RanGAP1 maintains chromosome stability in limb bud mesenchymal cells during bone development.

BACKGROUND: Bone development involves the rapid proliferation and differentiation of osteogenic lineage cells, which makes accurate chromosomal segregation crucial for ensuring cell proliferation and maintaining chromosomal stability. However, the mechanism underlying the maintenance of chromosome stability during the rapid proliferation and differentiation of Prx1-expressing limb bud mesenchymal cells into osteoblastic precursor cells remains unexplored. METHODS: A transgenic mouse model of RanGAP1 knockout of limb and head mesenchymal progenitor cells was constructed to explore the impact of RanGAP1 deletion on bone development by histomorphology and immunostaining. Subsequently, G-banding karyotyping analysis and immunofluorescence staining were used to examine the effects of RanGAP1 deficiency on chromosome instability. Finally, the effects of RanGAP1 deficiency on chromothripsis and bone development signaling pathways were elucidated by whole-genome sequencing, RNA-sequencing, and qPCR. RESULTS: The ablation of RanGAP1 in limb and head mesenchymal progenitor cells expressing Prx1 in mice resulted in embryonic lethality, severe cartilage and bone dysplasia, and complete loss of cranial vault formation. Moreover, RanGAP1 loss inhibited chondrogenic or osteogenic differentiation of mesenchymal stem cells (MSCs). Most importantly, we found that RanGAP1 loss in limb bud mesenchymal cells triggered missegregation of chromosomes, resulting in chromothripsis of chromosomes 1q and 14q, further inhibiting the expression of key genes involved in multiple bone development signaling pathways such as WNT, Hedgehog, TGF-ß/BMP, and PI3K/AKT in the chromothripsis regions, ultimately disrupting skeletal development. CONCLUSIONS: Our results establish RanGAP1 as a critical regulator of bone development, as it supports this process by preserving chromosome stability in Prx1-expressing limb bud mesenchymal cells.

Improving drug response prediction via integrating gene relationships with deep learning.

Predicting the drug response of cancer cell lines is crucial for advancing personalized cancer treatment, yet remains challenging due to tumor heterogeneity and individual diversity. In this study, we present a deep learning-based framework named Deep neural network Integrating Prior Knowledge (DIPK) (DIPK), which adopts self-supervised techniques to integrate multiple valuable information, including gene interaction relationships, gene expression profiles and molecular topologies, to enhance prediction accuracy and robustness. We demonstrated the superior performance of DIPK compared to existing methods on both known and novel cells and drugs, underscoring the importance of gene interaction relationships in drug response prediction. In addition, DIPK extends its applicability to single-cell RNA sequencing data, showcasing its capability for single-cell-level response prediction and cell identification. Further, we assess the applicability of DIPK on clinical data. DIPK accurately predicted a higher response to paclitaxel in the pathological complete response (pCR) group compared to the residual disease group, affirming the better response of the pCR group to the chemotherapy compound. We believe that the integration of DIPK into clinical decision-making processes has the potential to enhance individualized treatment strategies for cancer patients.

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.

AIMS: Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. METHODS AND RESULTS: Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-ß receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. CONCLUSION: Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.

Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils.

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/fl Il7rCre/+ mice or induced ILC2 depletion in Icosfl-DTR-fl/+ Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5-/- mice induces EOS differentiation in bone-marrow cells from Rorafl/fl Il7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5-/- and Il13-/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5-/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/fl Il7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

Effect of remimazolam induction on hemodynamics in patients undergoing valve replacement surgery: A randomized, double-blind, controlled trial.

