Background: Radiation pneumonitis is a common toxicity following lung stereotactic body radiation therapy (SBRT). We explored whether motion management technique, in conjunction with patient and treatment characteristics, is a predictor of radiation pneumonitis-free survival (PNFS).Methods: A single institution multi-center lung SBRT database was retrospectively reviewed. PNFS was defined as time to earliest onset of radiation pneumonitis or last clinical follow-up. Patients were simulated using a 4-dimensional approach, and those with 1 cm or greater tumor motion were selected for respiratory-gated treatment. Real-Time Position Management and phase-based gating were employed. Univariate and multivariable Cox proportional hazard models were fit for relevant covariates to determine the impact of free-breathing versus respiratory-gated treatment on PNFS.Results: The initial treatment courses of 208 patients were included, with a median follow-up length of 23 months. The median age at treatment was 71 years. About 91.8% of patient had early stage (T12) non-small cell lung cancer and were treated with common regimens including 10 Gy ×5, 12 Gy ×4 and 18 Gy ×3; 26.4% underwent respiratory-gated SBRT. The overall rate of grade 3 or higher radiation pneumonitis was 10.1%. PNFS was not significantly different between patients treated with respiratory-gated versus free-breathing SBRT (HR =0.88; P=0.707); tumor location and fractionation were predictors of PNFS in the multivariate setting. Conclusions: The method of motion management does not appear to impact PNFS when the tolerance for tumor displacement is 1 cm or less for free-breathing treatment planning and delivery. This approach may be appropriate when selecting patients for respiratory gating.
BACKGROUND: To accurately assess micronutrient status, it is necessary to characterize the effects of inflammation and the acute-phase response on nutrient biomarkers. OBJECTIVE: Within a norovirus human challenge study, we aimed to model the inflammatory response of C-reactive protein (CRP) and α-1-acid glycoprotein (AGP) by infection status, model kinetics of micronutrient biomarkers by inflammation status, and evaluate associations between inflammation and micronutrient biomarkers from 0 to 35 d post-norovirus exposure. METHODS: Fifty-two healthy adults were enrolled into challenge studies in a hospital setting and followed longitudinally; all were exposed to norovirus, half were infected. Post hoc analysis of inflammatory and nutritional biomarkers was performed. Subjects were stratified by inflammation resulting from norovirus exposure. Smoothed regression models analyzed the kinetics of CRP and AGP by infection status, and nutritional biomarkers by inflammation. Linear mixed-effects models were used to analyze the independent relations between CRP, AGP, and biomarkers for iron, vitamin A, vitamin D, vitamin B-12, and folate from 0 to 35 d post-norovirus exposure. RESULTS: Norovirus-infected subjects had median (IQR) peak concentrations for CRP [16.0 (7.9-29.5) mg/L] and AGP [0.9 (0.8-1.2) g/L] on day 3 and day 4 postexposure, respectively. Nutritional biomarkers that differed (P < 0.05) from baseline within the inflamed group were ferritin (elevated day 3), hepcidin (elevated days 2, 3), serum iron (depressed days 2-4), transferrin saturation (depressed days 2-4), and retinol (depressed days 3, 4, and 7). Nutritional biomarker concentrations did not differ over time within the uninflamed group. In mixed models, CRP was associated with ferritin (positive) and serum iron and retinol (negative, P < 0.05). CONCLUSION: Using an experimental infectious challenge model in healthy adults, norovirus infection elicited a time-limited inflammatory response associated with altered serum concentrations of certain iron and vitamin A biomarkers, confirming the need to consider adjustments of these biomarkers to account for inflammation when assessing nutritional status. These trials were registered at clinicaltrials.gov as NCT00313404 and NCT00674336.
