Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

Genome analyses reveal the hybrid origin of the staple crop white Guinea yam (Dioscorea rotundata).

White Guinea yam (Dioscorea rotundata) is an important staple tuber crop in West Africa. However, its origin remains unclear. In this study, we resequenced 336 accessions of white Guinea yam and compared them with the sequences of wild Dioscorea species using an improved reference genome sequence of D. rotundata In contrast to a previous study suggesting that D. rotundata originated from a subgroup of Dioscorea praehensilis, our results suggest a hybrid origin of white Guinea yam from crosses between the wild rainforest species D. praehensilis and the savannah-adapted species Dioscorea abyssinica We identified a greater genomic contribution from D. abyssinica in the sex chromosome of Guinea yam and extensive introgression around the SWEETIE gene. Our findings point to a complex domestication scenario for Guinea yam and highlight the importance of wild species as gene donors for improving this crop through molecular breeding.

The complete chloroplast genome of Onobrychis gaubae (Fabaceae-Papilionoideae): comparative analysis with related IR-lacking clade species.

BACKGROUND: Plastome (Plastid genome) sequences provide valuable markers for surveying evolutionary relationships and population genetics of plant species. Papilionoideae (papilionoids) has different nucleotide and structural variations in plastomes, which makes it an ideal model for genome evolution studies. Therefore, by sequencing the complete chloroplast genome of Onobrychis gaubae in this study, the characteristics and evolutionary patterns of plastome variations in IR-loss clade were compared. RESULTS: In the present study, the complete plastid genome of O. gaubae, endemic to Iran, was sequenced using Illumina paired-end sequencing and was compared with previously known genomes of the IRLC species of legumes. The O. gaubae plastid genome was 122,688 bp in length and included a large single-copy (LSC) region of 81,486 bp, a small single-copy (SSC) region of 13,805 bp and one copy of the inverted repeat (IRb) of 29,100 bp. The genome encoded 110 genes, including 76 protein-coding genes, 30 transfer RNA (tRNA) genes and four ribosome RNA (rRNA) genes and possessed 83 simple sequence repeats (SSRs) and 50 repeated structures with the highest proportion in the LSC. Comparative analysis of the chloroplast genomes across IRLC revealed three hotspot genes (ycf1, ycf2, clpP) which could be used as DNA barcode regions. Moreover, seven hypervariable regions [trnL(UAA)-trnT(UGU), trnT(GGU)-trnE(UUC), ycf1, ycf2, ycf4, accD and clpP] were identified within Onobrychis, which could be used to distinguish the Onobrychis species. Phylogenetic analyses revealed that O. gaubae is closely related to Hedysarum. The complete O. gaubae genome is a valuable resource for investigating evolution of Onobrychis species and can be used to identify related species. CONCLUSIONS: Our results reveal that the plastomes of the IRLC are dynamic molecules and show multiple gene losses and inversions. The identified hypervariable regions could be used as molecular markers for resolving phylogenetic relationships and species identification and also provide new insights into plastome evolution across IRLC.

Radiobiological evaluation considering setup error on single-isocenter irradiation in stereotactic radiosurgery.

PURPOSE: We calculated the dosimetric indices and estimated the tumor control probability (TCP) considering six degree-of-freedom (6DoF) patient setup errors in stereotactic radiosurgery (SRS) using a single-isocenter technique. METHODS: We used simulated spherical gross tumor volumes (GTVs) with diameters of 1.0 cm (GTV 1), 2.0 cm (GTV 2), and 3.0 cm (GTV 3), and the distance (d) between the target center and isocenter was set to 0, 5, and 10 cm. We created the dose distribution by convolving the blur component to uniform dose distribution. The prescription dose was 20 Gy and the dose distribution was adjusted so that D95 (%) of each GTV was covered by 100% of the prescribed dose. The GTV was simultaneously rotated within 0°-1.0° (δR) around the x-, y-, and z-axes and then translated within 0-1.0 mm (δT) in the x-, y-, and z-axis directions. D95, conformity index (CI), and conformation number (CN) were evaluated by varying the distance from the isocenter. The TCP was estimated by translating the calculated dose distribution into a biological response. In addition, we derived the x-y-z coordinates with the smallest TCP reduction rate that minimize the sum of squares of the residuals as the optimal isocenter coordinates using the relationship between 6DoF setup error, distance from isocenter, and GTV size. RESULTS: D95, CI, and CN were decreased with increasing isocenter distance, decreasing GTV size, and increasing setup error. TCP of GTVs without 6DoF setup error was estimated to be 77.0%. TCP were 25.8% (GTV 1), 35.0% (GTV 2), and 53.0% (GTV 3) with (d, δT, δR) = (10 cm, 1.0 mm, 1.0°). The TCP was 52.3% (GTV 1), 54.9% (GTV 2), and 66.1% (GTV 3) with (d, δT, δR) = (10 cm, 1.0 mm, 1.0°) at the optimal isocenter position. CONCLUSION: The TCP in SRS for multiple brain metastases with a single-isocenter technique may decrease with increasing isocenter distance and decreasing GTV size when the 6DoF setup errors are exceeded (1.0 mm, 1.0°). Additionally, it might be possible to better maintain TCP for GTVs with 6DoF setup errors by using the optimal isocenter position.

