consultant|Celgene: Honoraria|Fresenius: Advisor/Consultant|Fresenius: Honoraria|Genzyme: Advisor/Consultant|Genzyme: Honoraria|Gilead/Galapagos: Advisor/Consultant|Gilead/Galapagos: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Hexal: Advisor/Consultant|Hexal: Honoraria|Janssen-Cilag: Advisor/Consultant|Janssen-Cilag: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Medac: Advisor/Consultant|Medac: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Mundipharm: Advisor/Consultant|Mundipharm: Honoraria|Mylan: Advisor/Consultant|Mylan: Honoraria|Novartis: Advisor/Consultant|Novartis: Honoraria|octapharm: Advisor/Consultant|octapharm: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche/Chugai: Advisor/Consultant|Roche/Chugai: Honoraria|Sandoz: Advisor/Consultant|Sandoz: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria|Shire: Advisor/Consultant|Shire: Honoraria|SOBI: Advisor/Consultant|SOBI: Honoraria|Thermo Fisher: Advisor/Consultant|Thermo Fisher: Honoraria|UCB: Advisor/Consultant|UCB: Honoraria.

NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of “therapy-related” NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.

OBJECTIVEThe authors sought to describe the long-term recurrence patterns, prognostic factors, and effect of adjuvant or salvage radiotherapy (RT) on treatment outcomes for patients with spinal myxopapillary ependymoma (MPE).METHODSThe authors reviewed a tertiary institution IRB-approved database and collected data regarding patient, tumor, and treatment characteristics for all patients treated consecutively from 1974 to 2015 for histologically confirmed spinal MPE. Key outcomes included relapse-free survival (RFS), postrecurrence RFS, failure patterns, and influence of timing of RT on recurrence patterns. Cox proportional hazards regression and Kaplan-Meier analyses were utilized.RESULTSOf the 59 patients included in the study, the median age at initial surgery was 34 years (range 12–74 years), 30 patients (51%) were female, and the most common presenting symptom was pain (n = 52, 88%). Extent of resection at diagnosis was gross-total resection (GTR) in 39 patients (66%), subtotal resection (STR) in 15 (25%), and unknown in 5 patients (9%). After surgery, 10 patients (17%) underwent adjuvant RT (5/39 GTR [13%] and 5/15 STR [33%] patients). Median follow-up was 6.2 years (range 0.1–35.3 years). Overall, 20 patients (34%) experienced recurrence (local, n = 15; distant, n = 5). The median RFS was 11.2 years (95% CI 77 to not reached), and the 5- and 10-year RFS rates were 72.3% (95% CI 59.4–86.3) and 54.0% (95% CI, 36.4–71.6), respectively.STR was associated with a higher risk of recurrence (HR 6.45, 95% CI 2.15–19.23, p < 0.001) than GTR, and the median RFS after GTR was 17.2 years versus 5.5 years after STR. Adjuvant RT was not associated with improved RFS, regardless of whether it was delivered after GTR or STR. Of the 20 patients with recurrence, 12 (60%) underwent salvage treatment with surgery alone (GTR, n = 6), 4 (20%) with RT alone, and 4 (20%) with surgery and RT. Compared to salvage surgery alone, salvage RT, with or without surgery, was associated with a significantly longer postrecurrence RFS (median 9.5 years vs 1.6 years; log-rank, p = 0.006).CONCLUSIONSAt initial diagnosis of spinal MPE, GTR is key to long-term RFS, with no benefit to immediate adjuvant RT observed in this series. RT at the time of recurrence, however, is associated with a significantly longer time to second disease recurrence. Surveillance imaging of the entire neuraxis remains crucial, as distant failure is not uncommon in this patient population.