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Arif Ali;
Peixin Zhang;
W.K. Alfred Yung;
Yuhchyau Chen;
Benjamin Movsas;
Raul C. Urtasun;
Christopher U. Jones;
Kwang N. Choi;
Jeff M. Michalski;
A. Jennifer Fischbach;
Arnold M. Markoe;
Christopher J. Schultz;
Marta Penas-Prado;
Madhur K. Garg;
Alan C. Hartford;
Harold E. Kim;
Minhee Won;
Walter J Curran
From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m 2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1–3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.
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Enjae Jung;
Erin E. Perrone;
Pavan Brahmamdan;
Jacquelyn S. McDonough;
Ann M. Leathersich;
Jessica A. Dominguez;
Andrew T. Clark;
Amy C. Fox;
W. Michael Dunne;
Richard S. Hotchkiss;
Craig Coopersmith
World conditions place large populations at risk from ionizing radiation (IR) from detonation of dirty bombs or nuclear devices. In a subgroup of patients, ionizing radiation exposure would be followed by a secondary infection. The effects of radiation combined injury are potentially more lethal than either insult in isolation. The purpose of this study was to determine mechanisms of mortality and possible therapeutic targets in radiation combined injury. Mice were exposed to IR with 2.5 Gray (Gy) followed four days later by intratracheal methicillin-resistant Staphylococcus aureus (MRSA). While either IR or MRSA alone yielded 100% survival, animals with radiation combined injury had 53% survival (p = 0.01). Compared to IR or MRSA alone, mice with radiation combined injury had increased gut apoptosis, local and systemic bacterial burden, decreased splenic CD4 T cells, CD8 T cells, B cells, NK cells, and dendritic cells, and increased BAL and systemic IL-6 and G-CSF. In contrast, radiation combined injury did not alter lymphocyte apoptosis, pulmonary injury, or intestinal proliferation compared to IR or MRSA alone. In light of the synergistic increase in gut apoptosis following radiation combined injury, transgenic mice that overexpress Bcl-2 in their intestine and wild type mice were subjected to IR followed by MRSA. Bcl-2 mice had decreased gut apoptosis and improved survival compared to WT mice (92% vs. 42%; p<0.01). These data demonstrate that radiation combined injury results in significantly higher mortality than could be predicted based upon either IR or MRSA infection alone, and that preventing gut apoptosis may be a potential therapeutic target.
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Adriana Fonseca;
Caihong Xia;
Armando J. Lorenzo;
Mark Krailo;
Thomas Olson;
Farzana Pashankar;
Marcio H. Malogolowkin;
James F. Amatruda;
Deborah F. Billmire;
Carlos Rodriguez-Galindo;
A. Lindsay Frazier;
Furqan Shaikh
PURPOSE To investigate relapse detection methods among children and adolescents with nongerminomatous malignant germ cell tumors (MGCTs) and to determine whether tumor markers alone might be sufficient for surveillance. METHODS We retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs. The method used to detect relapse was assessed based on case report forms, tumor markers, imaging, and pathology reports. Relapses were classified into one of two categories on the basis of whether they were (1) detectable by tumor marker elevation or (2) not detectable by tumor markers. RESULTS A total of 302 patients were enrolled, and 284 patients had complete data for review. Seven patients had normal tumor markers at initial diagnosis, and none experienced a relapse. At a median follow-up of 5.3 years, 48 patients (16.9%) had experienced a relapse. After central review, 47 of 48 relapses (98%) were detected by tumor marker elevation. Of the 47 patients, 16 (33.3%) had abnormal tumor markers with normal/unknown imaging, 31 patients (64.6%) had abnormal tumor markers with abnormal imaging, and one patient (2.1%) had abnormal imaging with unknown marker levels at relapse. CONCLUSION Tumor marker elevation is a highly sensitive method of relapse surveillance, at least among children and adolescents with tumor marker elevation at initial diagnosis. Eliminating exposure to imaging with ionizing radiation may enhance the safety of relapse surveillance in patients treated for MGCT.
Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre- and post-radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre- and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre- to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted.
