A guide to interpreting systematic reviews and meta-analyses in neurosurgery and surgery.

INTRODUCTION: Systematic reviews (SRs) and meta-analyses (MAs) are methods of data analysis used to synthesize information presented in multiple publications on the same topic. A thorough understanding of the steps involved in conducting this type of research and approaches to data analysis is critical for appropriate understanding, interpretation, and application of the findings of these reviews. METHODS: We reviewed reference texts in clinical neuroepidemiology, neurostatistics and research methods and other previously related articles on meta-analyses (MAs) in surgery. Based on existing theories and models and our cumulative years of expertise in conducting MAs, we have synthesized and presented a detailed pragmatic approach to interpreting MAs in Neurosurgery. RESULTS: Herein we have briefly defined SRs sand MAs and related terminologies, succinctly outlined the essential steps to conduct and critically appraise SRs and MAs. A practical approach to interpreting MAs for neurosurgeons is described in details. Based on summary outcome measures, we have used hypothetical examples to illustrate the Interpretation of the three commonest types of MAs in neurosurgery: MAs of Binary Outcome Measures (Pairwise MAs), MAs of proportions and MAs of Continuous Variables. Furthermore, we have elucidated on the concepts of heterogeneity, modeling, certainty, and bias essential for the robust and transparent interpretation of MAs. The basics for the Interpretation of Forest plots, the preferred graphical display of data in MAs are summarized. Additionally, a condensation of the assessment of the overall quality of methodology and reporting of MA and the applicability of evidence to patient care is presented. CONCLUSION: There is a paucity of pragmatic guides to appraise MAs for surgeons who are non-statisticians. This article serves as a detailed guide for the interpretation of systematic reviews and meta-analyses with examples of applications for clinical neurosurgeons.

Prevalence of musculoskeletal complaints and health-related quality of life in a Maroon and Kalinya Indigenous rural village in Suriname.

PURPOSE: Musculoskeletal complaints (MSCs), a leading contributor to disability worldwide, have a major impact on health-related quality of life (HRQoL). Poor general health related to lifestyle factors such as smoking, alcohol consumption and physical inactivity can lead to a higher risk to suffer MSCs. For minority groups in Suriname such as the Maroons and the Indigenous peoples no research has been conducted regarding prevalence of MSCs, HRQoL and various lifestyle factors. The aims were to determine the prevalence of MSCs and HRQoL in two rural tribal villages in the forested interior of Suriname and to identify various lifestyle factors associated with HRQoL in these communities. METHOD: This was a cross-sectional community-based study using the Community Oriented Program for the Control of Rheumatic Diseases stage 1, phase 1 & 2 methodology in Goejaba, a Maroon village and Galibi, an Indigenous rural village. Sociodemographic data, self-reported comorbidities, past MSCs (for longer than seven days), lifestyle factors including smoking, alcohol use, body mass index (BMI) and physical activity (PA), and HRQoL (using the 36-item Short Form Survey (SF-36)) data were gathered among 153 Indigenous individuals in Galibi, and 516 Maroons in Goejaba. Regression models were constructed to explore associations between presence of MSCs, lifestyle factors and HRQoL. RESULTS: High prevalence rates for past MSCs were reported in Galibi (72.4%) and Goejaba (58.3%). In both communities, respondents with MSCs reported significantly worse HRQoL than persons without MSCs. MSCs and the presence of comorbidities had a strong negative association with HRQoL, whereas PA positively influenced the physical and mental health domains of the SF-36. Smoking, alcohol use and BMI showed no association with HRQoL. CONCLUSIONS: In this first study, a high prevalence for MSCs was reported in an Indigenous and Maroon rural community in Suriname. MSCs and comorbidities had a significant negative impact on HRQoL. PA was associated with higher self-reported HRQoL.

Spina bifida management in low- and middle-income countries - a comprehensive policy approach.

