Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer.

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.

Deep Learning-Based Localization and Detection of Malpositioned Endotracheal Tube on Portable Supine Chest Radiographs in Intensive and Emergency Medicine: A Multicenter Retrospective Study.

OBJECTIVES: We aimed to develop a computer-aided detection (CAD) system to localize and detect the malposition of endotracheal tubes (ETTs) on portable supine chest radiographs (CXRs). DESIGN: This was a retrospective diagnostic study. DeepLabv3+ with ResNeSt50 backbone and DenseNet121 served as the model architecture for segmentation and classification tasks, respectively. SETTING: Multicenter study. PATIENTS: For the training dataset, images meeting the following inclusion criteria were included: 1) patient age greater than or equal to 20 years; 2) portable supine CXR; 3) examination in emergency departments or ICUs; and 4) examination between 2015 and 2019 at National Taiwan University Hospital (NTUH) (NTUH-1519 dataset: 5,767 images). The derived CAD system was tested on images from chronologically (examination during 2020 at NTUH, NTUH-20 dataset: 955 images) or geographically (examination between 2015 and 2020 at NTUH Yunlin Branch [YB], NTUH-YB dataset: 656 images) different datasets. All CXRs were annotated with pixel-level labels of ETT and with image-level labels of ETT presence and malposition. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For the segmentation model, the Dice coefficients indicated that ETT would be delineated accurately (NTUH-20: 0.854; 95% CI, 0.824-0.881 and NTUH-YB: 0.839; 95% CI, 0.820-0.857). For the classification model, the presence of ETT could be accurately detected with high accuracy (area under the receiver operating characteristic curve [AUC]: NTUH-20, 1.000; 95% CI, 0.999-1.000 and NTUH-YB: 0.994; 95% CI, 0.984-1.000). Furthermore, among those images with ETT, ETT malposition could be detected with high accuracy (AUC: NTUH-20, 0.847; 95% CI, 0.671-0.980 and NTUH-YB, 0.734; 95% CI, 0.630-0.833), especially for endobronchial intubation (AUC: NTUH-20, 0.991; 95% CI, 0.969-1.000 and NTUH-YB, 0.966; 95% CI, 0.933-0.991). CONCLUSIONS: The derived CAD system could localize ETT and detect ETT malposition with excellent performance, especially for endobronchial intubation, and with favorable potential for external generalizability.

CT findings of 144 in-hospital patients with influenza pneumonia: A retrospective analysis.

BACKGROUND/PURPOSE: Patients with influenza infection during their period of admission may have worse computed tomography (CT) manifestation according to the clinical status. This study aimed to evaluate the CT findings of in-hospital patients due to clinically significant influenza pneumonia with correlation of clinical presentations. METHODS: In this retrospective, single center case series, 144 patients were included. All in-hospital patients were confirmed influenza infection and underwent CT scan. These patients were divided into three groups according to the clinical status of the most significant management: (1) without endotracheal tube and mechanical ventilator (ETTMV) or extracorporeal membrane oxygenation (ECMO); (2) with ETTMV; (3) with ETTMV and ECMO. Pulmonary opacities were scored according to extent. Spearman rank correlation analysis was used to evaluate the correlation between clinical parameters and CT scores. RESULTS: The predominant CT manifestation of influenza infection was mixed ground-glass opacity (GGO) and consolidation with both lung involvement. The CT scores were all reach significant difference among all three groups (8.73 ± 6.29 vs 12.49 ± 6.69 vs 18.94 ± 4.57, p < 0.05). The chest CT score was correlated with age, mortality, and intensive care unit (ICU) days (all p values were less than 0.05). In addition, the CT score was correlated with peak lactate dehydrogenase (LDH) level and peak C-reactive protein (CRP) level (all p values were less than 0.05). Concomitant bacterial infection had higher CT score than primary influenza pneumonia (13.02 ± 7.27 vs 8.95 ± 5.99, p < 0.05). CONCLUSION: Thin-section chest CT scores correlated with clinical and laboratory parameters in in-hospital patients with influenza pneumonia.

