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Charcot-Marie-Tooth (cmt) disease is the most common form of inherited neuropathy. Core features include peripheral neuropathy and secondary axonal degeneration, with a noted distal predominance of limb-muscle wasting, weakness, and sensory loss. Given the significant prevalence of cmt, superimposed neoplastic disease can be encountered within this patient population. Malignancies that are treated with vincristine (a microtubule-targeting agent), even at low doses as part of standard treatment, pose a significant challenge for patients with cmt. Here, we present the case of a child with cmt who was successfully treated for medulloblastoma without vincristine, a standard drug used for treatment of that disease, to avoid the risk of severe debilitating neuropathy. This report is the first of a patient successfully treated for medulloblastoma without vincristine. [ABSTRACT FROM AUTHOR]

Purpose: Volumetric modulated arc therapy (VMAT) has been shown clinically feasible for radiosurgical treatment of multiple cranial lesions even with a single isocenter. In this study, we investigated whether equivalent radiosurgical plan quality and reduced delivery time could be achieved in VMAT for patients with >4 cranial targets plans who had been previously treated at our institution with Gamma Knife (GK) radiosurgery. Methods: We identified a subset of 12 clinical Gamma Knife sessions with > 4 metastases. These were re-planned for multi-arc (MA) and single-arc (SA), single-isocenter VMAT (RapidArc) in Eclipse. Multi-arc plans utilized one 360° axial arc in concert with a 180° vertex arc, and two 45° off-axis transverse arcs. Single-arc plans solely used a 360° axial arc. The prescription for all targets was standardized to 18 Gy. Each plan was normalized for 100% prescription dose to 99-100% of target volume. Plan quality was analyzed by target conformity (RTOG CI) for all targets greater than 0.025 cm3 in volume (n = 65) as well as plan gradient index and 12 Gy isodose volume (V12Gy). The volume cutoff was chosen to balance the relevance of small target conformity and our desired target number for the study. Treatment times were also compared for each modality. GK treatment duration was defined as the time from GK room entry to frame removal. Average GK source age at time of treatment was approximately 3 years. Results: Compared to Gamma Knife, multi-arc VMAT improved average target conformity (CIGK=2.45, CIMA= 2.08; p = 0.0007) and reduced treatment time (tGK = 31.6 min/target, tMA = 1.7 min/target; p <1E-5), but slightly increased 12 Gy isodose volume (V12GyGK=11.92 cm3, V12GyMA = 13.71 cm3;p = 0.003) and plan gradient index (GIGK=3.17, GIMA = 7.28; p =0.0004) compared to GK. Single-arc VMAT plans were more quickly delivered but dosimetrically inferior to both GK and multi-arc VMAT. Conclusion: For multiple target CNS radiosurgery, compared to GK, multi-arc VMAT produced clinically equivalent conformity and drastically reduced treatment time, at slight expense to moderate dose spill. For some, single-isocenter, multi-arc VMAT radiosurgery may constitute a surrogate for other forms of radiosurgery due to its similar plan quality and high delivery efficiency. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic body radiation therapy (SBRT) has gained importance for treatment of early lung cancers in non-surgical candidates. The high fractional dose and tight margins require accurate target localization. We report clinical experience using intrafraction 2-D kilovoltage (kV) X-ray gantry mounted imaging during respiratory gated SBRT with intrafraction intervention based on real-time target localization. Methods: A total of 3105 localization images were analyzed from 51 fractions delivered to 17 patients with lung cancer. The patients underwent bronchoscopic implantation of fiducial markers in the tumor. Four-dimensional-CT-simulation was performed and treatment delivered by volumetric modulated arcs on a Varian TrueBeam system. Pre-treatment image guidance consisted of orthogonal kV images followed by cone beam CT. During treatment, kV images were acquired at the start of beam delivery for each respiratory cycle. Each image was displayed in real-time with a superimposed 1 cm diameter circle around the expected fiducial position to enable visualization of the target misalignment. The operator was able to suspend treatment if the fiducials were observed to move beyond an acceptable range and restart treatment if real-time imaging demonstrated acceptable positioning or reposition the patient. Additional treatment time due to patient repositioning was recorded. All intrafraction kV images were reviewed and real-time fiducial positions were compared to expected positions. Results: Fiducial motion was successfully tracked in real-time and real-time intervention was performed during treatment. The mean vector displacement was 2.45 mm (median 2.11 mm) and the root-mean-square cranial-caudal displacement was 2.06 mm. The vector displacement was within 5 mm (PTV expansion) of the expected position 93% of the time. However, we identified several large discrete shifts of up to 1 cm corresponding to intrafraction patient movement. Real time identification of these events allowed a halt to beam delivery, patient repositioning, and avoidance of a geographic miss. Median treatment time was 7 minutes and 58 seconds. Intrafraction patient repositioning was required 19 times with median additional time of 3 minutes and 5 seconds (minimum = 2 minutes 18 seconds and maximum = 8 minutes and 53 seconds). Conclusions: Real-timefiducialtracking with intrafraction kV imaging during lung SBRT is feasible and identifies infrequent but significant translational error in target localization due to intrafraction patient movement. Use of real-time imaging allows for treatment interruption and target realignment, which may improve the quality of the radiation therapy with minimal additional treatment time. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