INTRODUCTION: Globally, spina bifida (SB) occurs more often in low- and middle-income countries, where the healthcare demands are often quite challenging. Several social/societal issues and/or lack of government support makes for incomplete SB management in many areas. Clearly, neurosurgeons should be knowledgeable about initial closure techniques and the basics of SB management, but must also advocate for the patients outside our immediate scope of care. METHODS: Recently, the Comprehensive Policy Recommendations for the Management of Spina Bifida and Hydrocephalus in Low- and Middle-Income Countries (CHYSPR) and the Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders (IGAP) publications emphasized the need for a more unified approach to SB care. Although both documents discuss other neurological conditions, they support SB as a congenital malformation needing attention. RESULTS: We identified several similarities for comprehensive SB care in these approaches - including education, governance, advocacy, and the need for continuum of care. Prevention was recognized as the most important aspect for SB going forward. A significant return of investment was noted, and both documents recommend more active neurosurgical involvement (i.e., folic acid fortification). CONCLUSION: A new call for holistic and comprehensive care for SB management is recognized. Neurosurgeons are called upon to use solid science to educate governments and actively participate to advocate for better care and most importantly, prevention. Folic acid fortification schemes are mandatory and neurosurgeons should advocate for global strategies.

Differences in outcomes of mandatory motorcycle helmet legislation by country income level: A systematic review and meta-analysis.

BACKGROUND: The recent Lancet Commission on Legal Determinants of Global Health argues that governance can provide the framework for achieving sustainable development goals. Even though over 90% of fatal road traffic injuries occur in low- and middle-income countries (LMICs) primarily affecting motorcyclists, the utility of helmet laws outside of high-income settings has not been well characterized. We sought to evaluate the differences in outcomes of mandatory motorcycle helmet legislation and determine whether these varied across country income levels. METHODS AND FINDINGS: A systematic review and meta-analysis were completed using the PRISMA checklist. A search for relevant articles was conducted using the PubMed, Embase, and Web of Science databases from January 1, 1990 to August 8, 2021. Studies were included if they evaluated helmet usage, mortality from motorcycle crash, or traumatic brain injury (TBI) incidence, with and without enactment of a mandatory helmet law as the intervention. The Newcastle-Ottawa Scale (NOS) was used to rate study quality and funnel plots, and Begg's and Egger's tests were used to assess for small study bias. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were stratified by high-income countries (HICs) versus LMICs using the random-effects model. Twenty-five articles were included in the final analysis encompassing a total study population of 31,949,418 people. There were 17 retrospective cohort studies, 2 prospective cohort studies, 1 case-control study, and 5 pre-post design studies. There were 16 studies from HICs and 9 from LMICs. The median NOS score was 6 with a range of 4 to 9. All studies demonstrated higher odds of helmet usage after implementation of helmet law; however, the results were statistically significantly greater in HICs (OR: 53.5; 95% CI: 28.4; 100.7) than in LMICs (OR: 4.82; 95% CI: 3.58; 6.49), p-value comparing both strata < 0.0001. There were significantly lower odds of motorcycle fatalities after enactment of helmet legislation (OR: 0.71; 95% CI: 0.61; 0.83) with no significant difference by income classification, p-value: 0.27. Odds of TBI were statistically significantly lower in HICs (OR: 0.61, 95% CI 0.54 to 0.69) than in LMICs (0.79, 95% CI 0.72 to 0.86) after enactment of law (p-value: 0.0001). Limitations of this study include variability in the methodologies and data sources in the studies included in the meta-analysis as well as the lack of available literature from the lowest income countries or from the African WHO region, in which helmet laws are least commonly present. CONCLUSIONS: In this study, we observed that mandatory helmet laws had substantial public health benefits in all income contexts, but some outcomes were diminished in LMIC settings where additional measures such as public education and law enforcement might play critical roles.

Delivery of essential surgery by family physicians.