BACKGROUND: The stability of hemodynamics during anesthesia induction in patients undergoing valve replacement surgery is particularly important. Remimazolam is a new type of benzodiazepine drug, with supposed advantages of rapid induction, rapid recovery, stable hemodynamics, and mild respiratory inhibition. AIM: To evaluate the effect of remimazolam anesthesia induction on hemodynamics in patients undergoing valve replacement surgery. METHODS: This randomized, double-blind, controlled trial enrolled consecutive patients undergoing mitral valve replacement (MVR)/aortic valve replacement (AVR)/double-valve replacement (DVR) surgery on cardiopulmonary bypass (CPB). The study was conducted according to the Consolidated Standards of Reporting Trials statement. Participants were randomly assigned to receive either remimazolam or propofol induction of 30 patients each. All patients, data collectors, and data analyzers were blinded to the group allocation. The primary outcomes were the fluctuations in hemodynamic parameters (the difference of maximum or minimum heart rate to baseline, ▲HR, the difference of maximum or minimum mean arterial pressure to baseline, ▲MAP), the occurrence of cardiovascular events (hypotension, severe bradycardia), and the cumulative norepinephrine doses used per patient, averaged per group during induction. The secondary outcomes were hemodynamic parameters (heart rate, HR, mean arterial pressure, MAP, bispectral index, BIS, plasma lactic acid, Lac, and blood glucose, Glu values). RESULTS: A total of 60 patients with heart valve replacement were included in the final analysis, with 30 patients in each group. The ▲MAP was significantly lower in the remimazolam group than in the propofol group during induction (p < .05). The incidences of hypotension and the cumulative norepinephrine doses used per patient, averaged per group during induction were significantly lower in the remimazolam group than in the propofol group (p < .05). CONCLUSION: Remimazolam may be safe and effective for induction and may as an alternative to propofol during anesthesia induction in patients undergoing valve replacement surgery.

Eosinophils Protect Mice From Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm.

RATIONALE: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease. OBJECTIVE: To test whether and how eosinophils affect AAA growth. METHODS AND RESULTS: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 109/L, P<0.001). Univariate (odds ratio, 1.381, P<0.001) and multivariate (odds ratio, 1.237, P=0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in Apoe-/- and eosinophil-deficient Apoe-/-ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13-/- mice, but not eosinophil from Il4-/- mice, blocked AAA growth in Apoe-/-ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells. CONCLUSIONS: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

Type 2 innate lymphoid cells regulation by regulatory T cells attenuates atherosclerosis.

Regulatory T cells (Tregs) have been shown to attenuate the development and progression of atherosclerosis; however, the exact mechanism is still unclear. In our study, Tregs were adoptively transferred into ApoE-/- mice, and type 2 innate lymphoid cells (ILC2s) were expanded by the IL-2/Jes6-1 complex or depleted by anti-CD90.2 mAb in ApoE-/-Rag1-/- mice to study their effects on atherosclerosis. Then, Tregs were cocultured with ILC2s in vitro to analyze ILC2s number and IL-13 production. In vivo, ApoE-/-Rag1-/- mice were treated with activated Tregs with or without anti-CD90.2 mAb to explore whether Tregs reduced atherosclerosis through ILC2s. Finally, neutralizing antibodies and Transwell assay were used to investigate how Tregs regulate ILC2s. Our results show that both Tregs and ILC2s reduce atherosclerosis lesions and macrophage infiltration. Moreover, Tregs effectively expanded the number of ILC2s and increased their production of IL-13 in vivo and in vitro. Furthermore, the reductions in plaque size and macrophage infiltration by Tregs were partly reversed by anti-CD90.2 mAb. Mechanistically, our data reveal that IL-10, TGF-ß and cell-cell contacts are required for Tregs-ILC2s regulation. These results show that Tregs may play a partial protective role against atherosclerosis by expanding the number of ILC2s and consequently increasing IL-13 production.

Reduced Nhe1 (Na+-H+ Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysms.

IgE-mediated activation of Nhe1 (Na+-H+ exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficient Apoe-/-Nhe1+/- mice and Apoe-/-Nhe1+/+ littermates tested Nhe1 activity in experimental AAA, because Nhe1-/- mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe-/-Nhe1+/+ mice, such acidic areas were much smaller in lesions from Apoe-/-Nhe1+/- mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.

Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients.

The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.

Na+-H+ exchanger 1 determines atherosclerotic lesion acidification and promotes atherogenesis.