We describe an epidemiologic investigation and successful control measures for the first reported outbreak of bla NDM-1 -carrying Pseudomonas aeruginosa in Texas occurring in a veteran with transmission of the same organism and a bla NDM-5 -carrying Escherichia coli , respectively, to two roommates and bla NDM -carrying organism/s to a patient cared for by common staff., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2024.)

Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue, of which tumor loss of IFN-γ signaling genes is a major underlying mechanism. However, strategies of overcoming this resistance mechanism have been largely elusive. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1 KO ) impacts TILs. Here, we report that IFNγR1 KO melanomas have reduced infiltration and function of TILs. IFNγR1 KO melanomas harbor a network of constitutively active protein tyrosine kinases centered on activated JAK1/2. Mechanistically, JAK1/2 activation is mediated by augmented mTOR. Importantly, JAK1/2 inhibition with Ruxolitinib selectively suppresses the growth of IFNγR1 KO but not scrambled control melanomas, depending on T cells and host TNF. Together, our results reveal an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a targeted therapy to bypass ICB resistance of melanomas defective of IFN-γ signaling., (© 2022. The Author(s).)

Background: There are a limited data examining the effects of prior hemorrhage on outcomes after stereotactic radiosurgery (SRS). The goal of this study was to identify risk factors for arteriovenous malformation (AVM) rupture and compare outcomes, including post-SRS hemorrhage, between patients presenting with ruptured and unruptured AVMs., Methods: A retrospective review of consecutive patients undergoing SRS for intracranial AVMs between 2009 and 2019 at our institution was conducted. Chi-square and multivariable logistic regression analyses were utilized to identify patient and AVM factors associated with AVM rupture at presentation and outcomes after SRS including the development of recurrent hemorrhage in both ruptured and unruptured groups., Results: Of 210 consecutive patients with intracranial AVMs treated with SRS, 73 patients (34.8%) presented with AVM rupture. Factors associated with AVM rupture included smaller AVM diameter, deep venous drainage, cerebellar location, and the presence of intranidal aneurysms ( P < 0.05). In 188 patients with adequate follow-up time (mean 42.7 months), the overall post-SRS hemorrhage rate was 8.5% and was not significantly different between ruptured and unruptured groups (10.3 vs. 7.5%, P = 0.51). There were no significant differences in obliteration rate, time to obliteration, or adverse effects requiring surgery or steroids between unruptured and ruptured groups., Conclusion: Smaller AVM size, deep venous drainage, and associated intranidal aneurysms were associated with rupture at presentation. AVM rupture at presentation was not associated with an increased risk of recurrent hemorrhage or other complication after SRS when compared to unruptured AVM presentation. Obliteration rates were similar between ruptured and unruptured groups., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.