Hemorrhage risk prediction after computed tomography-guided lung biopsy: Clinical parameters and quantitative pulmonary vascular analysis.

BACKGROUND/PURPOSE: We evaluated the utility of combining quantitative pulmonary vasculature measures with clinical factors for predicting pulmonary hemorrhage after computed tomography (CT)-guided lung biopsy. METHODS: Patients who underwent CT-guided lung biopsy were retrospectively included in this study. Clinical and radiographic vasculature variables were evaluated as predictors of pulmonary hemorrhage. The radiographic pulmonary vascular analysis included vessel count, density, diameter, and area, and also blood volume in small vessels with a cross-sectional area ≤5 mm2 (BV5) and total blood vessel volume (TBV) in the lungs. Univariate and multivariate logistic regressions were used to identify the independent risk factors of higher-grade pulmonary hemorrhage and establish the prediction model presented as a nomogram. RESULTS: The study included 126 patients; discovery cohort n = 103, and validation cohort n = 23. All pulmonary hemorrhage, higher-grade (grade ≥2) pulmonary hemorrhage, and hemoptysis occurred in 42.9%, 15.9%, and 3.2% of patients who underwent CT-guided lung biopsies. In the discovery cohort, patients with larger lesion depth (p = 0.013), higher vessel density (p = 0.033), and higher BV5 (p = 0.039) were more likely to experience higher-grade hemorrhage. The nomogram prediction model for higher-grade hemorrhage built by the discovery cohort showed similar performance in the validation cohort. CONCLUSIONS: Higher-grade pulmonary hemorrhage may occur after CT-guided lung biopsy. Lesion depth, vessel density, and BV5 are independent risk factors for higher-grade pulmonary hemorrhage. Nomograms integrating clinical parameters and radiographic pulmonary vasculature measures offer enhanced capability for assessing hemorrhage risk following CT-guided lung biopsy, thereby facilitating improved patient clinical care.

Discrimination of invasive lung adenocarcinoma from Lung-RADS category 2 nonsolid nodules through visual assessment: a retrospective study.

OBJECTIVES: Invasive adenocarcinomas (IADs) have been identified among nonsolid nodules (NSNs) assigned as Lung Imaging Reporting and Data System (Lung-RADS) category 2. This study used visual assessment for differentiating IADs from noninvasive lesions (NILs) in this category. METHODS: This retrospective study included 222 patients with 242 NSNs, which were resected after preoperative computed tomography (CT)-guided dye localization. Visual assessment was performed by using the lung and bone window (BW) settings to classify NSNs into BW-visible (BWV) and BW-invisible (BWI) NSNs. In addition, nodule size, shape, border, CT attenuation, and location were evaluated and correlated with histopathological results. Logistic regression was performed for multivariate analysis. A p value of < 0.05 was considered statistically significant. RESULTS: A total of 242 NSNs (mean diameter, 7.6 ± 2.8 mm), including 166 (68.6%) BWV and 76 (31.4%) BWI NSNs, were included. IADs accounted for 31% (75) of the nodules. Only 4 (5.3%) IADs were identified in the BWI group and belonged to the lepidic-predominant (n = 3) and acinar-predominant (n = 1) subtypes. In univariate analysis for differentiating IADs from NILs, the nodule size, shape, CT attenuation, and visual classification exhibited statistical significance. Nodule size and visual classification were the significant predictors for IAD in multivariate analysis with logistic regression (p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of visual classification in IAD prediction were 94.7%, 43.1%, 42.8%, and 94.7%, respectively. CONCLUSIONS: The window-based visual classification of NSNs is a simple and objective method to discriminate IADs from NILs. CLINICAL RELEVANCE STATEMENT: The present study shows that using the bone window to classify nonsolid nodules helps discriminate invasive adenocarcinoma from noninvasive lesions. KEY POINTS: • Evidence has shown the presence of lung adenocarcinoma in Lung-RADS category 2 nonsolid nodules. • Nonsolid nodules are classified into the bone window-visible and the bone window-invisible nonsolid nodules, and this classification differentiates invasive adenocarcinoma from noninvasive lesions. • The Lung-RADS category 2 nonsolid nodules are unlikely invasive adenocarcinoma if they show nonvisualization in the bone window.

