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Purpose This study aimed to investigate the impact of postoperative radiotherapy (PORT) in de novo metastatic breast cancer (dnMBC) patients undergoing planned primary tumor resection (PTR) and to identify the subgroup of patients who would most benefit from PORT.Materials and Methods This study enrolled 426 patients with dnMBC administered PTR alone or with PORT. The primary and secondary outcomes were overall and progression-free survival (OS and PFS), respectively.Results The median follow-up time was 53.7 months (range, 3.1 to 194.4). The 5-year OS and PFS rates were 73.2% and 32.0%, respectively. For OS, clinical T3/4 category, triple-negative breast cancer (TNBC), postoperative chemotherapy alone were significantly poor prognostic factors, and administration of PORT failed to show its significance. Regarding PFS, PORT was a favorable prognostic factor (hazard ratio, 0.64; 95% confidence interval, 0.50 to 0.82; p < 0.001), in addition to T1/2 category, ≤ 5 metastases, and non-TNBC. According to the multivariate analyses of OS in the PORT group, we divided the patients into three groups (group 1, T1/2 and non-TNBC [n=193]; group 2, T3/4 and non-TNBC [n=171]; and group 3, TNBC [n=49]), and evaluated the effect of PORT. Although PORT had no significance for OS in all subgroups, it was a significant factor for good prognosis regarding PFS in groups 1 and 2, not in group 3.Conclusion PORT was associated with a significantly better PFS in patients with dnMBC who underwent PTR. Patients with clinical T1/2 category and non-TNBC benefited most from PORT, while those with TNBC showed little benefit.

This article examines three Japan–South Korea postwar compensation cases: the comfort women issue, the Sakhalin Island forced labor issue, and Korean atomic bomb survivor issue. These compensation movements produced vastly different results, even though the basic policy directions for compensation provision in all three cases were similar. Japan's approach toward the comfort women problem has been a complete failure, while its treatment of the Sakhalin forced labor issue and the atomic bomb issues has been more successful. This article's explanation of the different outcomes focuses on the character and geographical base of the civic groups leading these compensation movements. In South Korea, women's rights activists spearheaded the comfort women compensation movement and related victim-relief activities. The Korean non-governmental organizations (NGOs) that assisted the comfort women treated this problem not only as a women's rights issue, but also as a nationalist issue. In contrast, the Red Cross, a politically neutral international organization, promoted the Sakhalin forced labor and atomic bomb issues. In short, the different receptions accorded to those championing the comfort women issue and those promoting the Sakhalin forced labor and atomic bomb issues depended on the principal agent of each compensation process. This article aims to provide some implications for successfully implementing postwar compensation policies. It suggests that, if successful postwar compensation policy depends on successful perpetrator–victim reconciliation, establishing solidarity between perpetrator and victim countries’ civic groups is important. This can only be facilitated through the depoliticized and transparent operation of leading NGOs both inside and outside the redressal-seeking nation.

Background The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. Methods In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. Results ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. Conclusions Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Supplementary Table S22: Segmented b-allele deficits

Supplementary Tables S16-S19, describing IHC results on NHS/HPFS data

Supplementary Table S21: Segmented copy-number ratios

Supplementary Table S2: Somatic mutations

Supplementary Tables S1, S3 through S15, S20, and S23

The supplementary data contains supplemental methods, figures, tables and the clinical trial protocol in which patients from this study were enrolled.

A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor–expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935–43. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663

