How Does the Number of Brain Metastases Correlate With Normal Brain Exposure in Single-Isocenter Multitarget Multifraction Stereotactic Radiosurgery.

Purpose: To investigate the relationship between normal brain exposure in LINAC-based single-isocenter multitarget multifraction stereotactic radiosurgery or stereotactic radiation therapy (SRT) and the number or volume of treated brain metastases, especially for high numbers of metastases. Methods and Materials: A cohort of 44 SRT patients with 709 brain metastases was studied. Renormalizing to a uniform prescription of 27 Gy in 3 fractions, normal brain dose volume indices, including V23 Gy (volume receiving >23 Gy), V18 Gy (volume receiving >18 Gy), and mean dose, were evaluated on these plans against the number and the total volume of targets for each plan. To compare with exposures from whole-brain radiation therapy (WBRT), the SRT dose distributions were converted to equivalent dose in 3 Gy fractions (EQD3) using an alpha-beta ratio of 2 Gy. Results: With increasing number of targets and increasing total target volume, normal brain exposures to dose ≥18 Gy increases, and so does the mean normal brain dose. The factors of the number of targets and the total target volume are both significant, although the number of targets has a larger effect on the mean normal brain dose and the total target volume has a larger effect on V23 Gy and V18 Gy. The EQD3 mean normal brain dose with SRT planning is lower than conventional WBRT. On the other hand, SRT results in higher hot spot (ie, maximum dose outside of tumor) EQD3 dose than WBRT. Conclusions: Based on clinical SRT plans, our study provides information on correlations between normal brain exposure and the number and total volume of targets. As SRT becomes more greatly used for patients with increasingly extensive brain metastases, more clinical data on outcomes and toxicities is necessary to better define the normal brain dose constraints for high-exposure cases and to optimize the SRT management for those patients.

Revisiting the lung cancer screening eligibility criteria to promote equity for Black individuals.

BACKGROUND: Early detection using low-dose computed tomography reduces lung-cancer-specific mortality by 20% among high-risk individuals. Blacks are less likely than Whites to meet lung cancer screening (LCS) criteria under both the former and the updated United States Preventive Services Task Force (USPSTF) guidelines. The purpose of this study was to assess racial disparities in LCS eligibility and to propose tailored eligibility criteria for Blacks to enable equitable screening rate between Whites and Blacks. METHODS: Data for this study were obtained from the Behavioral Risk Factor Surveillance System (2017-2021). 101,552 subjects were included in the final analysis. By employing a systematic approach, we sought cut-off points at which Blacks were equally likely as Whites to be eligible for LCS. We evaluated the minimum age and smoking pack-years for Blacks while we retained the 2021 USPSTF criteria for Whites. The final decision was based on the minimum Wald's Chi-square statistics. RESULTS: The model we employed identified cut-off points at which Blacks were equally likely as Whites to be eligible for LCS. Retaining the 2021 USPSTF criteria for Whites, the model discovered a new pair of points for Blacks by reducing the minimum age to 43 years and decreasing the cumulative number of cigarettes smoked to 15 pack-years. Based on these cut-off points, we created tailored criteria for Blacks. Under the tailored criteria, Blacks (OR: 1.00; 95 %CI: 0.88-1.14) had the same odds of eligibility for LCS as Whites. The odds of eligibility for LCS by sex under the tailored criteria did not differ significantly for Black men (OR: 1.02; 95 %CI: 0.85-1.24) and Black women (OR: 0.95; 95 %CI: 0.81-1.12) compared to their respective White counterparts. CONCLUSIONS: These tailored criteria for Blacks eliminate the disparities between Blacks and Whites in LCS eligibility. Future studies should test the sensitivity and specificity of these tailored criteria.

Dosimetric evaluation of LINAC-based single-isocenter multi-target multi-fraction stereotactic radiosurgery with more than 20 targets: comparing MME, HyperArc, and RapidArc.