Evaluation of antitumor immunity by a combination treatment of high-dose irradiation, anti-PDL1, and anti-angiogenic therapy in murine lung tumors.

C57BL/6 mice implanted in the flank with murine Lewis lung carcinoma cells were randomized into control, anti-angiogenic, anti-PD-L1, radiotherapy (RT), RT + anti-angiogenic, RT + anti-PD-L1, and RT + anti-PD-L1 + anti-angiogenic therapy groups. Immune response and immunophenotyping were determined by flow cytometry. Vasculature analysis after RT and anti-angiogenic therapy was assessed by quantified power Doppler sonography. Antitumor response, survival, and rechallenged tumor growth were evaluated. RT increased PD-L1 expression on CD8+ T, CD4+ T, dendritic, myeloid-derived suppressor cells (MDSCs), and tumor cells and increased PD-1 expression on CD8+ and CD4+ T cells. Anti-angiogenic therapy insignificantly decreased the RT-induced PD-1 expression on CD8+ and CD4+ T cells, implying a weak reversal of the immune-suppressive environment. Transient vessel collapse was observed within days after RT, and blood flow recovered at 1 week after RT. RT + anti-PD-L1 suppressed the tumor growth, improved survival, and prolonged immune memory capable of protecting against tumor recurrence, evidenced by local accumulation of CD8+ T cells and reduction in MDSCs in microenvironment. Similar and more prominent effects were observed when anti-VEGF was added to RT + anti-PDL1 therapies, implying an additive, rather than synergistic, antitumor immunity. Phenotypic analyses revealed that anti-cancer treatments increased the proportion of effector memory T cells in TILs and splenocytes, and RT, alone or in combination with other treatments, further increased the proportion of central memory T cells in splenocytes. These results provide evidence on operating the immunosuppressive tumor environment and offer insights into the design of the new combination treatment.

Preclinical evaluation of PEGylated liposomal doxorubicin as an effective radiosensitizer in chemoradiotherapy for lung cancer.

PURPOSE: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. METHODS: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase­3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. RESULTS: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin­V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. CONCLUSIONS: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy.

Assessing tumor angiogenesis using dynamic contrast-enhanced integrated magnetic resonance-positron emission tomography in patients with non-small-cell lung cancer.

BACKGROUND: Angiogenesis assessment is important for personalized therapeutic intervention in patients with non-small-cell lung cancer (NSCLC). This study investigated whether radiologic parameters obtained by dynamic contrast-enhanced (DCE)-integrated magnetic resonance-positron emission tomography (MR-PET) could be used to quantitatively assess tumor angiogenesis in NSCLC. METHODS: This prospective cohort study included 75 patients with NSCLC who underwent DCE-integrated MR-PET at diagnosis. The following parameters were analyzed: metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), reverse reflux rate constant (kep), volume transfer constant (Ktrans), blood plasma volume fraction (vp), extracellular extravascular volume fraction (ve), apparent diffusion coefficient (ADC), and initial area under the time-to-signal intensity curve at 60 s post enhancement (iAUC60). Serum biomarkers of tumor angiogenesis, including vascular endothelial growth factor-A (VEGF-A), angiogenin, and angiopoietin-1, were measured by enzyme-linked immunosorbent assays simultaneously. RESULTS: Serum VEGF-A (p = 0.002), angiogenin (p = 0.023), and Ang-1 (p <  0.001) concentrations were significantly elevated in NSCLC patients compared with healthy individuals. MR-PET parameters, including MTV, Ktrans, and kep, showed strong linear correlations (p <  0.001) with serum angiogenesis-related biomarkers. Serum VEGF-A concentrations (p = 0.004), MTV values (p <  0.001), and kep values (p = 0.029) were significantly higher in patients with advanced-stage disease (stage III or IV) than in those with early-stage disease (stage I or II). Patients with initial higher values of angiogenesis-related MR-PET parameters, including MTV > 30 cm3 (p = 0.046), Ktrans > 200 10- 3/min (p = 0.069), and kep > 900 10- 3/min (p = 0.048), may have benefited from angiogenesis inhibitor therapy, which thus led to significantly longer overall survival. CONCLUSIONS: The present findings suggest that DCE-integrated MR-PET provides a reliable, non-invasive, quantitative assessment of tumor angiogenesis; can guide the use of angiogenesis inhibitors toward longer survival; and will play an important role in the personalized treatment of NSCLC.