Metastatic colorectal cancer (CRC) remains a substantial problem for mortality and requires screening and early detection efforts to increase survival. Epithelial-mesenchymal transition (EMT) and circulation of tumor cells in the blood play important roles in metastasis. To identify a novel target for metastasis of CRC, we conducted a gene microarray analysis using extracted RNA from the blood of preclinical models. We found that NCK-associated protein 1 (NCKAP1) was significantly increased in the blood RNA of patient-derived xenograft (PDX) models of colon cancer. In the NCKAP1 gene knockdown-induced human colon cancer cell lines HCT116 and HT29, there was a reduced wound healing area and significant inhibition of migration and invasion. As the result of marker screening for cytoskeleton and cellular interactions, CRC treated with siRNA of NCKAP1 exhibited significant induction of CDH1 and phalloidin expression, which indicates enhanced adherent cell junctions and cytoskeleton. In HCT116 cells with a mesenchymal state induced by TGFβ1, metastasis was inhibited by NCKAP1 gene knockdown through the inhibition of migration, and there was increased CTNNB1 expression and decreased FN expression. We established metastasis models for colon cancer to liver transition by intrasplenic injection shRNA of NCKAP1-transfected HCT116 cells or by implanting tumor tissue generated with the cells on cecal pouch. In metastasis xenograft models, tumor growth and liver metastasis were markedly reduced. Taken together, these data demonstrate that NCKAP1 is a novel gene regulating EMT that can contribute to developing a diagnostic marker for the progression of metastasis and new therapeutics for metastatic CRC treatment.

Background The Korean Radiation Oncology Group (KROG) 19 − 09 prospective cohort study aims to determine the effect of regional nodal irradiation on regional recurrence rates in ypN0 breast cancer patients. Dosimetric variations between radiotherapy (RT) plans of participating institutions may affect the clinical outcome of the study. We performed this study to assess inter-institutional dosimetric variations by dummy run. Methods Twelve participating institutions created RT plans for four clinical scenarios using computed tomography images of two dummy cases. Based on a reference structure set, we analyzed dose-volume histograms after collecting the RT plans. Results We found variations in dose distribution between institutions, especially in the regional nodal areas. Whole breast and regional nodal irradiation (WBI + RNI) plans had lower inter-institutional agreement and similarity for 95% isodose lines than WBI plans. Fleiss’s kappa values, which were used to measure inter-institutional agreement for the 95% isodose lines, were 0.830 and 0.767 for the large and medium breast WBI plans, respectively, and 0.731 and 0.679 for the large and medium breast WBI + RNI plans, respectively. There were outliers in minimum dose delivered to 95% of the structure (D95%) of axillary level 1 among WBI plans and in D95% of the interpectoral region and axillary level 4 among WBI + RNI plans. Conclusion We found inter-institutional and inter-case variations in radiation dose delivered to target volumes and organs at risk. As KROG 19 − 09 is a prospective cohort study, we accepted the dosimetric variation among the different institutions. Actual patient RT plan data should be collected to achieve reliable KROG 19 − 09 study results.

Objective To propose and evaluate an active method for sparing the small bowel in the treatment field of cervical cancer brachytherapy by prone position procedure. Methods The prone position procedure consists of five steps: making bladder empty, prone-positioning a patient on belly board, making the small bowel move to abdomen, filling the bladder with Foley catheter and finally turning the patient into the supine position. The proposed method was applied for the treatment of seven cervical cancer patients. Its effectiveness was evaluated and a correlation between the patient characteristics and the volumetric dose reduction of small bowel was also investigated. Brachytherapy treatment plans were built before and after the proposed method, and their dose-volume histograms were compared for targets and organs-at-risk. In this comparison, all plans were normalized to satisfy the same D90% for high-risk clinical target volume. Results For the enrolled patients, the average dose of small bowel was significantly reduced from 75.2 ± 4.9 Gy before to 60.2 ± 4.0 Gy after the prone position procedure, while minor dosimetric changes were observed in rectum, sigmoid and bladder. The linear correlation to body mass index, thickness and width of abdominopelvic cavity and bladder volume were 76.2, 69.7, 28.8 and −36.3%, respectively. Conclusions The application of prone position procedure could effectively lower the volumetric dose of the small bowel. The dose reduction in the small bowel had a strong correlation with the patient’s obesity and abdominal thickness. This means the patients for whom the proposed method would be beneficial can be judiciously selected for safe brachytherapy.