The pH in atherosclerotic lesions varies between individuals. IgE activates macrophage Na+-H+ exchanger (Nhe1) and induces extracellular acidification and cell apoptosis. Here, we show that the pH-sensitive pHrodo probe localizes the acidic regions in atherosclerotic lesions to macrophages, IgE, and cell apoptosis. In Apoe-/- mice, Nhe1-deficiency or anti-IgE antibody reduces atherosclerosis and blocks lesion acidification. Reduced atherosclerosis in Apoe-/- mice receiving bone marrow from Nhe1- or IgE receptor FcεR1-deficient mice, blunted foam cell formation and signaling in IgE-activated macrophages from Nhe1-deficient mice, immunocomplex formation of Nhe1 and FcεR1 in IgE-activated macrophages, and Nhe1-FcεR1 colocalization in atherosclerotic lesion macrophages support a role of IgE-mediated macrophage Nhe1 activation in atherosclerosis. Intravenous administration of a near-infrared fluorescent pH-sensitive probe LS662, followed by coregistered fluorescent molecular tomography-computed tomography imaging, identifies acidic regions in atherosclerotic lesions in live mice, ushering a non-invasive and radiation-free imaging approach to monitor atherosclerotic lesions in live subjects.

Helical tomotherapy to LINAC plan conversion utilizing RayStation Fallback planning.

RaySearch RayStation Fallback (FB) planning module can generate an equivalent backup radiotherapy treatment plan facilitating treatment on other linear accelerators. FB plans were generated from the RayStation FB module by simulating the original plan target and organ at risk (OAR) dose distribution and delivered in various backup linear accelerators. In this study, helical tomotherapy (HT) backup plans used in Varian TrueBeam linear accelerator were generated with the RayStation FB module. About 30 patients, 10 with lung cancer, 10 with head and neck (HN) cancer, and 10 with prostate cancer, who were treated with HT, were included in this study. Intensity-modulated radiotherapy Fallback plans (FB-IMRT) were generated for all patients, and three-dimensional conformal radiotherapy Fallback plans (FB-3D) were only generated for lung cancer patients. Dosimetric comparison study evaluated FB plans based on dose coverage to 95% of the PTV volume (R95), PTV mean dose (Dmean), Paddick's conformity index (CI), and dose homogeneity index (HI). The evaluation results showed that all IMRT plans were statistically comparable between HT and FB-IMRT plans except that PTV HI was worse in prostate, and PTV R95 and HI were worse in HN multitarget plans for FB-IMRT plans. For 3D lung cancer plans, only the PTV R95 was statistically comparable between HT and FB-3D plans, PTV Dmean was higher, and CI and HI were worse compared to HT plans. The FB plans using a TrueBeam linear accelerator generally offer better OAR sparing compared to HT plans for all the patients. In this study, all cases of FB-IMRT plans and 9/10 cases of FB-3D plans were clinically acceptable without further modification and optimization once the FB plans were generated. However, the statistical differences between HT and FB-IMRT/3D plans might not be of any clinically significant. One FB-3D plan failed to simulate the original plan without further optimization.

Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes.

Lung cancer is one of the most common human cancers worldwide. Among all lung cancer cases, non-small cell lung cancer (NSCLC) accounts for approximately 85%. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts that have been shown to play important roles in tumourigenesis and tumor progression. To reveal novel tumor-related lncRNAs in NSCLC and their associations with clinical subtypes, we herein identified 2935 probe sets mapped to lncRNAs on Affymetrix HG-U133 Plus 2.0 array with an lncRNA classification pipeline. We found 47 lncRNAs differentially expressed between normal lung tissues and tumor samples and 19 lncRNAs differed in expression between SCC and AC, two subtypes of NSCLC, after analyses of the gene expression profiles of five datasets downloaded from the gene expression omnibus (GEO) with a leave one dataset out validation process. The different lncRNA expression profiles between NSCLC and normal tissue and between the subtypes of NSCLC may have potential implications in the pathogenesis of this cancer. lncRNAs screening may be beneficial in the diagnosis, subclassification, and the personalized treatment of NSCLC.