Background: To evaluate the ability of individuals with metastatic cancer to provide informed consent to research participation, we used a structured vignette-based interview to measure 4 consenting standards across 3 participant groups., Methods: Participants included 61 individuals diagnosed with brain metastasis, 41 individuals diagnosed with non-CNS metastasis, and 17 cognitively intact healthy controls. All groups were evaluated using the Capacity to Consent to Research Instrument (CCRI), a performance-based measure of research consent capacity. The ability to provide informed consent to participate in research was evaluated across 4 consent standards: expressing choice, appreciation, reasoning, and understanding . Capacity performance ratings (intact, mild/moderate impairment, severe impairment) were identified based on control group performance., Results: Results revealed that the brain metastasis group performed significantly lower than healthy controls on the consent standard of understanding , while both metastatic cancer groups performed below controls on the consent standard of reasoning . Both metastatic cancer groups performed similar to controls on the standards of appreciation and expressing choice . Approximately 60% of the brain metastasis group, 54% of the non-CNS metastasis group, and 18% of healthy controls showed impaired research consent capacity., Conclusions: Our findings, using a performance-based assessment, are consistent with other research indicating that the research consent process may be overly cumbersome and confusing. This, in turn, may lead to research consent impairment not only in patient groups but also in some healthy adults with intact cognitive ability., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune checkpoint blockade therapies (ICBs) are a prominent breakthrough in cancer immunotherapy in recent years (named the 2013 "Breakthrough of the Year" by the Science magazine). Thus far, FDA-approved ICBs primarily target immune checkpoints CTLA-4, PD-1, and PD-L1. Notwithstanding their impressive long-term therapeutic benefits, their efficacy is limited to a small subset of cancer patients. In addition, ICBs induce inadvertent immune-related adverse events (irAEs) and can be costly for long-term use. To overcome these limitations, two strategies are actively being pursued: identification of predictive biomarkers for clinical response to ICBs and multi-pronged combination therapies. Biomarkers will allow clinicians to practice a precision medicine approach in ICBs (biomarker-based patient selection) such as treating triple-negative breast cancer patients that exhibit PD-L1 staining of tumor-infiltrating immune cells in ≥1% of the tumor area with nanoparticle albumin-bound (nab)-paclitaxel plus anti-PD-L1 and treating patients of MSI-H or MMR deficient unresectable or metastatic solid tumors with pembrolizumab (anti-PD-1). Importantly, the insights gained from these biomarker studies can guide rational combinatorial strategies such as CDK4/6 inhibitor/fractionated radiotherapy/HDACi in conjunction with ICBs to maximize therapeutic benefits. Further, with the rapid technological advents (e.g., ATCT-Seq), we predict more reliable biomarkers will be identified, which in turn will inspire more promising combination therapies.