While highly efficient in hematological malignancies, bispecific antibodies (bsAbs), alike the closely related CAR T cells, are as of yet not successful in solid tumors. Moreover, all presently available T cell-mobilizing strategies cause substantial side effects that endanger patients and limit applicable doses and thus efficacy. Here we report on the development of CC-1, a PSMAxCD3 bsAb that is constructed in a novel IgG-based format (IgGsc) and contains a proprietary PSMA binder with extended reactivity. CC-1 displays a prolonged serum half-life, especially when compared to the BiTE bsAb format. Extensive in vitro and in vivo characterization demonstrated the potency of CC-1 to induce T cell activity in a highly target cell-restricted manner, resulting in profound antitumor activity, which among others allowed for elimination of large established tumors in humanized mice (Zekri et al, EMBO 2020). Exclusively funded by public resources, we conducted GMP production of CC-1 and in November 2019 initiated a first in human trial enrolling castration resistant prostate carcinoma patients (NCT04104607). The trial consists of two parts: a dose escalation phase with intra-individual dose escalation until the target dose of 826µg to determine overall safety, tolerability as well as the maximum tolerated dose (MTD), and a dose expansion phase, where patients are treated on the MTD level to detect possible efficacy. In August 2021, recruitment in the dose escalation phase was completed and the target dose was reached without DLT upon treatment of the 9th patient. A total of 14 patients were treated, with the most frequently observed toxicity being cytokine release syndrome (CRS) in 79% of patients. CRS did not exceed grade 2 according to the Lee et al. grading system (Lee et al., 2014) and resolved in most cases without additional application of tocilizumab. Besides hypertension (observed in 50% of patients), no further CC-1 related toxicities (i.e., Xerostomia, or anaphylactic reaction) were observed. As expected, after prophylactic tocilizumab application decreased neutrophile counts and elevated liver enzymes were observed in 86% and 43% of patients, respectively. In terms of efficacy, a rapid and profound decline of elevated PSA levels was observed in all the heavily pre-treated patients, with up to 60% reduction compared to baseline. Three patients of the dose escalation phase received multiple treatment cycles at the highest dose level, based on clinical tolerability, documented induction of potent T cell activation as well as rapid and profound decline of elevated PSA levels. Taken together, CC-1 is a promising compound with a favorable toxicity profile and promising clinical activity. Recruitment in the dose expansion phase is ongoing with the respective data to be presented at the meeting. Citation Format: Jonas S. Heitmann, Juliane S. Walz, Martin Pflügler, Maddalena Marconato, Christian M. Tegeler, Julia Reusch, Jannik Labrenz, Richard Schlenk, Gundram Jung, Helmut Salih. CC-1, a bispecific PSMAxCD3 antibody for treatment of prostate carcinoma: Results of the ongoing phase I dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT141.

OBJECTIVE Neurosurgery is among the most competitive residencies, as evidenced by the high number of applicants for relatively few positions. Although it is important to recruit candidates who have the intellectual capacity and drive to succeed, traditional objective selection criteria, such as US Medical Licensing Examination (USMLE) (also known as Step 1) score, number of publications, and class ranking, have not been shown to consistently predict clinical and academic success. Furthermore, these traditional objective parameters have not been associated with specific personality traits. METHODS The authors sought to determine the efficacy of a personality assessment in the selection of neurosurgery residents. Specifically, the aim was to determine the correlation between traditional measures used to evaluate an applicant (e.g., USMLE score, number of publications, MD/PhD status) and corresponding validated personality traits. RESULTS Fifty-four neurosurgery residency applicants were interviewed at the Cleveland Clinic during the 2014–2015 application cycle. No differences in validated personality scores were identified between the 46 MD applicants and 8 MD/PhD applicants. The mean USMLE score (± SD) was 252.3 ± 11.9, and those in the high-USMLE-score category (USMLE score ≥ 260) had a significantly lower “imaginative” score (a stress measure of eccentric thinking and impatience with those who think more slowly). The average number of publications per applicant was 8.6 ± 7.9, and there was a significant positive correlation (r = 0.339, p = 0.016) between greater number of publications and a higher “adjustment” score (a measure of being even-tempered, having composure under pressure). Significant negative correlations existed between the total number of publications and the “excitable” score (a measure of being emotionally volatile) (r = −0.299, p = 0.035) as well as the “skeptical” score (measure of being sensitive to criticism) (r = −0.325, p = 0.021). The average medical school rank was 25.8, and medical school rankings were positively correlated with the “imaginative” score (r = 0.287, p = 0.044). CONCLUSIONS This is the first study to investigate the use of personality scores in the selection of neurosurgical residents. The use of personality assessments has the potential to provide insight into an applicant's future behavior as a resident and beyond. This information may be useful in the selection of neurosurgical residents and can be further used to customize the teaching of residents and for enabling them to recognize their own strengths and weaknesses for self-improvement.