Primary health care provides the framework for delivering the socially-informed, comprehensive and patient-centred care underlying robust health-care systems and is, therefore, central to achieving universal health coverage. Family physicians are best placed to embody primary health care's dual focus on community and population health because they are often employed in rural or district hospitals with limited human resources, particularly a lack of specialists. Here we want to illustrate how additional training for family physicians, the key clinicians in primary care, can play a critical role in reducing disparities in access to surgical, obstetric and anaesthesia care in low- and middle-income countries and in rural or remote settings. Examples are given of how training programmes can be developed in low-resource settings to equip family physicians with life-saving surgical skills and of how family physicians in high-income countries can be trained in the surgical skills essential for working overseas in low-income settings. Policy-makers should promote surgical practice among family physicians by supporting family medicine programmes that include additional surgical skills training and by expanding opportunities and incentives for family physicians to serve in rural areas. Moreover, national surgical plans should include a primary health care strategy for surgical care and, globally, family physicians should be considered in discussions of surgical care. Finally, surgeons, anaesthesiologists, obstetricians and family physicians should be encouraged to collaborate in ensuring that all patients, regardless of place of residence, receive safe and timely surgical care.

Les soins de santé primaires établissent le cadre requis pour des soins complets adaptés aux patients, gages d'un système de santé solide. Ils jouent donc un rôle central dans la mise en place d'une couverture maladie universelle. Dans ce contexte, les médecins de famille sont les mieux placés pour incarner une double perspective, la santé communautaire et la santé des populations, car ils travaillent souvent dans des hôpitaux ruraux ou de district qui disposent de ressources humaines limitées, surtout en termes de spécialistes. Le présent document montre dans quelle mesure une formation complémentaire dédiée aux médecins de famille, acteurs clés des soins de santé primaires, peut avoir un impact décisif sur la diminution des inégalités d'accès aux interventions chirurgicales, obstétriques et anesthésiques dans les pays à faible et moyen revenu, ainsi que dans les milieux ruraux ou isolés. Il existe de nombreux exemples qui illustrent la façon dont les programmes de formation peuvent être mis en œuvre dans les endroits manquant de ressources afin que les médecins de famille acquièrent des compétences chirurgicales vitales, et qui indiquent comment les médecins de famille des pays à haut revenu peuvent apprendre des techniques de chirurgie essentielles pour travailler outre-mer ou dans des régions plus défavorisées. Les législateurs devraient promouvoir la pratique chirurgicale chez les médecins de famille en soutenant les programmes qui incluent une formation complémentaire aux techniques de chirurgie, et en multipliant les opportunités et sources de motivation pour que les médecins de famille exercent dans les zones rurales. Par ailleurs, les projets nationaux devraient comporter une stratégie de soins de santé primaires pour les actes chirurgicaux et, globalement, les médecins de famille devraient être pris en compte dans les discussions consacrées aux interventions chirurgicales. Enfin, chirurgiens, anesthésistes, obstétriciens et médecins de famille devraient être encouragés à collaborer pour s'assurer que tous les patients, quel que soit leur lieu de résidence, puissent bénéficier de soins chirurgicaux au moment opportun et en toute sécurité.