The neurocognitive function change criteria after whole-brain radiation therapy for brain metastasis, in reference to health-related quality of life changes: a prospective observation study.

BACKGROUND: We sought to construct the optimal neurocognitive function (NCF) change criteria sensitive to health-related quality of life (HR-QOL) in patients who have undergone whole-brain radiation therapy (WBRT) for brain metastasis. METHODS: We categorized the patients by the changes of NCF into groups of improvement versus deterioration if at least one domain showed changes that exceeded the cut-off while other domains remained stable. The remaining patients were categorized as stable, and the patients who showed both significant improvement and deterioration were categorized as 'both.' We examined the clinical meaning of NCF changes using the cut-off values 1.0, 1.5, and 2.0 SD based on the percentage of patients whose HR-QOL changes were ≥ 10 points. RESULTS: Baseline, 4-month and 8-month data were available in 78, 41 (compliance; 85%), and 29 (81%) patients, respectively. At 4 months, improvement/stable/deterioration/both was seen in 15%/12%/41%/32% of the patients when 1.0 SD was used; 19%/22%/37%/22% with 1.5 SD, and 17%/37%/37%/9% with 2.0 SD. The HR-QOL scores on the QLQ-C30 functional scale were significantly worse in the deterioration group versus the others with 1.0 SD (p = 0.013) and 1.5 SD (p = 0.015). With 1.5 SD, the HR-QOL scores on the QLQ-BN20 was significantly better in the improvement group versus the others (p = 0.033). However, when 'both' was included in 'improvement' or 'deterioration,' no significant difference in HR-QOL was detected. CONCLUSIONS: The NCF cut-off of 1.5 SD and the exclusion of 'both' patients from the 'deterioration' and 'improvement' groups best reflects HR-QOL changes.

Radiobiological effects of the interruption time with Monte Carlo Simulation on multiple fields in photon beams.

PURPOSE: The interruption time is the irradiation interruption that occurs at sites and operations such as the gantry, collimator, couch rotation, and patient setup within the field in radiotherapy. However, the radiobiological effect of prolonging the treatment time by the interruption time for tumor cells is little evaluated. We investigated the effect of the interruption time on the radiobiological effectiveness with photon beams based on a modified microdosimetric kinetic (mMK) model. METHODS: The dose-mean lineal energy yD (keV/µm) of 6-MV photon beams was calculated by the particle and heavy ion transport system (PHITS). We set the absorbed dose to 2 or 8 Gy, and the interruption time (τ) was set to 1, 3, 5, 10, 30, and 60 min. The biological parameters such as α0, ß0, and DNA repair constant rate (a + c) values were acquired from a human non-small-cell lung cancer cell line (NCI-H460) for the mMK model. We used two-field and four-field irradiation with a constant dose rate (3 Gy/min); the photon beams were paused for interruption time τ. We calculated the relative biological effectiveness (RBE) to evaluate the interruption time's effect compared with no interrupted as a reference. RESULTS: The yD of 6-MV photon beams was 2.32 (keV/µm), and there was little effect by changing the water depth (standard deviation was 0.01). The RBE with four-field irradiation for 8 Gy was decreased to 0.997, 0.975, 0.900, and 0.836 τ = 1, 10, 30, 60 min, respectively. In addition, the RBE was affected by the repair constant rate (a + c) value, the greater the decrease in RBE with the longer the interruption time when the (a + c) value was large. CONCLUSION: The ~10-min interruption of 6-MV photon beams did not significantly impact the radiobiological effectiveness, since the RBE decrease was <3%. Nevertheless, the RBE's effect on tumor cells was decreased about 30% by increasing the 60 min interruption time at 8 Gy with four-field irradiation. It is thus necessary to make the interruption time as short as possible.