Objective Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.

OBJECTIVE Pedicle and lateral mass screw placement is technically demanding due to complex 3D spinal anatomy that is not easily visualized. Neurosurgical and orthopedic surgery residents must be properly trained in such procedures, which can be associated with significant complications and associated morbidity. Current training in pedicle and lateral mass screw placement involves didactic teaching and supervised placement in the operating room. The objective of this study was to assess whether teaching residents to place pedicle and lateral mass screws using navigation software, combined with practice using cadaveric specimens and Sawbones models, would improve screw placement accuracy. METHODS This was a single-blinded, prospective, randomized pilot study with 8 junior neurosurgical residents and 2 senior medical students with prior neurosurgery exposure. Both the study group and the level of training-matched control group (each group with 4 level of training-matched residents and 1 senior medical student) were exposed to a standardized didactic education regarding spinal anatomy and screw placement techniques. The study group was exposed to an additional pilot program that included a training session using navigation software combined with cadaveric specimens and accessibility to Sawbones models. RESULTS A statistically significant reduction in overall surgical error was observed in the study group compared with the control group (p = 0.04). Analysis by spinal region demonstrated a significant reduction in surgical error in the thoracic and lumbar regions in the study group compared with controls (p = 0.02 and p = 0.04, respectively). The study group also was observed to place screws more optimally in the cervical, thoracic, and lumbar regions (p = 0.02, p = 0.04, and p = 0.04, respectively). CONCLUSIONS Surgical resident education in pedicle and lateral mass screw placement is a priority for training programs. This study demonstrated that compared with a didactic-only training model, using navigation simulation with cadavers and Sawbones models significantly reduced the number of screw placement errors in a laboratory setting.

Background Interview experiences and postinterview communication during the residency match process can cause distress for applicants, and deserve further study. Objective We both quantified and qualified the nature of various interview behaviors during the 2015–2016 National Resident Matching Program (NRMP) Match and collected applicant perspectives on postinterview communication and preferences for policy change. Methods An anonymous, 31-question survey was sent to residency candidates applying to 8 residency programs at a single academic institution regarding their experiences at all programs where they interviewed. Results Of 6693 candidates surveyed, 2079 (31%) responded. Regarding interview experiences, applicants reported being asked at least once about other interviews, marital status, and children at the following rates: 72%, 38%, and 17%, respectively, and such questions arose at a reported mean of 25%, 14%, and 5% of programs, respectively. Female applicants were more frequently asked about children than male applicants (22% versus 14%, P Conclusions Applicants to several residency programs reported being asked questions that violate the NRMP Code of Conduct. The majority of applicants would prefer postinterview communication to be more regulated and less prevalent.

The Cleveland Clinic was established in 1921 under the direction of 4 experienced and iconic physicians: George Crile, Frank Bunts, William Lower, and John Phillips. The Clinic initially employed a staff of only 6 surgeons, 4 internists, 1 radiologist, and 1 biophysicist, but Crile was quick to realize the need for broadening its scope of practice. He asked his close friend, Harvey Cushing, for assistance in finding a suitable candidate to establish a department of neurosurgery at the Cleveland Clinic. With his full endorsement, Cushing recommended Dr. Charles Edward Locke Jr., a former student and burgeoning star in the field of neurosurgery. Unfortunately, Locke’s life and career both ended prematurely in the Cleveland Clinic fire of 1929, but not before he would leave a lasting legacy, both at the Cleveland Clinic and in the field of neurosurgery.