Background: Low-grade gliomas cause significant neurological morbidity by brain invasion. There is no universally accepted objective technique available for detection of enlargement of low-grade gliomas in the clinical setting; subjective evaluation by clinicians using visual comparison of longitudinal radiological studies is the gold standard. The aim of this study is to determine whether a computer-assisted diagnosis (CAD) method helps physicians detect earlier growth of low-grade gliomas., Methods and Findings: We reviewed 165 patients diagnosed with grade 2 gliomas, seen at the University of Alabama at Birmingham clinics from 1 July 2017 to 14 May 2018. MRI scans were collected during the spring and summer of 2018. Fifty-six gliomas met the inclusion criteria, including 19 oligodendrogliomas, 26 astrocytomas, and 11 mixed gliomas in 30 males and 26 females with a mean age of 48 years and a range of follow-up of 150.2 months (difference between highest and lowest values). None received radiation therapy. We also studied 7 patients with an imaging abnormality without pathological diagnosis, who were clinically stable at the time of retrospective review (14 May 2018). This study compared growth detection by 7 physicians aided by the CAD method with retrospective clinical reports. The tumors of 63 patients (56 + 7) in 627 MRI scans were digitized, including 34 grade 2 gliomas with radiological progression and 22 radiologically stable grade 2 gliomas. The CAD method consisted of tumor segmentation, computing volumes, and pointing to growth by the online abrupt change-of-point method, which considers only past measurements. Independent scientists have evaluated the segmentation method. In 29 of the 34 patients with progression, the median time to growth detection was only 14 months for CAD compared to 44 months for current standard of care radiological evaluation (p < 0.001). Using CAD, accurate detection of tumor enlargement was possible with a median of only 57% change in the tumor volume as compared to a median of 174% change of volume necessary to diagnose tumor growth using standard of care clinical methods (p < 0.001). In the radiologically stable group, CAD facilitated growth detection in 13 out of 22 patients. CAD did not detect growth in the imaging abnormality group. The main limitation of this study was its retrospective design; nevertheless, the results depict the current state of a gold standard in clinical practice that allowed a significant increase in tumor volumes from baseline before detection. Such large increases in tumor volume would not be permitted in a prospective design. The number of glioma patients (n = 56) is a limitation; however, it is equivalent to the number of patients in phase II clinical trials., Conclusions: The current practice of visual comparison of longitudinal MRI scans is associated with significant delays in detecting growth of low-grade gliomas. Our findings support the idea that physicians aided by CAD detect growth at significantly smaller volumes than physicians using visual comparison alone. This study does not answer the questions whether to treat or not and which treatment modality is optimal. Nonetheless, early growth detection sets the stage for future clinical studies that address these questions and whether early therapeutic interventions prolong survival and improve quality of life., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: HFS and NB are co-founders of MRIMATH LLC. LBN serves on the scientific advisory boards for Abbvie, Blue Earth Diagnostics, Karyopharm, and Kiyatec and the Data safety and monitoring board for UPENN and Ziopharm. JM is 1) the Recipient of funds related to structured buyout of an oncolytic virus company, Catherex, Inc, by Amgen. 2) Equity holder in an oncolytic virus company, Treovor, Inc. 3) Equity holder in an oncolytic virus company, Aettis, Inc. 4) Board Member, UAB Health System and UAB Health Services Foundation. 5) Research grant holder from NIH and Gateway to conduct clinical trials for malignant glioma using oncolytic viruses. these funding sources were not involved in the study under submission. 6) Employment: UAB SOM and UAB Health Services Foundation. 7) Patent applications for oncolytic virus and administration techniques thereof not applicable to this paper.