BACKGROUND: To compare the dosimetric quality of three widely used techniques for LINAC-based single-isocenter multi-target multi-fraction stereotactic radiosurgery (fSRS) with more than 20 targets: dynamic conformal arc (DCA) in BrainLAB Multiple Metastases Elements (MME) module and volumetric modulated arc therapy (VMAT) using RapidArc (RA) and HyperArc (HA) in Varian Eclipse. METHODS: Ten patients who received single-isocenter fSRS with 20-37 targets were retrospectively replanned using MME, RA, and HA. Various dosimetric parameters, such as conformity index (CI), Paddick CI, gradient index (GI), normal brain dose exposures, maximum organ-at-risk (OAR) doses, and beam-on times were extracted and compared among the three techniques. Wilcoxon signed-rank test was used for statistical analysis. RESULTS: All plans achieved the prescribed dose coverage goal of at least 95% of the planning target volume (PTV). HA plans showed superior conformity compared to RA and MME plans. MME plans showed superior GI compared to RA and HA plans. RA plans resulted in significantly higher low and intermediate dose exposure to normal brain compared to HA and MME plans, especially for lower doses of ≥ 8Gy and ≥ 5Gy. No significant differences were observed in the maximum dose to OARs among the three techniques. The beam-on time of MME plans was about two times longer than RA and HA plans. CONCLUSIONS: HA plans achieved the best conformity, while MME plans achieved the best dose fall-off for LINAC-based single-isocenter multi-target multi-fraction SRS with more than 20 targets. The choice of the optimal technique should consider the trade-offs between dosimetric quality, beam-on time, and planning effort.

Association of Radiation Dose to the Amygdala-Orbitofrontal Network with Emotion Recognition Task Performance in Patients with Low-Grade and Benign Brain Tumors.

BACKGROUND: Although data are limited, difficulty in social cognition occurs in up to 83% of patients with brain tumors. It is unknown whether cranial radiation therapy (RT) dose to the amygdala-orbitofrontal network can impact social cognition. METHODS: We prospectively enrolled 51 patients with low-grade and benign brain tumors planned for cranial RT. We assessed longitudinal changes on an emotion recognition task (ERT) that measures the ability to recognize emotional states by displaying faces expressing six basic emotions and their association with the RT dose to the amygdala-orbitofrontal network. ERT outcomes included the median time to choose a response (ERTOMDRT) or correct response (ERTOMDCRT) and total correct responses (ERTHH). RESULTS: The RT dose to the amygdala-orbitofrontal network was significantly associated with longer median response times on the ERT. Increases in median response times occurred at lower doses than decreases in total correct responses. The medial orbitofrontal cortex was the most important variable on regression trees predicting change in the ERTOMDCRT. DISCUSSION: This is, to our knowledge, the first study to show that off-target RT dose to the amygdala-orbitofrontal network is associated with performance on a social cognition task, a facet of cognition that has previously not been mechanistically studied after cranial RT.

A comprehensive evaluation of advanced dose calculation algorithms for brain stereotactic radiosurgery.

PURPOSE: Accurate dose calculation is important in both target and low dose normal tissue regions for brain stereotactic radiosurgery (SRS). In this study, we aim to evaluate the dosimetric accuracy of the two advanced dose calculation algorithms for brain SRS. METHODS: Retrospective clinical case study and phantom study were performed. For the clinical study, 138 SRS patient plans (443 targets) were generated using BrainLab Elements Voxel Monte Carlo (VMC). To evaluate the dose calculation accuracy, the plans were exported into Eclipse and recalculated with Acuros XB (AXB) algorithm with identical beam parameters. The calculated dose at the target center (Dref), dose to 95% target volume (D95), and the average dose to target (Dmean) were compared. Also, the distance from the skull was analyzed. For the phantom study, a cylindrical phantom and a head phantom were used, and the delivered dose was measured by an ion chamber and EBT3 film, respectively, at various locations. The measurement was compared with the calculated doses from VMC and AXB. RESULTS: In clinical cases, VMC dose calculations tended to be higher than AXB. It was found that the difference in Dref showed > 5% in some cases for smaller volumes < 0.3 cm3 . Dmean and D95 differences were also higher for small targets. No obvious trend was found between the dose difference and the distance from the skull. In phantom studies, VMC dose was also higher than AXB for smaller targets, and VMC showed better agreement with the measurements than AXB for both point dose and high dose spread. CONCLUSION: The two advanced calculation algorithms were extensively compared. For brain SRS, AXB sometimes calculates a noticeable lower target dose for small targets than VMC, and VMC tends to have a slightly closer agreement with measurements than AXB.

Stroke death in patients receiving radiation for head and neck cancer in the modern era.