Comparison of daily versus nondaily image-guided radiotherapy protocols for patients treated with intensity-modulated radiotherapy for head and neck cancer.

BACKGROUND: The purpose of this study was to determine the feasibility of nondaily image-guided radiotherapy (RT) strategies with intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS: Alignment data was analyzed from 103 consecutive patients treated by IMRT for head and neck cancer who had undergone daily imaging with onboard mega-voltage CT (MVCT), resulting in 3275 images. Geometric setup errors that would have occurred using less-than-daily imaging were hypothetically estimated for 4 temporal less-than-daily image-guided RT protocols. RESULTS: For image-guided RT on the first fraction, weekly image-guided RT, first 5 + weekly image-guided RT, and alternating day image-guided RT, the respective incidences of geometric miss were 50.5%, 33.8%, 30.1%, and 15.7% assuming 3-mm uncertainty margins; and 18.7%, 11.7%, 10.3%, and 4.1% with 5-mm margins. CONCLUSION: Less-than-daily image-guided RT strategies result in a high incidence of potential miss when 3-mm uncertainty margins are utilized. Less-than-daily image-guided RT strategies should incorporate margins of at least 5 mm.

Development of a standardized method for contouring the lumbosacral plexus: a preliminary dosimetric analysis of this organ at risk among 15 patients treated with intensity-modulated radiotherapy for lower gastrointestinal cancers and the incidence of radiation-induced lumbosacral plexopathy.

PURPOSE: To generate a reproducible step-wise guideline for the delineation of the lumbosacral plexus (LSP) on axial computed tomography (CT) planning images and to provide a preliminary dosimetric analysis on 15 representative patients with rectal or anal cancers treated with an intensity-modulated radiotherapy (IMRT) technique. METHODS AND MATERIALS: A standardized method for contouring the LSP on axial CT images was devised. The LSP was referenced to identifiable anatomic structures from the L4-5 interspace to the level of the sciatic nerve. It was then contoured retrospectively on 15 patients treated with IMRT for rectal or anal cancer. No dose limitations were placed on this organ at risk during initial treatment planning. Dosimetric parameters were evaluated. The incidence of radiation-induced lumbosacral plexopathy (RILSP) was calculated. RESULTS: Total prescribed dose to 95% of the planned target volume ranged from 50.4 to 59.4 Gy (median 54 Gy). The mean (± standard deviation [SD]) LSP volume for the 15 patients was 100 ± 22 cm(3) (range, 71-138 cm(3)). The mean maximal dose to the LSP was 52.6 ± 3.9 Gy (range, 44.5-58.6 Gy). The mean irradiated volumes of the LSP were V40Gy = 58% ± 19%, V50Gy = 22% ± 23%, and V55Gy = 0.5% ± 0.9%. One patient (7%) was found to have developed RILSP at 13 months after treatment. CONCLUSIONS: The true incidence of RILSP in the literature is likely underreported and is not a toxicity commonly assessed by radiation oncologists. In our analysis the LSP commonly received doses approaching the prescribed target dose, and 1 patient developed RILSP. Identification of the LSP during IMRT planning may reduce RILSP. We have provided a reproducible method for delineation of the LSP on CT images and a preliminary dosimetric analysis for potential future dose constraints.

Vector analysis of prostate patient setup with image-guided radiation therapy via kV cone beam computed tomography.