Purpose: To measure dosimetric and spatial accuracy of stereotactic radiosurgery (SRS) delivered to targets as small as the trigeminal nerve (TN) using a standard external beam treatment planning system (TPS) and multileaf collimator-(MLC) equipped linear accelerator without cones or other special attachments or modifications., Methods: Dosimetric performance was assessed by comparing computed dose distributions to film measurements. Comparisons included the γ-index, beam profiles, isodose lines, maximum dose, and spatial accuracy. Initially, single static 360° arcs of MLC-shaped fields ranging from 1.6 × 5 to 30 × 30 mm 2 were planned and delivered to an in-house built block phantom having approximate dimensions of a human head. The phantom was equipped with markings that allowed accurate setup using planar kV images. Couch walkout during multiple-arc treatments was investigated by tracking a ball pointer, initially positioned at cone beam computed tomography (CBCT) isocenter, as the couch was rotated. Tracks were mapped with no load and a 90 kg stack of plastic plates simulating patient treatment. The dosimetric effect of walkout was assessed computationally by comparing test plans that corrected for walkout to plans that neglected walkout. The plans involved nine 160° arcs of 2.4 × 5 mm 2 fields applied at six different couch angles. For end-to-end tests that included CT simulation, target contouring, planning, and delivery, a cylindrical phantom mimicking a 3 mm lesion was constructed and irradiated with the nine-arc regimen. The phantom, lacking markings as setup aids was positioned under CBCT guidance by registering its surface and internal structures with CTs from simulation. Radiochromic film passing through the target center was inserted parallel to the coronal and the sagittal plane for assessment of spatial and dosimetric accuracy., Results: In the single-arc block phantom tests computed maximum doses of all field sizes agreed with measurements within 2.4 ± 2.0%. Profile widths at 50% maximum agreed within 0.2 mm. The largest targeting error was 0.33 mm. The γ-index (3%, 1 mm) averaged over 10 experiments was >1 in only 1% of pixels for field sizes up to 10 × 10 mm 2 and rose to 4.4% as field size increased to 20 × 20 mm 2 . Table walkout was not affected by load. Walkout shifted the target up to 0.6 mm from CBCT isocenter but, according to computations shifted the dose cloud of the nine-arc plan by only 0.16 mm. Film measurements verified the small dosimetric effect of walkout, allowing walkout to be neglected during planning and treatment. In the end-to-end tests average and maximum targeting errors were 0.30 ± 0.10 and 0.43 mm, respectively. Gamma analysis of coronal and sagittal dose distributions based on a 3%/0.3 mm agreement remained <1 at all pixels. To date, more than 50 functional SRS treatments using MLC-shaped static field arcs have been delivered., Conclusion: Stereotactic radiosurgery (SRS) can be planned and delivered on a standard linac without cones or other modifications with better than 0.5 mm spatial and 5% dosimetric accuracy., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

In the original publication [1] two author names were missing the middle names. The corrected versions can be found in this Erratum.

Purpose: To investigate radiation oncologists' opinions on important considerations to offering re-irradiation (re-RT) as a treatment option for recurrent glioma., Materials and Methods: A survey was conducted with 13 radiation oncologists involved in the care of central nervous system tumor patients. The survey was comprised of 49 questions divided into 2 domains: a demographic section (10 questions) and a case section (5 re-RT cases with 5 to 6 questions representing one or several re-RT treatment dilemmas as may be encountered in the clinic). Respondents were asked to rate the relevance of various factors to offering re-RT, respond to the cases with a decision to offer re-RT vs. not, volume to be treated, margins to be employed, dose/fractionation suggested and any additional comments with respect to rationale in each scenario., Results: Sixty nine percent of responders have been practicing for greater than 10 years and 61% have re-RT 20 to 100 patients to date, with 54% seeing 2-5 re-RT cases per month and retreating 1-2 patients per month. Recurrent tumor volume, time since previous radiation therapy, previously administered dose to organs at risk and patient performance status were rated by the majority of responders (85%, 92%, 77%, and 69% respectively) as extremely relevant or very relevant to offering re-RT as an option., Conclusion: The experts' practice of re-RT is still heterogeneous, reflecting the paucity of high-quality prospective data available for decision-making. Nevertheless, practicing radiation oncologists can support own decisions by referring to the cases found suitable for re-RT in this survey.