Objectives: Head and neck cancer is a common malignancy frequently treated with chemotherapy and radiotherapy. Studies have shown an increased risk of stroke with the receipt of radiotherapy, but data on stroke-related mortality are limited, particularly in the modern era. Evaluating stroke mortality related to radiotherapy is vital given the curative nature of head and neck cancer treatment and the need to understand the risk of severe stroke in this population. Methods: We analyzed the risk of stroke death among 122,362 patients (83,651 patients who received radiation and 38,711 patients who did not) with squamous cell carcinoma of the head and neck (HNSCC) diagnosed between 1973 and 2015 in the SEER database. Patients in radiation vs. no radiation groups were matched using propensity scores. Our primary hypothesis was that radiotherapy would increase the hazard of death from stroke. We also examined other factors impacting the hazard of stroke death, including whether radiotherapy was performed during the modern era when IMRT and modern stroke care were available as well as increased HPV-mediated cancers of the head and neck. We hypothesized that the hazard of stroke death would be less in the modern era. Results: There was an increased hazard of stroke-related death in the group receiving radiation therapy (HR 1.203, p = 0.006); however, this was a very small absolute increase, and the cumulative incidence function of stroke death was significantly reduced in the modern era (p < 0.001), cohorts with chemotherapy (p=0.003), males (p=0.002), younger cohorts (p<0.001) and subsites other than nasopharynx (p=0.025). Conclusions: While radiotherapy for head and neck cancer increases the hazard of stroke death, this is reduced in the modern era and remains a very small absolute risk.

Cognitive and neuroimaging outcomes in individuals with benign and low-grade brain tumours receiving radiotherapy: a protocol for a prospective cohort study.

INTRODUCTION: Radiation-induced cognitive decline (RICD) occurs in 50%-90% of adult patients 6 months post-treatment. In patients with low-grade and benign tumours with long expected survival, this is of paramount importance. Despite advances in radiation therapy (RT) treatment delivery, better understanding of structures important for RICD is necessary to improve cognitive outcomes. We hypothesise that RT may affect network topology and microstructural integrity on MRI prior to any gross anatomical or apparent cognitive changes. In this longitudinal cohort study, we aim to determine the effects of RT on brain structural and functional integrity and cognition. METHODS AND ANALYSIS: This study will enroll patients with benign and low-grade brain tumours receiving partial brain radiotherapy. Patients will receive either hypofractionated (>2 Gy/fraction) or conventionally fractionated (1.8-2 Gy/fraction) RT. All participants will be followed for 12 months, with MRIs conducted pre-RT and 6-month and 12 month post-RT, along with a battery of neurocognitive tests and questionnaires. The study was initiated in late 2018 and will continue enrolling through 2024 with final follow-ups completing in 2025. The neurocognitive battery assesses visual and verbal memory, attention, executive function, processing speed and emotional cognition. MRI protocols incorporate diffusion tensor imaging and resting state fMRI to assess structural connectivity and functional connectivity, respectively. We will estimate the association between radiation dose, imaging metrics and cognitive outcomes. ETHICS AND DISSEMINATION: This study has been approved by the Research Subjects Review Board at the University of Rochester (STUDY00001512: Cognitive changes in patients receiving partial brain radiation). All results will be published in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04390906.

Exploratory Analysis of Associations Between Whole Blood Mitochondrial Gene Expression and Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue is a prevalent, debilitating, and persistent condition. Mitochondrial dysfunction is a putative contributor to cancer-related fatigue, but relationships between mitochondrial function and cancer-related fatigue are not well understood. OBJECTIVES: We investigated the relationships between mitochondrial DNA (mtDNA) gene expression and cancer-related fatigue, as well as the effects of fish and soybean oil supplementation on these relationships. METHODS: A secondary analysis was performed on data from a randomized controlled trial of breast cancer survivors 4-36 months posttreatment with moderate-severe cancer-related fatigue. Participants were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g each daily for 6 weeks. At pre- and postintervention, participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and provided whole blood for assessment of mtDNA gene expression. The expression of 12 protein-encoding genes was reduced to a single dimension using principal component analysis for use in regression analysis. Relationships between mtDNA expression and cancer-related fatigue were assessed using linear regression. RESULTS: Among 68 participants, cancer-related fatigue improved and expression of all mtDNA genes decreased over 6 weeks with no effect of treatment group on either outcome. Participants with lower baseline mtDNA gene expression had greater improvements in cancer-related fatigue. No significant associations were observed between mtDNA gene expression and cancer-related fatigue at baseline or changes in mtDNA gene expression and changes in cancer-related fatigue. DISCUSSION: Data from this exploratory study add to the growing literature that mitochondrial dysfunction may contribute to the etiology and pathophysiology of cancer-related fatigue.