Detecting small pulmonary nodules with spiral ultrashort echo time sequences in 1.5 T MRI.

OBJECTIVE: This study investigated ultrashort echo time (UTE) sequences in 1.5 T magnetic resonance imaging (MRI) for small lung nodule detection. MATERIALS AND METHODS: A total of 120 patients with 165 small lung nodules before video-associated thoracoscopic resection were enrolled. MRI sequences included conventional volumetric interpolated breath-hold examination (VIBE, scan time 16 s), spiral UTE (TE 0.05 ms) with free-breathing (scan time 3.5-5 min), and breath-hold sequences (scan time 20 s). Chest CT provided a standard reference for nodule size and morphology. Nodule detection sensitivity was evaluated on a lobe-by-lobe basis. RESULTS: The nodule detection rate was significantly higher in spiral UTE free-breathing (> 78%, p < 0.05) and breath-hold sequences (> 75%, p < 0.05) compared with conventional VIBE (> 55%), reaching 100% when nodule size was > 16 mm, and reaching 95% when nodules were in solid morphology, regardless of size. The inter-sequence reliability between free-breathing and breath-hold spiral UTE was good (κ > 0.80). Inter-reader agreement was also high (κ > 0.77) for spiral UTE sequences. Nodule size measurements were consistent between CT and spiral UTE MRI, with a minimal bias up to 0.2 mm. DISCUSSION: Spiral UTE sequences detect small lung nodules that warrant surgery, offers realistic scan times for clinical work, and could be implemented as part of routine lung MRI.

Efficacy and safety of balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Data on the efficacy and safety of balloon pulmonary angioplasty (BPA) in Taiwanese patients with chronic thromboembolic pulmonary hypertension (CTEPH) are lacking. In this study, we evaluated the effects of BPA on clinical parameters including hemodynamics, echocardiography and functional status in patients with inoperable CTEPH in Taiwan. METHODS: We retrospectively collected the clinical data of inoperable CTEPH patients who underwent ≥3 BPA sessions. Pulmonary hemodynamic parameters of right heart catheterization, echocardiography, 6-min walk distance and World Health Organization (WHO) functional class were collected and analyzed before and after BPA treatment. RESULTS: A total of 59 BPA sessions were performed in 13 inoperable CTEPH patients. No periprocedural deaths or major complications requiring tracheal intubation with mechanical ventilation occurred. WHO functional class significantly improved in all 13 patients (P < 0.001), and 6-min walk distance improved from 344 ± 147 to 450 ± 120 m (P = 0.014). Additionally, the plasma level of N-terminal pro-brain natriuretic peptide significantly decreased (P = 0.007). Hemodynamic data were available in 11 patients after ≥3 BPA sessions. Both mean pulmonary artery pressure and pulmonary vascular resistance significantly decreased from 44.6 ± 11.7 mmHg to 32.6 ± 5.1 mmHg (P = 0.005) and 745 ± 389 dyn·s·cm-5 to 366 ± 120 dyn·s·cm-5 (P = 0.002), respectively. Cardiac output also increased from 3.69 ± 1.12 L/min to 4.33 ± 0.94 L/min (P = 0.021). CONCLUSION: BPA improved both clinical symptoms and hemodynamic data in inoperable CTEPH Taiwanese patients without major periprocedural complications.

Is a timely assessment of the hematocrit necessary for cardiovascular magnetic resonance-derived extracellular volume measurements?