OBJECT The authors investigated quality of life (QOL) outcomes after primary versus revision discectomy. METHODS A retrospective review was performed for all patients who had undergone a primary or revision discectomy at the Cleveland Clinic Center for Spine Health from January 2008 through December 2011. Among patients in the revision cohort, they identified those who needed a second revision discectomy. Patient QOL measures were recorded before and after surgery. These measures included responses to the EQ-5D health questionnaire, Patient Health Questionnaire–9, Pain and Disability Questionnaire, and quality-adjusted life years (QALYs). Cohorts were compared by using independent-sample t-tests and Fisher exact tests for continuous and categorical variables, respectively. Multivariable logistic regression was performed to adjust for confounding. RESULTS A total of 196 patients were identified (116 who underwent primary discectomy and 80 who underwent revision discectomy); average follow-up time was 150 days. There were no preoperative QOL differences between groups. Postoperatively, both groups improved significantly in all QOL measures. For QALYs, the primary cohort improved by 0.25 points (p < 0.001) and the revision cohort improved by 0.18 points (p < 0.001). QALYs improved for significantly more patients in the primary than in the revision cohort (76% vs 59%, respectively; p = 0.02), and improvement exceeded the minimum clinically important difference for more patients in the primary cohort (62% vs 45%, respectively; p = 0.03). Of the 80 patients who underwent revision discectomy, yet another recurrent herniation (third herniation) occurred in 14 (17.5%). Of these, 4 patients (28.6%) chose to undergo a second revision discectomy and the other 10 (71.4%) underwent conservative management. For those who underwent a second revision discectomy, QOL worsened according to all questionnaire scores. CONCLUSIONS QOL, pain and disability, and psychosocial outcomes improved after primary and revision discectomy, but the improvement diminished after revision discectomy.

Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on high-resolution molecular diagnostics. The value of comprehensive molecular profiling based on whole-exome/genome sequencing (WES/WGS) and global RNA sequencing to guide therapeutic decisions in individual patients remains to be established. We report the results of MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a multicenter registry trial for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors conducted under the auspices of NCT Heidelberg/Dresden and the German Cancer Consortium (DKTK). Based on a standardized workflow for selection and consenting of patients, sample processing, WES/WGS and RNA sequencing, bioinformatic analysis, and technical validation of potentially actionable findings, we have analyzed more than 1300 poor-prognosis (median overall survival, 12 months) patients representing a broad spectrum of entities. Evaluation of the data by a cross-institutional molecular tumor board has allowed categorization into 7 different intervention baskets and formulation of evidence-based recommendations for clinical management in more than 80% of patients, which were implemented in approximately one third of cases. Overall response and disease control rates on molecularly guided treatment were significantly improved compared to prior systemic therapies, which translated into a progression-free survival (PFS) ratio of greater than 1.3 in more than 40% of cases. In 5% of patients, comprehensive genomic profiling allowed to refine the clinical diagnosis, as exemplified by several soft-tissue sarcomas not otherwise specified and carcinomas of unknown primary site that could be categorized based on their genotypes and subsequent histopathologic re-evaluation. Finally, systematic analysis of germline alterations revealed that 11% of patients had pathogenic (ACMG Class 4 or 5) variants in known tumor predisposition genes, and that 4% were carriers for autosomal recessive disorders. This prospective trial demonstrates that molecular profiling based on WES/WGS and RNA sequencing in a multi-institutional clinical setting is feasible, complements and advances routine molecular diagnostics, and creates clinically meaningful therapeutic opportunities in a significant proportion of patients. To improve clinical translation, the MASTER platform is now linked to a growing portfolio of cross-institutional basket trials. In the intermediate term, genomic profiling within MASTER will be integrated with additional layers of patient characterization and extended to additional treatment modalities (e.g. radiotherapy and surgical interventions). Citation Format: Peter Horak, Christoph Heining, Simon Kreutzfeldt, Christoph E. Heilig, Lino Möhrmann, Laura Gieldon, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Katja Beck, Daniela Richter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meißburger, Frederick Klauschen, Sebastian Ochsenreither, Gunnar Folprecht, Jens Siveke, Sebastian Bauer, Thomas Kindler, Christian Brandts, Melanie Börries, Nikolas von Bubnoff, Karsten Spiekermann, Philipp J. Jost, Klaus Schulze-Osthoff, Michael Bitzer, Peter Schirmacher, Christof von Kalle, Richard Schlenk, Barbara Klink, Barbara Hutter, Wilko Weichert, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Hanno Glimm, Stefan Fröhling. Clinical relevance of comprehensive genomic analysis in advanced-stage cancers and rare malignancies: Results from the MASTER trial of the German Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 468.

Background Approaches to the foramen magnum and upper cervical spine traditionally include the posterior midline, far lateral, and endoscopic endonasal approaches. The far lateral approach is a well-established technique for the removal of pathology ventrolateral to the brainstem and the craniocervical junction, but it may be too extensive for lesions limited to areas far from the midline. Objective To present an alternative to the commonly used approaches to the foramen magnum and upper cervical. Methods We used an approach directly overlying ventral or lateral pathology. Results Two cases are presented in which the direct lateral approach followed by an occipitocervical fusion was successfully performed. Conclusion This approach can be considered for patients in whom a ventral decompression is necessary but an endoscopic endonasal approach is undesirable or when a ventral, lateral, and ventrolateral resection of tumor, pannus, or infection is required.