Inflammation, Attention, and Processing Speed in Patients With Breast Cancer Before and After Chemotherapy.

BACKGROUND: Inflammation may contribute to cognitive difficulties in patients with breast cancer. We tested 2 hypotheses: inflammation is elevated in patients with breast cancer vs noncancer control participants and inflammation in patients is associated with worse attention and processing speed over the course of chemotherapy. METHODS: Serum cytokines (interleukin [IL]-4, 6, 8, 10; tumor necrosis factor [TNF]-α) and soluble receptors [sTNFRI, II]) were measured in 519 females with breast cancer before and after chemotherapy and 338 females without cancer serving as control participants. Attention and processing speed were measured by Rapid Visual Processing (RVP), Backward Counting (BCT), and Trail Making-A (TMT-A) tests. Linear regression models examined patient vs control cytokines and receptor levels, adjusting for covariates. Linear regression models also examined relationships between patient cytokines and receptor levels and test performance, adjusting for age, body mass index, anxiety, depression, cognitive reserve, and chemotherapy duration. Statistical tests were 2-sided (α = .05). RESULTS: sTNFRI and sTNFRII increased over time in patients relative to controls, whereas IL-4, IL-6, and IL-10 decreased. Prechemotherapy, higher IL-8 associated with worse BCT (ß = 0.610, SE = 0.241, P = .01); higher IL-4 (ß = -1.098, SE = 0.516, P = .03) and IL-10 (ß = -0.835, SE = 0.414, P = .04) associated with better TMT-A. Postchemotherapy, higher IL-8 (ß = 0.841, SE = 0.260, P = .001), sTNFRI (ß = 6.638, SE = 2.208, P = .003), and sTNFRII (ß = 0.913, SE = 0.455, P = .045) associated with worse BCT; higher sTNFRII also associated with worse RVP (ß = -1.316, SE = 0.587, P = .03). At prechemotherapy, higher IL-4 predicted RVP improvement over time (ß = 0.820, SE = 0.336, P = .02); higher sTNFRI predicted worse BCT over time (ß = 5.566, SE = 2.367, P = .02). Longitudinally, increases in IL-4 associated with BCT improvement (ß = -0.564, SE = 0.253, P = .03). CONCLUSIONS: Generally, worse attention and processing speed were associated with higher inflammatory cytokines and receptors and lower anti-inflammatory cytokines in patients; future confirmatory studies are needed.

Risk of brain metastases in T1-3N0 NSCLC: a population-based analysis.

AIM: Several consensus guidelines recommend against routine brain imaging at diagnosis of T1-3N0 non-small cell lung cancer (NSCLC). METHODS: From the Surveillance, Epidemiology and End Results registry, patients with pathologically confirmed T1-3N0 NSCLC were identified. Risks of brain metastases at time of initial diagnosis were analyzed. RESULTS: Patients selected to not undergo primary NSCLC resection had approximately tenfold greater incidence of brain metastases versus those who did. Younger age, adenocarcinoma histology, higher tumor stage and higher histologic grade were all significantly (p < 0.0001) associated with greater likelihood of presenting with brain metastases. CONCLUSION: Given the morbidity and mortality of brain metastases, routine brain screening after NSCLC diagnosis (particularly adenocarcinoma) may be justifiable, though more refined cost-benefit analyses are warranted.

Salvage Treatment and Survival for Relapsed Follicular Lymphoma Following Primary Radiation Therapy: A Collaborative Study on Behalf of ILROG.

PURPOSE: We previously reported that ∼30% of patients with localized follicular lymphoma (FL) staged by 18F-fluorodeoxyglucose positron emission tomography-computed tomography receiving primary radiation therapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed. METHODS AND MATERIALS: We conducted a multicenter, retrospective study of patients aged ≥18 years who received RT ≥ 24 Gy for stage I to II, grade 1 to 3A FL, staged with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier analysis and univariable and multivariable analyses with Cox regression. RESULTS: Of 512 patients with median follow-up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median of 23 months (range, 1-143) after primary RT. Median follow-up was 33 months after relapse. Three-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others-88.7% versus 97.6%, respectively (P = .01)-and remained significantly worse on multivariable analyses (follicular lymphoma international prognostic index-adjusted hazard ratio, 3.61; P = .009). Histology at relapse included 93 indolent (grade 1-3A), 3 FL grade 3B/not otherwise specified, and 18 diffuse large B-cell lymphoma; 35 patients did not undergo biopsy. Of those with follow-up ≥3 months who underwent biopsy (n = 74) or had presumed (n = 23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) had RT, and 4 (4.1%) had systemic therapy + RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n = 59, including 20 initially observed) 3-year FFP was 73.9%. CONCLUSIONS: Prognosis for patients with relapsed FL after primary radiation therapy is excellent, supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival compared with those with longer disease-free interval.

Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

Oral health and microbiota status in professional rugby players: A case-control study.

OBJECTIVE: Elite athletes are prone to develop oral diseases, which could increase the risk for injuries. The aim of this study was to evaluate the oral health and the composition of oral microbiota of elite rugby players compared to the general population. METHODS: We set up a case-control study by screening 24 professional rugby players (PRG) and 22 control patients (CG) for dental and gingival examinations and performed a taxonomic analysis and a predicted functional analysis of oral microbiota. RESULTS: The Decay, Missing and Filled (DMF) teeth index (5.54 ± 6.18 versus 2.14 ± 3.01; p = 0.01) and the frequency of gingivitis (58,33% versus 13.63%) were significantly increased in PRG compared to CG. PRG were characterized by a dysbiotic oral microbiota (Shannon Index: 3.32 ± 0.62 in PRG versus 3.79 ± 0.68 in CG; p = 0.03) with an increase of Streptococcus (58.43 ± 16.84 versus 42.60 ± 17.45; p = 0.005), the main genus implicated in caries. Predicted metagenomics of oral microbiota in rugby players was suggestive of a cariogenic metagenome favourable to the development of caries. CONCLUSIONS: Our study shows that the oral health of PRG was poorer than the general population. PRG are characterized by a dysbiotic oral microbiota with an increase of the relative abundance of Streptococcus genus, positively correlated to the weight and negatively correlated to the diversity of oral microbiota. CLINICAL SIGNIFICANCE: Dental screening should be included in the medical follow-up of professional rugby players as a part of their health management. New strategies such as using probiotics like Lactobacillus could help to control the dysbiosis of oral microbiota.

Cognitive Changes in Cancer Survivors.

Advances in cancer treatments have led to substantially improved survival for patients with cancer. However, many patients experience changes in cognition as a side effect of both cancer and cancer treatment. This occurs with both central nervous system (CNS) tumors and non-CNS tumors and in both children and adults. Studies of patients with non-CNS cancer have shown that cancer-related cognitive impairment (CRCI), which can include changes in memory, executive function, attention, and processing speed, occurs in up to 30% of patients prior to any treatment and in up to 75% of patients during treatment. A subset of patients with non-CNS and CNS cancer appear to be at higher risk for CRCI, so much research has gone into identifying who is vulnerable. Risk factors for CRCI in adults include cognitive reserve, age, genetic factors, and ethnicity; risk factors for children include genetic factors, female sex, younger age at diagnosis, chemotherapy dose, and both dose and field size for radiation. Although the field has made substantial strides in understanding and treating CRCI, more research is still needed to improve outcomes for both pediatric and adult cancer survivors.

Whole exome sequencing in the rat.

BACKGROUND: The rat genome was sequenced in 2004 with the aim to improve human health altered by disease and environmental influences through gene discovery and animal model validation. Here, we report development and testing of a probe set for whole exome sequencing (WES) to detect sequence variants in exons and UTRs of the rat genome. Using an in-silico approach, we designed probes targeting the rat exome and compared captured mutations in cancer-related genes from four chemically induced rat tumor cell lines (C6, FAT7, DSL-6A/C1, NBTII) to validated cancer genes in the human database, Catalogue of Somatic Mutations in Cancer (COSMIC) as well as normal rat DNA. Paired, fresh frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) liver tissue from naive rats were sequenced to confirm known dbSNP variants and identify any additional variants. RESULTS: Informatics analysis of available gene annotation from rat RGSC6.0/rn6 RefSeq and Ensembl transcripts provided 223,636 unique exons representing a total of 26,365 unique genes and untranslated regions. Using this annotation and the Rn6 reference genome, an in-silico probe design generated 826,878 probe sequences of which 94.2% were uniquely aligned to the rat genome without mismatches. Further informatics analysis revealed 25,249 genes (95.8%) covered by at least one probe and 23,603 genes (93.5%) had every exon covered by one or more probes. We report high performance metrics from exome sequencing of our probe set and Sanger validation of annotated, highly relevant, cancer gene mutations as cataloged in the human COSMIC database, in addition to several exonic variants in cancer-related genes. CONCLUSIONS: An in-silico probe set was designed to enrich the rat exome from isolated DNA. The platform was tested on rat tumor cell lines and normal FF and FFPE liver tissue. The method effectively captured target exome regions in the test DNA samples with exceptional sensitivity and specificity to obtain reliable sequencing data representing variants that are likely chemically induced somatic mutations. Genomic discovery conducted by means of high throughput WES queries should benefit investigators in discovering rat genomic variants in disease etiology and in furthering human translational research.