BACKGROUND: Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) requires a hematocrit (Hct) to correct contrast volume distributions in blood. However, the timely assessment of Hct can be challenging and has limited the routine clinical application of ECV. The goal of the present study was to evaluate whether ECV measurements lead to significant error if a venous Hct was unavailable on the day of CMR. METHODS: 109 patients with CMR T1 mapping and two venous Hcts (Hct0: a Hct from the day of CMR, and Hct1: a Hct from a different day) were retrospectively identified. A synthetic Hct (Hctsyn) derived from native blood T1 was also assessed. The study used two different ECV methods, (1) a conventional method in which ECV was estimated from native and postcontrast T1 maps using a region-based method, and (2) an inline method in which ECV was directly measured from inline ECV mapping. ECVs measured with Hct0, Hct1, and Hctsyn were compared for each method, and the reference ECV (ECV0) was defined using the Hct0. The error between synthetic (ECVsyn) and ECV0was analyzed for the two ECV methods. RESULTS: ECV measured using Hct1 and Hctsyn were significantly correlated with ECV0 for each method. No significant differences were observed between ECV0 and ECV measured with Hct1 (ECV1; 28.4 ± 6.6% vs. 28.3 ± 6.1%, p = 0.789) and between ECV0 and ECV calculated with Hctsyn (ECVsyn; 28.4 ± 6.6% vs. 28.2 ± 6.2%, p = 0.45) using the conventional method. Similarly, ECV0 was not significantly different from ECV1 (28.5 ± 6.7% vs. 28.5 ± 6.2, p = 0.801) and ECVsyn (28.5 ± 6.7% vs. 28.4 ± 6.0, p = 0.974) using inline method. ECVsyn values revealed relatively large discrepancies in patients with lower Hcts compared with those with higher Hcts. CONCLUSIONS: Venous Hcts measured on a different day from that of the CMR examination can still be used to measure ECV. ECVsyn can provide an alternative method to quantify ECV without needing a blood sample, but significant ECV errors occur in patients with severe anemia.

Extended-field bone marrow sparing radiotherapy for primary chemoradiotherapy in cervical cancer patients with para-aortic lymphadenopathy: Volumetric-modulated arc therapy versus helical tomotherapy.

BACKGROUND: Extended-field (EF) bone marrow-sparing (BMS) radiotherapy is attracting interest for cervical cancer patients with para-aortic lymphadenopathy. OBJECTIVE: To compare dosimetric quality of volumetric-modulated arc therapy (VMAT) vs. helical tomotherapy (HT) during EF BMS radiotherapy. METHODS: HT dose-volume histogram parameters including (1) coverage, homogeneity, and conformity of target volumes, (2) sparing of organs-at-risk, (3) monitor units, and (4) estimated treatment time were compared with those of VMAT in 20 cervical cancer patients who underwent EF BMS radiotherapy. The pelvic and para-aortic regions received 45-Gy dose (25 fractions), with simultaneous integrated boost of 55 Gy (25 fractions) for pelvic and para-aortic lymphadenopathy, followed by a parametrial boost of 9 Gy (5 fractions). RESULTS: The HT-based and VMAT techniques achieved adequate and similar target volume coverage with good dose homogeneity and conformity, while sparing all organs-at-risk, including the rectum, bladder, bowel, bone marrow, femoral head, kidney, and spinal cord. The HT treatment plan had significantly higher monitor units (p < 0.001) and longer estimated treatment times (p < 0.001). CONCLUSIONS: VMAT and HT plans are suitable for EF BMS radiotherapy, which can achieve adequate target volume coverage while sufficiently sparing normal tissue. In addition, VMAT, compared to HT planning, yielded shorter estimated treatment times.

Riociguat Improves Pulmonary Hemodynamics in Patients with Inoperable Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Few studies have investigated the effects of riociguat on pulmonary hemodynamics in Asian patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study, we evaluated the effects of riociguat on pulmonary hemodynamics in inoperable CTEPH patients. METHODS: We retrospectively collected the clinical data of 11 inoperable CTEPH patients. Pulmonary hemodynamic parameters of right heart catheterization, echocardiography, 6-minute walk distance and World Health Organization (WHO) functional class were assessed at baseline and after riociguat treatment. RESULTS: The median duration of riociguat treatment was 12 months, and all 11 patients tolerated riociguat 7.5 mg/day well after titration. With regards to pulmonary hemodynamic data, both mean pulmonary artery pressure and pulmonary vascular resistance significantly decreased from 41 ± 8 mmHg to 38 ± 9 mmHg (p = 0.045) and 787 ± 417 dyn·s·cm-5 to 478 ± 267 dyn·s·cm-5 (p = 0.007), respectively. With regards to clinical symptoms, WHO functional class significantly improved in nine of the 11 patients, and there was no change in the other two patients (p = 0.004). In addition, the median level of N-terminal pro-brain natriuretic peptide also significantly decreased from 281 (117-5943) pg/ml to 226 (48-1276) pg/ml (p = 0.021). CONCLUSIONS: Riociguat treatment improved both clinical symptoms and pulmonary hemodynamics in the inoperative CTEPH patients in this study.