Context: Accurate estimation of life expectancy in patients with brain metastases is critical for counseling and choosing appropriate therapy. Performance status is the single greatest determinant of overall survival in this population. However, current measures of performance status are subjective and often based on brief clinical encounters. Gait speed is an objective, reliable predictor of overall health and survival., Objective: The purpose of this study was to evaluate the relationship between gait speed and survival in patients with brain metastases., Methods: We conducted a retrospective review of all patients with documented gait speed and Karnofsky performance status seen in consultation for newly diagnosed brain metastases from 2014 to 2015. Gait speed was measured during neurological examination over 4 m at normal pace. Graded prognostic assessment scores were calculated from clinical information. The primary outcomes were overall survival and 30-day mortality., Results: Eighty-five of 88 patients (97%) met inclusion criteria. Overall, the median gait speed was 0.7 m/s (range 0-1.0 m/s). Gait speed was associated with increased overall survival in addition to graded prognostic assessment score. Median survival was longer in patients with normal gait speed (>0.6 m/s, 11.9 months) compared to those with slow gait speed (≤0.6 m/s, 4.5 months, P < 0.001) or who were nonambulatory (1.1 months, P < 0.001). Thirty-day mortality for normal, slow, and nonambulatory patients was 0%, 15%, and 42%, respectively. The graded prognostic assessment overestimated actual survival for nonambulatory patients (2.2 vs. 1.1 months) and underestimated for those with normal gait speed (4.4 vs. 11.9 months)., Conclusion: Gait speed is associated with overall survival in patients with newly diagnosed brain metastases. Gait speed assessment is simple, objective, and may provide additional prognostic information to improve life expectancy estimation and management decisions., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Cancer center websites are trusted sources of internet information about treatment options for prostate cancer. The quality of information on these websites is unknown. The objective of this study was to evaluate the quality of information on cancer center websites addressing prostate cancer treatment options, outcomes, and toxicity., Materials and Methods: We evaluated the websites of all National Cancer Institute-designated cancer centers to determine if sufficient information was provided to address eleven decision-specific knowledge questions from the validated Early Prostate Cancer Treatment Decision Quality Instrument. We recorded the number of questions addressed, the number of clicks to reach the prostate cancer-specific webpage, evaluation time, and Spanish and mobile accessibility. Correlation between evaluation time and questions addressed were calculated using the Pearson coefficient., Results: Sixty-three websites were reviewed. Eighty percent had a prostate cancer-specific webpage reached in a median of three clicks. The average evaluation time was 6.5 minutes. Information was available in Spanish on 24% of sites and 59% were mobile friendly. Websites provided sufficient information to address, on average, 19% of questions. No website addressed all questions. Evaluation time correlated with the number of questions addressed (R(2) = 0.42, p < 0.001)., Conclusions: Cancer center websites provide insufficient information for men with localized prostate cancer due to a lack of information about and direct comparison of specific treatment outcomes and toxicities. Information is also less accessible in Spanish and on mobile devices. These data can be used to improve the quality and accessibility of prostate cancer treatment information on cancer center websites.

Dose assessment after radiological disasters is imperative to decrease mortality through rationally directed medical intervention. Our goal was to identify biomarkers capable of qualitative (nonirradiated/irradiated) and/or quantitative (dose) assessment of radiation exposure. Using real-time quantitative PCR, biodosimetry genes were identified in blood samples from cancer patients undergoing total-body irradiation. Time- (5, 12, 23, 48 h) and dose- (0-8 Gy) dependent changes in gene expression were examined in C57BL/6 mice. A training set was used to derive weighted voting classification algorithms (nonirradiated/irradiated) and continuous regression (dose assessment) models that were tested in a separate validation set of mice. Of eight biodosimetry genes identified in cancer patients ( ACTA2 , BBC3 , CCNG1 , CDKN1A , GADD45A , MDK , SERPINE1 , Tnfrsf10b ), expression of BBC3 , CCNG1 , CDKN1A , SERPINE1 and Tnfrsf10b was significantly (P < 0.05) increased in irradiated mice. CCNG1 and CDKN1A expression segregated irradiated mice from controls with an accuracy, specificity and sensitivity of 96.3, 100.0 and 94.4%, respectively, at 48 h. Multiple linear regression analysis predicted doses for the 0-, 1-, 2-, 4-, 6- and 8-Gy treatment groups as 0.0 ± 0.2, 1.6 ± 1.0, 2.9 ± 1.4, 5.1 ± 2.0, 5.3 ± 0.7 and 10.5 ± 5.6 Gy, respectively. These results suggest that gene expression analysis could be incorporated into biodosimetry protocols for qualitative and quantitative assessment of radiation exposure.