Immediate titanium cranioplasty after debridement and craniectomy for postcraniotomy surgical site infection.

BACKGROUND: For postcraniotomy surgical site infection (SSI) involving the bone, typical management involves craniectomy, debridement, and delayed cranioplasty. Disadvantages to delayed cranioplasty include cosmetic deformity, vulnerability of unprotected brain, and risks and costs associated with an additional operation. Many authors have attempted bone flap salvage by using various techniques. OBJECTIVE: We evaluate our experience with immediate titanium mesh cranioplasty at the time of craniectomy and debridement. METHODS: We retrospectively reviewed SSIs in patients that underwent craniotomy for treatment of a brain tumor. These patients were treated with craniectomy, debridement, and immediate titanium mesh cranioplasty followed by antibiotics. The primary outcome was recurrent infection. RESULTS: Twelve patients met the inclusion criteria. Risk factors for infection included preoperative radiation therapy (33%), prior craniotomy (33%), and postoperative CSF leak (25%). Median follow-up was 14 months. Ten (83%) patients had long-term resolution without recurrent infection. One patient required additional surgical debridement for persistent infection with successful placement of new titanium mesh. Another patient developed recurrent infection but opted for hospice care because of tumor progression. CONCLUSION: This series demonstrates the safety and feasibility of performing immediate titanium cranioplasty at the time of craniectomy and debridement in patients with postcraniotomy infections. This has been shown in patients with risk factors for poor wound healing. Immediate cranioplasty avoids the drawbacks, risks, and costs of delayed cranioplasty.

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Despite the fact that it has been intensively studied during the last decade, the function of the histone variant H2A.Z remains enigmatic. In the last few years, we and others have determined the localization of H2A.Z in various organisms. These studies have revealed that H2A.Z occupies different well defined regions in the genome. Interestingly, H2A.Z occupies the promoters and regulatory regions of active genes, as well as constitutive and facultative heterochromatin. The localization of H2A.Z on genomic regions with so diverse functions suggests that the roles of H2A.Z are multiple, only increasing the mystery around this molecule. The way H2A.Z finds its way into these regions is not fully understood but mechanisms that direct the specific incorporation of H2A.Z in promoters and enhancers have been well described. In this "point of view," we will review our recent work suggesting that non-targeted incorporation, coupled to targeted depletion of H2A.Z, is a novel mechanism for localizing H2A.Z to some regions. We propose that the various functions of H2A.Z may be a consequence of the mechanism used for its incorporation, as well as its interactions with other histone variants.

Absence of an association between glucose levels and surgical site infections in patients undergoing craniotomies for brain tumors.

OBJECT: In select patient populations, hyperglycemia has been shown to increase the risk of surgical site infection (SSI), whereas stringent glucose control has improved outcomes. To date, no study has focused on whether SSIs in patients with brain tumors undergoing resection are associated with hyperglycemia. METHODS: The authors performed a retrospective chart review of patients who underwent a craniotomy after receiving a diagnosis of brain tumor. From 2001 to 2008, 2485 patients underwent a craniotomy for tumor resection at the Brain Tumor & Neuro-Oncology Center at the Cleveland Clinic. Fifty-seven of these patients (2.3%) developed SSIs postoperatively. A matched case-control study design was used, with 57 patients who developed SSIs after craniotomy (cases) matched with 57 patients who did not develop SSIs (controls). The results were analyzed using both univariate and multivariate conditional logistic regression. RESULTS: Glucose level was not a significant factor in postoperative SSI (p = 0.83) after adjusting for duration of surgery and adherence to antibiotic prophylaxis. However, duration of surgery was significantly associated with postoperative SSI (p = 0.047). CONCLUSIONS: For patients who undergo craniotomy for definitive resection of a brain tumor, duration of surgery described more variation in the model to predict SSI than blood glucose levels.