Object The goal in this study was to determine the role of radiation therapy (RT) in the treatment of spinal myxopapillary ependymomas (MPEs). Methods Thirty-seven patients with histologically verified spinal MPEs were reviewed. Kaplan-Meier analyses and Cox proportional hazard regression were used to determine what patient and treatment factors influenced overall survival (OS) and recurrence. Results At the time of initial diagnosis, the median age was 33 years and the Karnofsky Performance Scale score was 80. In 86.5% of cases, the most common presenting symptom was pain. All patients received surgery as their initial treatment. Nine patients also received RT along with surgery, with a median total dose of 50.2 Gy. The mean survival time was 12.2 years; however, only 4 of 37 patients had died at the time of this study. None of the patient or treatment parameters significantly correlated with OS. Sixteen patients (43.2%) were found to have a recurrence, with a median time to recurrence of 7.7 years. None of the patient or treatment parameters correlated with recurrence-free survival for an initial recurrence. The median time to the second recurrence (recurrence following therapy for initial recurrence) was 1.6 years. Use of RT as salvage therapy after initial recurrence significantly correlated with longer times to a second recurrence. The median recurrence-free survival time before the second recurrence was 9.6 years for those who received RT versus 1.1 years for those who did not receive RT (p = 0.0093). None of the other parameters significantly correlated with a second recurrence. Conclusions Radiation therapy may have a role as salvage therapy in delaying recurrences of spinal MPEs.

BACKGROUND: In this preliminary study we used a goat model to quantify pressure at an interbody bone graft interface. Although the study was designed to assess fusion status, the concept behind the technology could lead to early detection of implant failure and potential hazardous complications related to motion-preservation devices. The purpose of this study was to investigate the feasibility of in vivo pressure monitoring as a strategy to determine fusion status. METHODS: Telemetric pressure transducers were implanted, and pressure at the bone graft interfaces of cervical interbody fusion autografts placed into living goats (Groups A and B) was evaluated. Group A constituted the 4-month survival group and Group B the 6-month survival group. One goat served as the study control (Group C) and was not implanted with a pressure transducer. An additional six cadaveric goat cervical spines (Group D) were obtained from a local slaughterhouse and implanted with bone grafts and ventral plates and used for in vitro biomechanical comparison to the specimens from Groups A and B. RESULTS: All goats demonstrated an increase in interface pressure within the first 10 days postoperatively, with the largest relative change in pressure occurring between the sixth and ninth days. The goats from Groups A and B had a 200% to 400% increase in relative pressure. CONCLUSIONS: Although this was a pilot study to assess pressure as an indicator for a fusion or pseudarthrosis, the preliminary data suggest that early bone healing is detectable by an increase in pressure. Thus, pressure may serve as an indicator of fusion status by detecting altered biomechanical parameters.

BACKGROUND Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro. METHODS We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50–100 μg/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA. RESULTS The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance. CONCLUSIONS Future trials should combine VPA with chemotherapy or demethylating agents. Cancer 2006. © 2005 American Cancer Society.

Objective Work hour restrictions and current quality, financial, and legal concerns have reduced resident operative volume and autonomy. Although laboratory (cadaveric or animal) dissection has a rich history in neurosurgery, its current role in resident training is unclear. Recent literature suggests educators have looked to simulation to accelerate the learning curve of acquiring neurosurgical technical skills. The purpose of this study was to determine the prevalence, characteristics, and extent of laboratory dissection in neurosurgical residency programs in the United States. Methods A survey was sent to program directors of all 100 neurosurgical residency programs in the United States. Results Response rate was 65%. Most programs (93.8%) incorporate laboratory dissection into resident training. Most programs have 1–3 (36.1%) or 4–6 (39.3%) sessions annually. Residents in postgraduate years 2–6 (85.2%–93.4%) most commonly participate. The most common topics are cranial approaches (100%), spinal approaches (88.5%), spine instrumentation (80.3%), and endoscopy (50.8%). Thirty-one (47.7%) programs use artificial physical model or virtual reality simulators; the most common simulators are endoscopy (15.4%), microvascular anastomosis (13.8%), and endovascular (10.8%). Only 8 programs (13.1%) formally grade dissection skills. Educators (95.4%) believe laboratory dissection is an integral component of training and no respondent believed simulation could currently provide greater educational benefit than laboratory dissection. Most (89.2%) respondents would support a national “suggested” dissection curriculum and manual. Conclusions In neurosurgical resident education, laboratory dissection is widely used; however, significant variation exists. Nonetheless, program directors believe laboratory dissection plays an integral role in neurosurgical training and is currently associated with greater educational benefit than simulation.