Predicting tumor responses and patient survival in chemoradiotherapy-treated patients with non-small-cell lung cancer using dynamic contrast-enhanced integrated magnetic resonance-positron-emission tomography.

PURPOSE: We investigated whether radiologic parameters by dynamic contrast-enhanced (DCE) integrated magnetic resonance-positron-emission tomography (MR-PET) predicts tumor response to treatment and survival in non-metastatic non-small-cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT). METHODS: Patients underwent DCE integrated MR-PET imaging 1 week before CRT. The following parameters were analyzed: primary tumor size, gross tumor volume, maximal standardized uptake value (SUVmax), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC), volume transfer constant (Ktrans), reverse reflux rate constant (kep), extracellular extravascular volume fraction (ve), blood plasma volume fraction (vp), and initial area under the time-concentration curve defined over the first 60 s post-enhancement (iAUC60). CRT responses were defined using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). RESULTS: Thirty patients were included. Non-responders demonstrated higher baseline TLG (p = 0.012), and lower baseline Ktrans (p = 0.020) and iAUC60 (p = 0.016) compared to responders, indicating the usefulness of DCE integrated MR-PET to predict treatment responses. Receiver operating characteristic curve indicated that TLG has the best differentiation capability to predict responders. By setting the threshold of TLG to 277, the sensitivity, specificity, and accuracy were 66.7%, 83.3%, and 75.0%, respectively, with an area under the curve of 0.776. The median follow-up time was 19.6 (range 7.8-32.0) months. In univariate analyses, baseline TLG >277 (p = 0.005) and baseline Ktrans <254 (10-3 min-1; p = 0.015) correlated with poor survival after CRT. In multivariate analysis, baseline TLG >277 remained the significant factor in predicting progression (p = 0.012) and death (p = 0.031). CONCLUSIONS: The radiologic parameters derived from DCE integrated MR-PET scans are useful for predicting treatment response in NSCLC patients treated with CRT; furthermore, these parameters are correlated with clinical and survival outcomes including tumor progression and death.

Response assessment of stereotactic body radiation therapy using dynamic contrast-enhanced integrated MR-PET in non-small cell lung cancer patients.

PURPOSE: To evaluate the response in patients undergoing SBRT using dynamic contrast-enhanced (DCE) integrated magnetic resonance positron emission tomography (MR-PET). Stereotactic body radiation therapy (SBRT) is efficacious as a front-line local treatment for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We prospectively enrolled 19 lung tumors in 17 nonmetastatic NSCLC patients who were receiving SBRT as a primary treatment. They underwent DCE-integrated 3T MR-PET before and 6 weeks after SBRT. The following image parameters were analyzed: tumor size, standardized uptake value (SUV), apparent diffusion coefficient, Ktrans , kep , ve , vp , and iAUC60 . Chest computed tomography (CT) was performed at 3 months after SBRT. RESULTS: SBRT treatment led to tumor changes including significant decreases in the SUVmax (-61%, P < 0.001), Ktrans mean (-72%, P = 0.005), Ktrans standard deviation (SD; -85%, P = 0.046), kep mean (-53%, P = 0.014), kep SD (-63%, P = 0.001), and vp SD (-58%, P = 0.002). The PET SUVmax was correlated with the MR kep mean (P = 0.002) and kep SD (P < 0.001). The percentage reduction in Ktrans mean (P < 0.001) and kep mean (P = 0.034) at 6 weeks post-SBRT were significantly correlated with the percentage reduction in tumor size, as measured using CT at 3 months after SBRT. Univariate analyses revealed a trend toward disease progression when the initial SUVmax > 10 (P = 0.083). CONCLUSION: In patients with NSCLC who are receiving SBRT, DCE-integrated MR-PET can be used to evaluate the response after SBRT and to predict the local treatment outcome. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:191-199.