La atención primaria de salud establece el marco para la prestación de una atención socialmente informada, integral y centrada en el paciente, que es la base de los sistemas sólidos de atención sanitaria y, por lo tanto, es fundamental para lograr la cobertura sanitaria universal. Los médicos de familia son los que mejor pueden asumir el doble enfoque de la atención primaria en la salud de la comunidad y de la población porque trabajan con frecuencia en hospitales rurales o de distrito que tienen recursos humanos limitados, en especial por la falta de especialistas. En este documento, se pretende ilustrar cómo la capacitación adicional de los médicos de familia, quienes son los profesionales clínicos clave en la atención primaria, puede desempeñar una función esencial en la reducción de las desigualdades que existen para acceder a los procedimientos quirúrgicos, obstétricos y de anestesia en los países de ingresos bajos y medios y en los zonas rurales o remotas. También se dan ejemplos de cómo se pueden elaborar programas de capacitación en entornos de bajos recursos para preparar a los médicos de familia con técnicas quirúrgicas que salvan vidas y de cómo se puede capacitar a los médicos de familia de los países de altos ingresos sobre las técnicas quirúrgicas esenciales para que trabajen en el extranjero en entornos de bajos ingresos. Los responsables de formular políticas deben promover la práctica quirúrgica entre los médicos de familia mediante su apoyo a los programas de medicina familiar que incluyan una capacitación adicional sobre técnicas quirúrgicas, así como la ampliación de las oportunidades y de los incentivos para que los médicos de familia presten servicios en las zonas rurales. Además, los planes quirúrgicos nacionales deben incluir una estrategia de atención primaria de salud para la intervención quirúrgica y, a nivel mundial, los médicos de familia se deben tener en cuenta en los debates sobre la intervención quirúrgica. Por último, se debe alentar a los cirujanos, anestesiólogos, obstetras y médicos de familia a que colaboren para garantizar que todos los pacientes, sea cual sea su lugar de residencia, reciban servicios quirúrgicos seguros y oportunos.

Globalization of national surgical, obstetric and anesthesia plans: the critical link between health policy and action in global surgery.

Efforts from the developed world to improve surgical, anesthesia and obstetric care in low- and middle-income countries have evolved from a primarily volunteer mission trip model to a sustainable health system strengthening approach as private and public stakeholders recognize the enormous health toll and financial burden of surgical disease. The National Surgical, Obstetric and Anesthesia Plan (NSOAP) has been developed as a policy strategy for countries to address, in part, the health burden of diseases amenable to surgical care, but these plans have not developed in isolation. The NSOAP has become a phenomenon of globalization as a broad range of partners - individuals and institutions - help in both NSOAP formulation, implementation and financing. As the nexus between policy and action in the field of global surgery, the NSOAP reflects a special commitment by state actors to make progress on global goals such as Universal Health Coverage and the United Nations Sustainable Development Goals. This requires a continued global commitment involving genuine partnerships that embrace the collective strengths of both national and global actors to deliver sustained, safe and affordable high-quality surgical care for all poor, rural and marginalized people.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

A comparison of publication to TBI burden ratio of low- and middle-income countries versus high-income countries: how can we improve worldwide care of TBI?

OBJECTIVE: Traumatic brain injury (TBI) is a global public health problem and more than 70% of trauma-related deaths are estimated to occur in low- and middle-income countries (LMICs). Nevertheless, there is a consistent lack of data from these countries. The aim of this work is to estimate the capacity of different and heterogeneous areas of the world to report and publish data on TBI. In addition, we wanted to estimate the countries with the highest and lowest number of publications when taking into account the relative TBI burden. METHODS: First, a bibliometric analysis of all the publications about TBI available in the PubMed database from January 1, 2008, to December 31, 2018, was performed. These data were tabulated by country and grouped according to each geographical region as indicated by the WHO: African Region (AFR), Region of the Americas (PAH), South-East Asia Region (SEAR), European Region (EUR), Eastern Mediterranean Region (EMR), and Western Pacific Region (WPR). In this analysis, PAH was further subdivided into Latin America (AMR-L) and North America (AMR-US/Can). Then a "publication to TBI volume ratio" was derived to estimate the research interest in TBI with respect to the frequency of this pathology. RESULTS: Between 2008 and 2018 a total of 8144 articles were published and indexed in the PubMed database about TBI. Leading WHO regions in terms of contributions were AMR-US/Can with 4183 articles (51.36%), followed by EUR with 2003 articles (24.60%), WPR with 1507 (18.50%), AMR-L with 141 articles (1.73%), EMR with 135 (1.66%), AFR with 91 articles (1.12%), and SEAR with 84 articles (1.03%). The highest publication to TBI volume ratios were found for AMR-US/Can (90.93) and EUR (21.54), followed by WPR (8.71) and AMR-L (2.43). Almost 90 times lower than the ratio of AMR-US/Can were the ratios for AFR (1.15) and SEAR (0.46). CONCLUSIONS: An important disparity currently exists between countries with a high burden of TBI and those in which most of the research is conducted. A call for improvement of data collection and research outputs along with an increase in international collaboration could quantitatively and qualitatively improve the ability of LMICs to ameliorate TBI care and develop clinical practice guidelines.