Effect of setup error in the single-isocenter technique on stereotactic radiosurgery for multiple brain metastases.

In conventional stereotactic radiosurgery (SRS), treatment of multiple brain metastases using multiple isocenters is time-consuming resulting in long dose delivery times for patients. A single-isocenter technique has been developed which enables the simultaneous irradiation of multiple targets at one isocenter. This technique requires accurate positioning of the patient to ensure optimal dose coverage. We evaluated the effect of six degrees of freedom (6DoF) setup errors in patient setups on SRS dose distributions for multiple brain metastases using a single-isocenter technique. We used simulated spherical gross tumor volumes (GTVs) with diameters ranging from 1.0 to 3.0 cm. The distance from the isocenter to the target's center was varied from 0 to 15 cm. We created dose distributions so that each target was entirely covered by 100% of the prescribed dose. The target's position vectors were rotated from 0°-2.0° and translated from 0-1.0 mm with respect to the three axes in space. The reduction in dose coverage for the targets for each setup error was calculated and compared with zero setup error. The calculated margins for the GTV necessary to satisfy the tolerance values for loss of GTV coverage of 3% to 10% were defined as coverage-based margins. In addition, the maximum isocenter to target distance for different 6DoF setup errors was calculated to satisfy the tolerance values. The dose coverage reduction and coverage-based margins increased as the target diameter decreased, and the distance and 6DoF setup error increased. An increase in setup error when a single-isocenter technique is used may increase the risk of missing the tumor; this risk increases with increasing distance from the isocenter and decreasing tumor size.

[A Case of a"Watch and Wait Therapy"Approach after Preoperative Chemoradiotherapy for Rectal Cancer Accompanied by Severe Emphysema].

A 72-year-old man was referred to our hospital for treatment for rectal cancer. Digital rectal examination and colonoscopy revealed a 4 cm tumor located at the anterior rectal wall 5 cm away from the anal verge, and pathological examination confirmed that the tumor was adenocarcinoma. A computed tomography scan detected neither regional lymph node metastasis nor distant metastasis. Hence, he was diagnosed with cT3N0M0, cStage Ⅱa rectal cancer. The preoperative general examination revealed bradyarrhythmia and severe emphysema, and he was considered to be high risk for general anesthesia. After placement of a pacemaker, preoperative capecitabine-based chemoradiotherapy(CRT)(50.4 Gy in 28 fractions of 1.8 Gy each)was implemented. The digital rectal examination and imaging evaluation 4 weeks after preoperative CRT revealed that the tumor disappeared, and pathological examination showed no malignant findings. Considering the risks of general anesthesia, the"watch and wait therapy"approach was adopted with sufficient informed consent. At present, 15 months after preoperative CRT, no evidence of regrowth or distant metastasis has been detected under rigorous follow- up evaluations.

The impact of the three degrees-of-freedom fiducial marker-based setup compared to soft tissue-based setup in hypofractionated intensity-modulated radiotherapy for prostate cancer.

PURPOSE: We evaluated the setup accuracy of a three-degree-of-freedom fiducial marker (3DOF-FM)-based setup compared to a soft tissue (ST)-based setup in hypofractionated intensity-modulated radiotherapy (IMRT) for prostate cancer. MATERIALS AND METHODS: We analyzed the setup accuracy for 17 consecutive prostate cancer patients with three implanted FMs who underwent hypofractionated IMRT. The 3DOF-ST-based setup using cone-beam computed tomography (CT) was performed after a six DOF-bony structure (BS)-based setup using an ExacTrac x-ray system. The 3DOF-FM-based matching using the ExacTrac x-ray system was done during the BS- and ST-based setups. We determined the mean absolute differences and the correlation between the FM- and ST-based translational shifts relative to the BS-based setup position. The rotational mean shifts detected by the ExacTrac x-ray system were also evaluated. RESULTS: The mean differences in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) dimensions were 0.69, 0.0, and 0.30 mm, respectively. The Pearson correlation coefficients for both shifts were 0.92 for AP, 0.91 for SI, and 0.68 for LR. The percentages of shift agreements within 2 mm were 85% for AP, 93% for SI, and 99% for LR. The absolute values of rotational shifts were 0.1° for AP, 0.3°, and 1.2° for LR. CONCLUSIONS: The setup accuracy of the 3DOF-FM-based setup has the potential to be interchangeable with a ST-based setup. Our data are likely to be useful in clinical practice along with the popularization of the hypofractionated IMRT in prostate cancer.