High mammographic breast density predicts locoregional recurrence after modified radical mastectomy for invasive breast cancer: a case-control study.

BACKGROUND: We aimed to evaluate the influence of mammographic breast density at diagnosis on the risk of cancer recurrence and survival outcomes in patients with invasive breast cancer after modified radical mastectomy. METHODS: This case-control study included 121 case-control pairs of women diagnosed with invasive breast cancer between 2004 and 2009, and who had undergone modified radical mastectomy and had mammographic breast density measured before or at diagnosis. Women with known locoregional recurrence or distant metastasis were matched by pathological disease stage, age, and year of diagnosis to women without recurrence. Locoregional recurrence was defined as recurrence in the ipsilateral chest wall, or axillary, internal mammary, or supraclavicular nodes. The median follow-up duration was 84.0 months for case patients and 92.9 months for control patients. RESULTS: Patients with heterogeneously dense (50-75% density) and extremely dense (>75% density) breasts had an increased risk of locoregional recurrence (hazard ratios 3.1 and 5.7, 95% confidence intervals 1.1-9.8 and 1.2-34.9, p = 0.043 and 0.048, respectively) than did women with less dense breasts. Positive margins after surgery also increased the risk of locoregional recurrence (hazard ratio 3.3, 95% confidence interval 1.3-8.3, p = 0.010). Multivariate analysis that included dense breasts (>50% density), positive margin, no adjuvant radiotherapy, and no adjuvant chemotherapy revealed that dense breasts were significant factors for predicting locoregional recurrence risk (hazard ratio 3.6, 95% confidence interval 1.2-11.1, p = 0.025). CONCLUSIONS: Our results demonstrate that dense breast tissue (>50% density) increased the risk of locoregional recurrence after modified radical mastectomy in patients with invasive breast cancer. Additional prospective studies are necessary to validate these findings. TRIAL REGISTRATION: The study is retrospectively registered with ClinicalTrials.gov, number NCT02771665 , on May 11, 2016.

Radiosensitization in esophageal squamous cell carcinoma: Effect of polo-like kinase 1 inhibition.

PURPOSE: This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib. METHODS AND MATERIALS: Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models. RESULTS: Volasertib decreased ESCC cell proliferation in a dose- and time-dependent manner. Combination of volasertib and radiation caused G2/M cell cycle arrest, increased cyclin B levels, and induced apoptosis. Volasertib significantly enhanced radiation-induced death in ESCC cells by a mechanism involving the enhancement of histone H3 phosphorylation and significant cell cycle interruption. The combination of volasertib plus irradiation delayed the growth of ESCC tumor xenografts markedly compared with either treatment modality alone. CONCLUSIONS: The in vitro results suggested that targeting PLK1 might be a viable approach to improve the effects of radiation in ESCC. In vivo studies showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control when compared to irradiation or drug treatment alone.

Transcatheter arterial embolization with N-butyl cyanoacrylate for nonvariceal upper gastrointestinal bleeding in hemodynamically unstable patients: results and predictors of clinical outcomes.