Consensus statement from the International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury : Consensus statement.

BACKGROUND: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries. RESULTS: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval. CONCLUSIONS: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction.

Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer.

Background: Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods: The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. Results: A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion: Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA.

Global neurosurgery: current and potential impact of neurosurgeons at the World Health Organization and the World Health Assembly. Executive summary of the World Federation of Neurosurgical Societies-World Health Organization Liaison Committee at the 71st World Health Assembly.

Since the creation of the World Health Organization (WHO) in 1948, the annual World Health Assembly (WHA) has been the major forum for discussion, debate, and approval of the global health agenda. As such, it informs the framework for the policies and budgets of many of its Member States. For most of its history, a significant portion of the attention of health ministers and Member States has been given to issues of clean water, vaccination, and communicable diseases. For neurosurgeons, the adoption of WHA Resolution 68.15 changed the global health landscape because the importance of surgical care for universal health coverage was highlighted in the document. This resolution was adopted in 2015, shortly after the publication of The Lancet Commission on Global Surgery Report titled "Global Surgery 2030: evidence and solutions for achieving health, welfare and economic development." Mandating global strengthening of emergency and essential surgical care and anesthesia, this resolution has led to the formation of surgical and anesthesia collaborations that center on WHO and can be facilitated via the WHA. Participation by neurosurgeons has grown dramatically, in part due to the official relations between WHO and the World Federation of Neurosurgical Societies, with the result that global neurosurgery is gaining momentum.

Multiplex KRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction.

Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy. Patients and methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care. Results: Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of ≥ 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001). Conclusion(s): Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival.

Cost-Effectiveness of Craniotomy for Epidural Hematomas at a Major Government Hospital in Cambodia.

BACKGROUND: Epidural hematoma (EDH) is a common and potentially deadly occurrence following a severe traumatic brain injury. Our aim was to determine whether craniotomy is cost-effective when indicated for the treatment of EDH when a trained neurosurgeon is available. METHODS: A decision tree was used to model the cost-effectiveness of craniotomy available versus craniotomy unavailable for the management of traumatic EDH from a Cambodian societal and provider perspective. Costs and effectiveness parameters were obtained from patient data at a large government hospital in Cambodia. Outcomes were measured in quality-adjusted life years (QALYs). Incremental cost per QALY and budget impact were calculated for each intervention at a willingness-to-pay (WTP) threshold of $9787.80/QALY (3× GDP per capita PPP). The time horizon reflected full life span, and costs and QALYs were discounted at 3%. Sensitivity analysis was also conducted. RESULTS: Compared to craniotomy unavailable for EDH ($945.80; 11.78 QALYs), craniotomy available came at a higher cost and greater effectiveness ($1520.73; 12.78 QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of $574.93. One-way analysis demonstrated that craniotomy unavailable became more cost-effective than craniotomy available when the percent chance of having a GOS of 4 or 5 was 60% for patients with an EDH where craniotomy was indicated but not performed. Probabilistic sensitivity analysis revealed that craniotomy available was more cost-effective than conservative management in 84.4% of simulations at the WTP threshold. CONCLUSIONS: Craniotomy is a cost-effective treatment for patients with a traumatic EDH who meet criteria for operation when trained neurosurgeons are available onsite.

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.

BACKGROUND: We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies. PATIENTS AND METHODS: Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available. RESULTS: Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively. CONCLUSION: The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01339871.

Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment.

INTRODUCTION: KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA). PATIENTS AND METHODS: Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS (wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations. RESULTS: Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004). CONCLUSION: Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.