First Eigenmode Transmission by High Efficient CSI Estimation for Multiuser Massive MIMO Using Millimeter Wave Bands.

Drastic improvements in transmission rate and system capacity are required towards 5th generation mobile communications (5G). One promising approach, utilizing the millimeter wave band for its rich spectrum resources, suffers area coverage shortfalls due to its large propagation loss. Fortunately, massive multiple-input multiple-output (MIMO) can offset this shortfall as well as offer high order spatial multiplexing gain. Multiuser MIMO is also effective in further enhancing system capacity by multiplexing spatially de-correlated users. However, the transmission performance of multiuser MIMO is strongly degraded by channel time variation, which causes inter-user interference since null steering must be performed at the transmitter. This paper first addresses the effectiveness of multiuser massive MIMO transmission that exploits the first eigenmode for each user. In Line-of-Sight (LoS) dominant channel environments, the first eigenmode is chiefly formed by the LoS component, which is highly correlated with user movement. Therefore, the first eigenmode provided by a large antenna array can improve the robustness against the channel time variation. In addition, we propose a simplified beamforming scheme based on high efficient channel state information (CSI) estimation that extracts the LoS component. We also show that this approximate beamforming can achieve throughput performance comparable to that of the rigorous first eigenmode transmission. Our proposed multiuser massive MIMO scheme can open the door for practical millimeter wave communication with enhanced system capacity.

Superiority of a soft tissue-based setup using cone-beam computed tomography over a bony structure-based setup in intensity-modulated radiotherapy for prostate cancer.

The purpose of this study was to test the superiority of a soft tissue-based setup using cone-beam computed tomography (CBCT) to a bony structure-based setup using the ExacTrac system in intensity-modulated radiotherapy (IMRT) for prostate cancer. We studied 20 patients with localized prostate cancer who received IMRT between November 2010 and February 2012. After the initial setup, the pelvic bony structure-based setup and ExacTrac system were applied. After that, CBCT and a soft tissue-based setup were used. A shift in the isocenter between the ExacTrac-based and CBCT-based setup was recorded in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) axes. The shift was considered an interfractional prostate shift. Post-treatment CBCT was also taken once a week to measure the intrafractional prostate shift, based on the coordinates of the isocenter between pre- and post-treatment CBCT. The planning target volume (PTV) margins were determined using van Herk's method. We measured the elapsed time required for soft tissue matching and the entire treatment time using CBCT. The means ± standard deviation (SD) of the inter- and intrafractional shifts were 0.9 ± 2.8 mm and -0.3 ± 1.4 mm in the AP, 0.9 ± 2.2 mm and -0.1 ± 1.2 mm in the SI, and 0.1 ± 0.7 mm and -0.1 ± 0.7 mm in the LR directions. The PTV margins in the cases of bony structure-based and soft tissue-based setups were 7.3 mm and 2.7 mm in the AP, 5.8 mm and 2.3 mm in the SI, and 1.9 mm and 1.2 mm in the LR directions. Even though the median elapsed time using CBCT was expanded in 5.9 min, the PTV margins were significantly reduced. We found the calculated PTV margins in the soft tissue-based setup using CBCT were small, and this arrangement was superior to the bony structure-based setup in prostate IMRT.

The Relationship between the Contouring Time of the Metal Artifacts Area and Metal Artifacts in Head and Neck Radiotherapy.

(1) Background: The impacts of metal artifacts (MAs) on the contouring workload for head and neck radiotherapy have not yet been clarified. Therefore, this study evaluated the relationship between the contouring time of the MAs area and MAs on head and neck radiotherapy treatment planning. (2) Methods: We used treatment planning computed tomography (CT) images for head and neck radiotherapy. MAs were classified into three severities by the percentage of CT images containing MAs: mild (<25%), moderate (25−75%), and severe (>75%). We randomly selected nine patients to evaluate the relationship between MAs and the contouring time of the MAs area. (3) Results: The contouring time of MAs showed moderate positive correlations with the MAs volume and the number of CT images containing MAs. Interobserver reliability of the extracted MAs volume and contouring time were excellent and poor, respectively. (4) Conclusions: Our study suggests that the contouring time of MAs areas is related to individual commitment rather than clinical experience. Therefore, the development of software combining metal artifact reduction methods with automatic contouring methods is necessary to reducing interobserver variability and contouring workload.