PURPOSE: To assess the safety, efficacy, clinical outcomes, and prognostic factors associated with transcatheter arterial embolization (TAE) with N-butyl cyanoacrylate (NBCA) for nonvariceal upper gastrointestinal (GI) hemorrhage in hemodynamically unstable patients. MATERIALS AND METHODS: Between January 2008 and December 2012, 49 hemodynamically unstable patients (systolic blood pressure < 90 mm Hg and ongoing transfusion requirement) underwent emergency TAE with NBCA for nonvariceal upper GI bleeding and were included in the study. The technical (cessation of extravasation) and clinical (no residual bleeding within 7 d) success rates, incidence of ischemic complications, and clinical and technical predictors of recurrent bleeding within 30 days were analyzed. RESULTS: The technical and clinical success rates were 98% and 71%, respectively. There were no ischemic bowel complications; one patient experienced hepatic infarction with elevated liver enzymes. The incidence of major complications was 2%. The incidence of rebleeding within 30 days was 39%. Hematologic malignancies (P = .017), coagulopathy (P = .003), steroid pulse therapy (P = .025), and the absence of NBCA in the target lesions (P = .003) were associated with recurrent bleeding. CONCLUSIONS: NBCA embolization can be safely performed in hemodynamically unstable patients with active nonvariceal upper GI bleeding. The clinical factors associated with rebleeding might influence the clinical outcome.

Differential clinical characteristics, treatment response and prognosis of locally advanced adenocarcinoma/adenosquamous carcinoma and squamous cell carcinoma of cervix treated with definitive radiotherapy.

OBJECTIVE: To compare tumor characteristics and clinical outcome of patients with cervical locally advanced adenocarcinoma (AC)/adenosquamous carcinoma (ASC) and squamous cell carcinoma (SCC). DESIGN: Retrospective study. SETTING: National Taiwan University Hospital, Taipei, Taiwan. POPULATION: All patients with cervical SCC (n = 35), AC or ASC (n = 194) with FIGO stage ≥IIB who received definitive radiotherapy or concurrent chemoradiotherapy (CCRT) from January 1995 to December 2009. METHOD: Medical and histopathological record review. MAIN OUTCOME MEASURES: Progression-free survival (PFS), local recurrence-free survival, distant metastasis-free survival, and overall survival (OS). RESULTS: Compared with the SCC subgroup, patients with AC/ASC were significantly younger (p = 0.007), more of them without clinical symptoms were diagnosed by abnormal Pap smear findings (p = 0.043), and less responded to treatment (p = 0.018). After a median follow-up of 59.3 months, patients with AC/ASC had worse 5-year PFS (30.0% vs. 47.6%, p = 0.044), worse 5-year distant metastasis-free survival (41.5% vs. 69.9%, p = 0.005), and trends toward worse 5-year local recurrence-free survival (64.4% vs. 76.2%, p = 0.165) and worse 5-year OS (41.3% vs. 58.1%, p = 0.090) than patients with SCC. In univariate analysis, early FIGO stage and complete treatment response were significantly associated with PFS and OS. Histology of non-AC/ASC and Point A biologically equivalent doses in 2-Gy fractions >85 Gy were significantly associated with better PFS, and CCRT was significantly associated with better OS. In multivariate analysis, complete treatment response and early FIGO stage remained significant factors for predicting better PFS and OS. CONCLUSIONS: Cervical AC/ASC may be more aggressive than is SCC. For cervical AC/ASC, more comprehensively effective treatments are warranted.

Solid Pseudopapillary Neoplasms of the Pancreas: Imaging Differentiation between Benignity and Malignancy.

BACKGROUND/AIMS: To evaluate the clinical, pathologic, and imaging findings of solid pseudopapillary neoplasm (SPN) of the pancreas in order to differentiate benign from malignant pancreatic neoplasms. METHODOLOGY: We retrospectively identified 23 patients with 24 SPNs confirmed by pathology at National Taiwan University Hospital between January, 2001 and March, 2012. All computed tomography and magnetic resonance imaging were reviewed by two radiologists in consensus. Each tumor was analyzed for location of tumor, tumor margin, proportion of solid component, capsule morphology, growth pattern, presence of calcification, presence of upstream pancreatic duct dilatation, and enhancement pattern. RESULTS: SPN of the pancreas demonstrated variable degrees of hemorrhagic degeneration and calcification. Focal discontinuity of capsule was consistently observed in five malignant tumors (p = 0.004). There were no statistical differences between benign and malignant tumors based on location of tumor, tumor margin, proportion of solid component, growth pattern, presence of calcification, presence of upstream pancreatic duct dilatation, or enhancement pattern CONCLUSION: Among the various imaging features, we found that focal discontinuity of the capsule may suggest malignancy.