PURPOSE: To analyze the daily setup variations in a cohort of intensity-modulated radiation therapy (IMRT) prostate cancer patients who had received daily image-guided RT without the use of fiducial markers to determine if daily image guidance is necessary. METHODS AND MATERIALS: 2134 Kilovoltage (kV) cone beam computed tomography (CBCT) images were analyzed, with three shifts recorded for each image. The number of times that the vector of the combined shifts would have exceeded the planning tumor volume (PTV) margin was tallied. Then, the average scalar shift of the first five images was removed from all subsequent images for a given patient, and the number of days for which the shift vector was greater than the three-dimensional clinical tumor volume-PTV (3D CTV-PTV) margin (8 mm, created with rolling ball technique) was recorded. Additionally, the scalar shifts from every other fraction were studied to determine if the individual patient's shift vector would be adequately sampled if CBCT was not performed daily, thus reducing patient imaging dose without compromising treatment quality. RESULTS: There were 297 cases where the vector shift was initially greater than the PTV margin. By correcting each patient's data set by the average shift of their first five images the total was 248 cases. By considering only every other image of each patient data set (after correction for the first 5 days), only 137 days in which the CTV was outside the PTV would have been seen. CONCLUSIONS: Daily imaging is recommended for prostate cancer IMRT patients in order to know the 3D (vector) position of the CTV and to ensure that it is always within the PTV margin. Correcting the data set by the average shift from the first 5 days reduces the overall number of outlier days but does not eliminate them completely.

Dwell position inaccuracy in the Varian GammaMed HDR ring applicator.

Varian has issued two Product Notification Letters warning of known inaccuracies in dwell positions for their GammaMed HDR ring applicator. This inaccuracy was measured for two sets of applicators. Autoexposed radiographs were taken of the HDR source at different dwell positions and analyzed per Varian recommendations using tools within the BrachyVision treatment planning program. Comparison between programmed and actual dwell positions showed the actual positions shifted distally by an average of 0.34 cm (0.17 cm-0.59 cm) across all positions in all rings. A correction method was developed and tested. During planning, the tip of the ring was extrapolated distally beyond its actual position in the patient image set and a proximal offset of the same distance was applied to the dwell positions. A global shift of 0.3 mm corrected all but the most proximal actual dwell position to within +2 mm of the planned position.

Comparison of intensity-modulated radiotherapy using helical tomotherapy and segmental multileaf collimator-based techniques for nasopharyngeal carcinoma: dosimetric analysis incorporating quality assurance guidelines from RTOG 0225.

Intensity-modulated radiotherapy (IMRT) treatment plans generated by segmental multileaf collimator (SMLC) and helical tomotherapy (HT) techniques for patients with nasopharyngeal carcinoma were compared using standardized criteria proposed by Radiation Therapy Oncology Group (RTOG) protocol 0225. The goal was to deliver a prescribed dose of 70 Gy to at least 95% of the planning target volume (PTV) encompassing gross tumor, and 59.4 Gy and 50.4 Gy, respectively, to areas at high and low risk for microscopic disease, over 33 treatments while respecting constraints to organs at risk (OAR). HT-IMRT significantly reduced dose to the contralateral parotid gland and improved dose homogeneity to the PTVs. Mean doses to the inner and middle ears were also reduced by 18% and 24%, respectively, on the ipsilateral side, and 24%, and 35%, respectively, on the contralateral side using HT-IMRT compared to SMLC-IMRT. Additionally, HT-IMRT reduced mean doses to brainstem (p = 0.02), larynx (p = 0.03), and oral cavity (p = 0.03). These findings suggest that HT-IMRT may be of improve the therapeutic ratio in the radiotherapeutic treatment of nasopharyngeal carcinoma.

Utility of megavoltage fan-beam CT for treatment planning in a head-and-neck cancer patient with extensive dental fillings undergoing helical tomotherapy.