the goal in this study was to determine the role of radiation therapy (RT) in the treatment of spinal myxopapillary ependymomas (MPEs).thirty-seven patients with histologically verified spinal MPEs were reviewed. Kaplan-Meier analyses and Cox proportional hazard regression were used to determine what patient and treatment factors influenced overall survival (OS) and recurrence.at the time of initial diagnosis, the median age was 33 years and the Karnofsky Performance Scale score was 80. In 86.5% of cases, the most common presenting symptom was pain. All patients received surgery as their initial treatment. Nine patients also received RT along with surgery, with a median total dose of 50.2 Gy. The mean survival time was 12.2 years; however, only 4 of 37 patients had died at the time of this study. None of the patient or treatment parameters significantly correlated with OS. Sixteen patients (43.2%) were found to have a recurrence, with a median time to recurrence of 7.7 years. None of the patient or treatment parameters correlated with recurrence-free survival for an initial recurrence. The median time to the second recurrence (recurrence following therapy for initial recurrence) was 1.6 years. Use of RT as salvage therapy after initial recurrence significantly correlated with longer times to a second recurrence. The median recurrence-free survival time before the second recurrence was 9.6 years for those who received RT versus 1.1 years for those who did not receive RT (p = 0.0093). None of the other parameters significantly correlated with a second recurrence.radiation therapy may have a role as salvage therapy in delaying recurrences of spinal MPEs.

ObjectDeep infections of the spine are a significant cause of morbidity and death. Such infections complicate 0.7 to 11.9% of spinal procedures. Management includes intravenous antibiotic therapy, debridement and irrigation with primary closure, placement of drains, use of irrigation systems, and/or healing through secondary intention with wound packing. Vacuum-assisted closure (VAC) is a new alternative for treatment of patients with complex postoperative spinal infections. The aim of this study was to investigate the safety of this treatment method in this patient population.MethodsThe authors reviewed the charts of 16 consecutive patients treated with negative-pressure wound therapy at their institution between 2002 and 2006. All had deep infections of the spine and were treated with surgical debridement and placement of VAC dressings. All infections were postoperative. Members of the infectious disease service were involved in the care of all patients, and all patients received intravenous antibiotic therapy. The authors reviewed operative notes, discharge summaries, and notes from follow-up visits and assessed outcome on the basis of the same records.Three patients were lost to follow up, leaving a group of 13 with follow up of at least 90 days. Two patients experienced bleeding complications related to the continuous negative pressure of the VAC device. In two cases, the infections persisted and required reoperation. In one case, a skin graft was required because of nonhealing granulation tissue. One of the patients with bleeding complications died as a result of delayed complications related to intraoperative blood loss, blood loss via the VAC system, and refusal of a blood transfusion on religious grounds.ConclusionsNegative-pressure wound therapy has been employed as a treatment strategy for patients with complex postoperative spinal infections, but little is known of the complications associated with VAC in the spinal surgery patient population. Serious complications, including death, may be associated with use of the VAC system.