Multicomponent mathematical model for tumor volume calculation with setup error using single-isocenter stereotactic radiotherapy for multiple brain metastases.

We evaluated the tumor residual volumes considering six degrees-of-freedom (6DoF) patient setup errors in stereotactic radiotherapy (SRT) with multicomponent mathematical model using single-isocenter irradiation for brain metastases. Simulated spherical gross tumor volumes (GTVs) with 1.0 (GTV 1), 2.0 (GTV 2), and 3.0 (GTV 3)-cm diameters were used. The distance between the GTV center and isocenter (d) was set at 0-10 cm. The GTV was simultaneously translated within 0-1.0 mm (T) and rotated within 0°-1.0° (R) in the three axis directions using affine transformation. We optimized the tumor growth model parameters using measurements of non-small cell lung cancer cell lines' (A549 and NCI-H460) growth. We calculated the GTV residual volume at the irradiation's end using the physical dose to the GTV when the GTV size, d, and 6DoF setup error varied. The d-values that satisfy tolerance values (10%, 35%, and 50%) of the GTV residual volume rate based on the pre-irradiation GTV volume were determined. The larger the tolerance value set for both cell lines, the longer the distance to satisfy the tolerance value. In GTV residual volume evaluations based on the multicomponent mathematical model on SRT with single-isocenter irradiation, the smaller the GTV size and the larger the distance and 6DoF setup error, the shorter the distance that satisfies the tolerance value might need to be.

Verification of Qfix Encompass™ couch modeling using the Acuros XB algorithm and HypeArc™ using a high-spatial-resolution two-dimensional diode array.

We modeled the Qfix Encompass™ immobilization system and further verified the calculated dose distribution of the AcurosXB (AXB) dose calculation algorithm using SRS MapCHECKⓇ (SRSMC) in the HyperArc™ (HA) clinical plan. An Encompass system with a StereoPHAN™ QA phantom was scanned by SOMATOM go.Sim and imported to an Eclipse™ treatment planning system to create a treatment plan for Encompass modeling. The Encompass modeling was performed in the StereoPHAN with a pinpoint ion chamber for 6 MV and 6 MV flattening filter free (6 MV FFF), and 2 × 2 cm2, 4 × 4 cm2, and 6 × 6 cm2 irradiation field sizes. The dose calculation algorithm used was AXB ver. 15.5 with a 1.0 mm calculation grid size. The Hounsfield unit (HU) values of the Encompass modeling were set to 400, -100, -200, and -300 for Encompass, and -400, -600, -700, and -800 for the Encompass base. We evaluated the dose distribution after Encompass modeling by SRSMC using gamma analysis in 12 patients. We adopted HU values of -200 for Encompass, -800 for Encompass base for 6 MV, and -200 for Encompass and -700 for Encompass. Base for 6 MV FFF was adopted as the HU values for the Encompass modeling based on the measurement results. The proposed Encompass modeling resulted in a mean pass rate evaluation >98% for both 6 MV and 6 MV FFF when the 1%/1 mm criterion was used, demonstrating that the proposed HU value can be adopted to calculate more accurate dose distributions.

Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.

BACKGROUND: Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. OBSERVATIONS: Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. LESSONS: Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

Main bronchial diverticula in the subcarinal region: their relation to airflow limitations.

BACKGROUND: To date, bronchial diverticula have generally been treated as a pathological condition associated with chronic obstructive pulmonary disease (COPD), although only a limited amount of published information is available on the relationship between bronchial diverticula as depicted by multidetector computed tomography (MDCT) and airflow limitations. PURPOSE: To evaluate the relationship between airflow limitations and main bronchial diverticula in the subcarinal region using spirometry and thin-section MDCT. MATERIAL AND METHODS: A total of 189 consecutive adult patients were retrospectively evaluated based on spirometry and thin-section MDCT of the chest. All examinations were performed at our institution between June and October 2008. The study group included 70 women and 119 men with a mean age of 65 years (range 19-86 years). The relationship between the FEV(1)% and bronchial diverticula in the subcarinal region was analyzed (Student's t-test). RESULTS: The indications for conducting the examinations were pulmonary diseases (82 patients), cardiovascular diseases (22), extrapulmonary malignancies (74), and other conditions (11). A total of 84/189 (44.4%) patients showed bronchial diverticula, and the FEV(1)% of 70/84 (83.3%) patients was above 70. The FEV(1)% of patients with lesions ranged from 26.0 to 97.8 (mean 76.8), whereas the range was 28.1-94.4 (mean 73.7) in those without lesions. There was no significant association between the FEV(1)% and the presence of subcarinal bronchial diverticula (P > 0.05). CONCLUSION: Our data demonstrate that thin-section chest CT commonly demonstrates main bronchial diverticula in the subcarinal region in patients without airflow limitations. We propose that the presence of a small number of tiny bronchial diverticula under the carina may not be a criterion for the diagnosis of COPD.