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Mutlay Sayan;
Nikhil Yegya-Raman;
Stephanie H. Greco;
Bin Gui;
Andrew Zhang;
Anupama Chundury;
Miral S. Grandhi;
Howard S. Hochster;
Timothy J. Kennedy;
Russel C. Langan;
Usha Malhotra;
Vinod K. Rustgi;
Mihir Shah;
Kristen R. Spencer;
Darren R. Carpizo;
John L. Nosher;
Salma K. Jabbour
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.
Social monogamy is a mating strategy rarely employed by mammalian species. Laboratory studies in socially monogamous prairie voles Microtus ochrogaster demonstrate that oxytocin and vasopressin act within the mesolimbic dopamine pathway to facilitate pair-bond formation. Species differences in oxytocin receptor (OTR) and vasopressin 1a receptor (V1aR) distribution in this pathway are associated with species differences in mating strategy. Here, we characterize the neuroanatomical distribution of OTR and V1aR binding sites in naturally occurring populations of Taiwan voles Microtus kikuchii, which purportedly display social monogamy. Live trapping was conducted at two sites in 2009-2010 and receptor autoradiography for OTR and V1aR was performed on brains from 24 animals. OTR binding in two brain regions where OTR signaling regulates pair-bonding were directly compared with that of prairie voles. Our results show that like prairie voles, Taiwan voles exhibit OTR in the prefrontal cortex, insular cortex, claustrum, nucleus accumbens, caudate-putamen, dorsal lateral septal nucleus, central amygdala and ventromedial hypothalamus. Unlike prairie voles, Taiwan voles exhibit OTR binding in the CA3 field of the hippocampus, as well as the indusium griseum, which has only previously been documented in tuco-tucos Ctenomys haigi, Ctenomys sociabilis, Syrian hamsters Mesocricetus auratus and naked mole-rats Heterocephalus glaber. V1aR binding was present in the ventral pallidum, lateral septum, nucleus basalis, bed nucleus of the stria terminalis, hippocampus, medial amygdala, and anterior, ventromedial and dorsomedial hypothalamus. Marked individual differences in V1aR binding were noted in the cingulate cortex and several thalamic nuclei, remarkably similar to prairie voles. While pharmacological studies are needed to determine whether oxytocin and vasopressin are involved in pair-bond formation in this species, our results lay a foundation for future investigations into the role of these neuropeptides in Taiwan vole social behavior.
Objective: Both stereotactic radiosurgery (SRS) and fractionated radiation therapy (FRT) techniques are used for treatment of intracranial meningiomas with excellent local control (LC) rates. Although SRS techniques are convenient, toxicity including treatment-related edema can significantly impact patient quality of life. The long-term clinical outcomes of patients with magnetic resonance imaging (MRI)–defined meningiomas treated with radiation therapy (RT) alone are reported. Methods: The charts of 211 patients with meningiomas diagnosed by contrast-enhanced MRI treated with either SRS or FRT between 1991 and 2012 at a single institution were reviewed. Actuarial rates for LC and development of treatment-related radiographic edema (TRE) were determined by the Kaplan-Meier method. Results: There were 211 patients who received radiation therapy for 223 lesions. Median follow-up was 5.7 years. Eleven patients experienced a local failure; of these, 2 were ultimately found to have pathologically proven metastatic carcinoma. Two- and 5-year LC was 97.8% and 94.6%, respectively, with no significant difference based on modality of therapy. Actuarial rate for development of TRE at 1 and 2 years was 30.1% and 34.6% for the SRS group and 1.6% and 2.5% for the FRT group, respectively (P < 0.001). Conclusions: RT alone using a limited margin is an effective treatment option for MRI-defined meningiomas and should be considered even without biopsy if surgery will present significant morbidity. Although LC with SRS versus FRT was comparable, FRT was associated with a significantly decreased risk of TRE.
Purpose: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer.
Methods and Materials: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates.
Results: Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients).
Conclusions: Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.