Object.Pedicle screw instrumentation of the thoracic spine remains technically challenging. Transverse process and costotransverse screw fixation techniques have been described as alternatives to pedicle screw fixation (PSF). In this study, the authors introduce thoracic transfacet PSF and compare its experimental biomechanical results with those of standard PSF in short-term cyclic loading in cadaveric thoracic specimens.Methods.Specimens were tested intact for six cycles at compressive loads of 250 N offset by 1 cm along appropriate axes to induce flexion, extension, and left and right lateral bending. The specimens were then fixed with either a pedicle screw/rod construct or transfacet pedicle screws and retested in the same fashion. After this sequence, specimens were loaded until failure in flexion mode at a rate of 5 mm/minute was observed.Both fixation constructs provided significantly greater stiffnesses than that demonstrated when the specimen was intact (p < 0.05, two-way analysis of variance). Additionally, the two constructs were statistically equivalent in terms of stiffness and load-to-failure values (p < 0.05, two-tailed nonpaired t-test). The only difference observed was that the low midthoracic region (T7–9) was biomechanically weaker than the upper midthoracic and lower thoracic areas in flexion after the destabilization and instrumentation-augmented stabilization procedures.Conclusions.In selected thoracic surgical procedures, transfacet PSF may, after analysis of long-term biomechanical data, potentially become a reasonable alternative to conventional PSF.

Dear Editor, We read with interest the paper by Epstein entitled: The need to add motor evoked potential monitoring to somatosensory and electromyographic monitoring in cervical spine surgery.[1] The paper reviews the spine surgery literature regarding the use of intraoperative neural monitoring (IONM). Theoretically, IONM should alert the operative team that impending neurological injury is possible and a corrective maneuver performed to prevent such. IONM may be problematic in that it might alarm and result in an abandonment or alteration of the surgical procedure when no true neurological deficit is subsequently demonstrated (false positive). More worrisome, however, is the situation when no alert is observed and neurological injury ensued (false negative). Debate may be held with regard to the most appropriate surgical procedures for the use of IONM. Ideally, this should involve procedures in which potentially harmful maneuvers can be reversed. A classic example is deformity correction, which can be reversed if IONM suggests such. In cases in which “surgical reversal” is not possible, IONM has been shown to demonstrate true and false positives, however, studies have not demonstrated improved outcomes.[7] Many infer that IONM is associated with improved clinical results. However, it should be noted that the referenced studies compared outcomes with historical cohorts. Epstein et al.[2] reported 100 cases of IONM monitored cervical surgeries with no new neurological deficit. The historical cohort of this study included 218 patients operated in years 1985-1989, 8 of which became quadriplegic. This control population is clearly an outlier, as quadriplegia following elective cervical spine surgery for degenerative conditions is, indeed, a rarity and the rate is far less than the nearly 4% reported in the referenced study. Other studies cited by Epstein[1] show a high rate of false positives or false negatives with IONM, and low rate of true positives.[3,5,6] During degenerative cervical spine surgery, neurological injury may occur any of several phases. It may occur during induction of anesthesia with resultant hypotension, during positioning (flexion or extension) of the cervical spine in either prone or supine position, from intraoperative hypotension, and/or from direct surgical trauma. With the exception of hypotension and positioning, none of these potential causes of neurological injury are reversible. IONM, therefore can only signal that a neurological injury may have occurred, but does not afford the surgeon an enhanced opportunity to remedy or mitigate the neurological injury. When spinal cord injury occurs from direct surgical trauma, IONM serves only to document the timing of the trauma and cannot assist with altering the clinical outcome. There may then be little utility for IONM in degenerative cervical spine surgery. This conclusion has been borne out in the literature. Resnick et al.[7] reviewed the literature regarding IONM for degenerative cervical spine surgery. Their published guidelines concluded that relying on IONM changes as an indication for altering surgical procedure or administration of steroids has not been shown to reduce the incidence of neurological deterioration. The addition of IONM to degenerative cervical surgery has financial implications, however, cost-benefit analysis has not demonstrated benefit.[4] IONM is also often used for medico-legal reasons. Epstein reviewed the cervical spine surgery verdicts and determined the causes for verdicts were negligent surgery, lack of informed consent, failure to diagnose/treat, and failure to brace. She speculated that failure to adequately perform IONM may become the fifth reason for verdicts in cervical spine surgery. As the guidelines for cervical spinal surgery do not include the use of IONM,[7] and no clear algorithm for intraoperative action when IONM changes are observed, the routine use of IONM cannot serve as protection against a plaintiffs’ verdict. In the authors’ opinion, IONM in spine surgery has a definite role. This role includes intradural tumor surgery, deformity surgery, and cases in which patient positioning in and of itself poses neurological risk. IONM, however, has not been proven effective as a neuroprotective maneuver in the majority of cervical degenerative surgical procedures.