Reduced-dose WBRT combined with SRS for 1-4 brain metastases aiming at minimizing neurocognitive function deterioration without compromising brain tumor control.

Background and purpose: To minimize cognitive decline without increasing brain tumor recurrence (BTR) by reduced-dose whole-brain radiotherapy (RD-WBRT) (25 Gy, 10 fractions) + stereotactic radiosurgery (SRS) in patients with ≤ 4 brain metastases. Materials and methods: Eligible patients with ≤ 4 brain metastases on contrast-enhanced MRI and Karnofsky Performance Status ≥ 70. The primary endpoint was the non-inferiority of BTR at distant sites in the brain (BTR-distant)-free survival at 6 months compared to that of the standard dose (SD)-WBRT (30 Gy, 10 fractions) + SRS arm in a randomized clinical trial (JROSG99-1) of SRS with/without SD-WBRT. Secondary endpoints included BTR at any brain sites (BTR-all) and neurocognitive function assessed by a six-test standardized battery. Results: Forty patients from seven institutions were enrolled (median age 69 years). The primary tumor site was a lung in 28 patients; 20 patients had a solitary brain metastasis. The median survival time was 19.0 months (95 %CI: 13.8 %-27.5 %). The BTR-distant-free survival at 6 months was 76.9 % (59.5 %-87.7 %), which is comparable to that of historical control although predetermined non-inferiority (>71 %) could not be confirmed (p = 0.16). The cumulative incidence of BTR-all at 6 months accounting for the competing risk of death was 23.0 % (11.4-37.1), which was not worse than that of historical control (p = 0.774). The frequency of the cumulative incidence of persistent cognitive decline at 6 months was 48.6 % under the [>2.0 SD in ≥ 1 test] definition. Conclusions: RD-WBRT may yield comparable intracranial tumor control when combined with SRS, and may reduce the risk of neurocognitive decline compared to that after SD-WBRT.

The impact of target positioning error and tumor size on radiobiological parameters in robotic stereotactic radiosurgery for metastatic brain tumors.

This study aimed to evaluate the effect of target positioning error (TPE) on radiobiological parameters, such as tumor control probability (TCP) and normal tissue complication probability (NTCP), in stereotactic radiosurgery (SRS) for metastatic brain tumors of different sizes using CyberKnife. The reference SRS plans were created using the circular cone of the CyberKnife for each spherical gross tumor volume (GTV) with diameters (φ) of 5, 7.5, 10, 15, and 20 mm, contoured on computed tomography images of the head phantom. Subsequently, plans involving TPE were created by shifting the beam center by 0.1-2.0 mm in three dimensions relative to the reference plans using the same beam arrangements. Conformity index (CI), generalized equivalent uniform dose (gEUD)-based TCP, and NTCP of estimated brain necrosis were evaluated for each plan. When the gEUD parameter "a" was set to - 10, the CI and TCP for the reference plan at the φ5-mm GTV were 0.90 and 80.8%, respectively. The corresponding values for plans involving TPE of 0.5-mm, 1.0-mm, and 2.0-mm were 0.62 and 77.4%, 0.40 and 62.9%, and 0.12 and 7.2%, respectively. In contrast, the NTCP for all GTVs were the same. The TCP for the plans involving a TPE of 2-mm was 7.2% and 68.8% at the φ5-mm and φ20-mm GTV, respectively. The TPEs corresponding to a TCP reduction rate of 3% at the φ5-mm and φ20-mm GTV were 0.41 and 0.99 mm, respectively. TPE had a significant effect on TCP in SRS for metastatic brain tumors using CyberKnife, particularly for small GTVs.