The purpose of this study was to demonstrate the potential utility of megavoltage fan-beam computed tomography (MV-FBCT) for treatment planning in a patient undergoing helical tomotherapy for nasopharyngeal carcinoma in the presence of extensive dental artifact. A 28-year-old female with locally advanced nasopharyngeal carcinoma presented for radiation therapy. Due to the extensiveness of the dental artifact present in the oral cavity kV-CT scan acquired at simulation, which made treatment planning impossible on tomotherapy planning system, MV-FBCT imaging was obtained using the HI-ART tomotherapy treatment machine, with the patient in the treatment position, and this information was registered with her original kV-CT scan for the purposes of structure delineation, dose calculation, and treatment planning. To validate the feasibility of the MV-FBCT-generated treatment plan, an electron density CT phantom (model 465, Gammex Inc., Middleton, WI) was scanned using MV-FBCT to obtain CT number to density table. Additionally, both a "cheese" phantom (which came with the tomotherapy treatment machine) with 2 inserted ion chambers and a generic phantom called Quasar phantom (Modus Medical Devices Inc., London, ON, Canada) with one inserted chamber were used to confirm dosimetric accuracy. The MV-FBCT could be used to clearly visualize anatomy in the region of the dental artifact and provide sufficient soft-tissue contrast to assist in the delineation of normal tissue structures and fat planes. With the elimination of the dental artifact, the MV-FBCT images allowed more accurate dose calculation by the tomotherapy system. It was confirmed that the phantom material density was determined correctly by the tomotherapy MV-FBCT number to density table. The ion chamber measurements agreed with the calculations from the MV-FBCT generated phantom plan within 2%. MV-FBCT may be useful in radiation treatment planning for nasopharyngeal cancer patients in the setting of extensive dental artifacts.

Initial clinical experience with helical tomotherapy for head and neck cancer.

BACKGROUND: To report a single-institutional experience with the use of helical tomotherapy (HT)-based intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS: Seventy-seven consecutive patients were treated with HT for squamous cell carcinoma of the head and neck to a median dose of 66 Gy (range, 60 to 72 Gy). Megavoltage CT scans were obtained as part of an image-guided registration protocol for patient alignment before each treatment. Concurrent chemotherapy was administered to 48 patients (62%). RESULTS: The 2-year estimates of overall survival, local-regional control, and disease-free survival were 82%, 77%, and 71%, respectively. Spatial evaluation of local-regional failures revealed that 16 of the 18 patients who progressed in the primary site or neck failed in the high-dose planning target volume (PTV). CONCLUSIONS: HT appears to achieve clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Clinical impact of magnetic resonance imaging on Gamma Knife surgery for brain metastases.

OBJECT: Stereotactic radiosurgery is beneficial for patients with a limited number of small brain metastases. Increased numbers of brain metastases, not infrequently at unreachable locations, are identified using thin-section magnetic resonance (MR) imaging on the day of Gamma Knife surgery (GKS). To improve patient selection and design better treatment strategies, a retrospective study was conducted to determine factors that may contribute to detecting additional brain metastases on the day of GKS. METHODS: A total of 100 patients with brain metastases who underwent GKS between October 2003 and May 2006 at the University of California Davis Medical Center were included in the present study. Patients were categorized by age, sex, Karnofsky Performance Scale score, status of systemic disease, histological characteristics of the primary tumor, and whether they received previous whole-brain radiotherapy (WBRT). The number of lesions identified by diagnostic MR imaging at referral, by thin-section double-contrast MR imaging on the day of GKS, and the actual lesions treated by GKS were recorded. The diagnostic MR images were categorized in terms of section thickness and time interval before GKS. CONCLUSIONS: The characteristics of this patient population match well with the general GKS practice. Fifty-six had been treated with WBRT. On average, patients presented with 2.2 +/- 1.7 lesions, a number based on their original diagnostic MR imaging, had 3.6 +/- 3.4 lesions identified on the thin-section treatment MR imaging (p < 0.05), and underwent treatment of 3.1 +/- 2.6 lesions on the day of GKS. Significantly, treatment was compromised in 21 patients, in whom not all additional lesions could be treated with the initial headframe placement. Analysis shows that a significantly greater number of lesions were detected using thin-section MR imaging on the day of GKS in patients who had undergone thick-section diagnostic MR imaging, did not receive WBRT, and had progressive systemic disease. To optimize treatment planning and minimize additional treatment, the number of metastases needs to be determined accurately before frame placement, ideally by performing thin-section MR imaging, as used on the day of GKS.