Purpose: Previous preclinical studies suggested that concurrent capecitabine and radiation could be an effective new treatment modality for glioblastoma (GBM). In the current study, we investigate toxicity and response to this regimen and explore associations between gene expression and patient outcome., Experimental Design: Eighteen newly diagnosed GBM patients received concurrent capecitabine at 625 mg/m2 BID (25% escalation) and irradiation (60 Gy total) for 6 weeks followed by 4 weeks of capecitabine only. Maintenance capecitabine was administered for 14 days every 3 weeks until progression or unacceptable toxicity. Expression analysis of 94 genes involved in capecitabine metabolism and radiation response was done on tissues obtained before therapy. The relationship of gene expression with time-to-progression (TTP) and overall survival (OS) was investigated using univariate Cox proportional hazards regression, semi-supervised principle component analysis, and class prediction modeling., Results: The maximum tolerated dose of capecitabine was 625 mg/m2 BID. Median patient TTP and OS were 247 and 367 days, respectively. Cox regression identified 24 genes significantly (P<0.025) associated with patient outcome. Semi-supervised principle component analysis identified two patient populations significantly different in both TTP (P=0.005) and OS (P=0.015). Class prediction modeling determined that eight genes (RAD54B, MTOR, DCTD, APEX2, TK1, RRM2, SLC29A1, and ERCC6) could collectively classify patients into outcome subgroups with 100% accuracy and precision., Conclusions: Capecitabine and concurrent radiation for newly diagnosed GBM seems to be well tolerated and comparable to temozolomide and radiation. A gene expression profile predictive of patient outcome that may be useful in patient stratification for therapy was also elucidated., (Copyright (c) 2010 AACR.)

Virtually all malignant gliomas recur. Treatment options at recurrence have relied upon surgical intervention, radiation therapy or cytotoxic chemotherapy. Unfortunately, none are associated with significant improvements in survival. Advances in treatment options at recurrence have been dependent upon the combination of surgical resection, focal radiation and chemotherapy. Despite aggressive interventions, few patients have meaningful improvements. Current research focuses on novel targeted molecular therapy that will hopeful be able to take advantage of advances in our understanding of the biology of glial neoplasms.

Unlabelled: TM-601, a 36-amino-acid peptide, selectively binds to glioma cells but not normal brain parenchyma. A phase I/II clinical trial of intracavitary 131I-TM-601 in adult patients with recurrent high-grade glioma was performed to determine the biodistribution and toxicity of this potential therapy. We evaluated imaging and biodistribution data from this trial to assess whether 131I-TM-601 might be useful in determining tumor extent., Methods: Adult patients with recurrent high-grade gliomas underwent tumor resection, implantation of an intracavitary reservoir, and a single-dose injection of 370 MBq (10 mCi) 131I-TM-601 (0.25-1.0 mg of 131I-TM-601) 2-4 wks after surgery. Total-body planar scans and whole-brain SPECT scans were obtained on days 0, 1, 2, 3, and 6-8 after injection. Postresection MR images were coregistered to the SPECT scans using image analysis software. Analysis of the rate of radioactive decay and biologic elimination from the body and at the cavity site was performed. T1-weighted with gadolinium contrast (T1-Wc), T2-weighted (T2), and SPECT volumes were estimated by stereological Cavalieri sections and compared for overlap., Results: Nonbound 131I-TM-601 was eliminated by 48 h after injection with the remaining radiolabeled peptide bound to tumor for at least 6-8 d. Biologic decay rates from 24 to 168 h after injection were only slightly shorter than the physical decay of 131I (6.3 vs. 8.0 d). A comparison of tumor volume estimates using all 3 imaging parameters indicated that 131I-TM-601-determined tumor volumes more closely paralleled T2 volumes than T1-Wc volumes. Overlap between coregistered MRI and SPECT scans corroborated the presence of radiolabeled peptide in the vicinity of infiltrating tumor up to 168 h after injection., Conclusion: 131I-TM-601 provides a reliable estimate for primary tumor extent. Further modification of this radiopeptide with other better imaging isotopes may provide an important tool for determining tumor extent and differentiating regions of viable tumor from necrosis.