INTRODUCTION Screening and treatment of latent tuberculosis infections (LTBI) are required before starting biologics in patients with immune-mediated inflammatory diseases (IMIDs). This study aimed to assess the safety of LTBI treatment in older patients with IMIDs. METHODS The medical records of 916 patients treated for LTBI before the start of biologics for IMIDs between January 2004 and December 2018 were reviewed. The safety profiles of LTBI treatment were retrospectively compared according to age. RESULTS Among the 916 patients, 201 were aged > 60 years (older age group). The older age group showed female predominance, more frequent history of previous tuberculosis, and more comorbidities, and received biologics mainly for rheumatoid arthritis. Most patients (74.0%) took isoniazid and rifampicin daily for 3 months. The treatment completion rate was 90.4% in the overall population and was lower in the older age group (91.9% vs. 85.1%, P = 0.005). Adverse drug events were more frequent in the older age group (22.9% vs. 9.8%, P

BACKGROUND Over 90% of patients with cancer experience 1 or more symptoms caused directly by cancer or its treatment. These symptoms negatively impact on the completion of planned treatment as well as patients’ health-related quality of life (HRQoL). It often results in serious complications and even life-threatening outcomes. Thus, it has been recommended that surveillance of symptom burden should be performed and managed during cancer treatment. However, differences in symptom profiles in various patients with cancer have not been fully elucidated for use in performing surveillance in the real world. OBJECTIVE This study aims to evaluate the burden of symptoms in patients with various types of cancers during chemotherapy or radiation therapy using the PRO-CTCAE (Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events) and its impact on quality of life. METHODS We performed a cross-sectional study of patients undergoing outpatient-based chemotherapy, radiation therapy, or both at the National Cancer Center at Goyang or at the Samsung Medical Center in Seoul, Korea between December 2017 and January 2018. To evaluate cancer-specific symptom burden, we developed 10 subsets for using the PRO-CTCAE-Korean. To measure HRQoL, we used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Participants answered questions prior to their clinic appointments on tablets. Multivariable linear regression was used to analyze symptoms based on cancer type and to evaluate the association between the PRO-CTCAE items and the EORTC QLQ-C30 summary score. RESULTS The mean age (SD) of the patients was 55.0 (11.9) years, and 39.94% (540/1352) were male. Overall, symptoms in the gastrointestinal category were the most dominant in all cancers. Fatigue (1034/1352, 76.48%), decreased appetite (884/1352, 65.38%), and numbness and tingling (778/1352, 57.54%) were the most frequently reported. Patients reported more local symptoms caused by a specific cancer. In terms of nonsite-specific symptoms, patients commonly reported concentration (587/1352, 43.42%), anxiety (647/1352, 47.86%), and general pain (605/1352, 44.75%). More than 50% of patients with colorectal (69/127, 54.3%), gynecologic (63/112, 56.3%), breast (252/411, 61.3%), and lung cancers (121/234, 51.7%) experienced decreased libido, whereas 67/112 (59.8%) patients with gynecologic cancer and lymphoma/myeloma reported pain during sexual intercourse. Patients with breast, gastric, and liver cancers were more likely to have the hand-foot syndrome. Worsening PRO-CTCAE scores were associated with poor HRQoL (eg, fatigue: coefficient –8.15; 95% CI –9.32 to –6.97), difficulty in achieving and maintaining erection (coefficient –8.07; 95% CI –14.52 to –1.61), poor concentration (coefficient –7.54; 95% CI –9.06 to –6.01), and dizziness (coefficient –7.24; 95% CI –8.92 to –5.55). CONCLUSIONS The frequency and severity of symptoms differed by cancer types. Higher symptom burden was associated with poor HRQoL, which suggests the importance of appropriate surveillance of PRO symptoms during cancer treatment. Considering patients had comprehensive symptoms, it is necessary to include a holistic approach in the symptom monitoring and management strategies based on comprehensive patient-reported outcome measurements.

Background/Aim: To compare absolute volume (AV) assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) for the response evaluation of desmoid tumors (DTs) treated with radiotherapy. Patients and Methods: Eighteen patients with DTs ≥3 cm in size were included. Results: The median follow-up duration was 78.0 months. Five patients achieved a complete response according to RECIST, seven reached a partial response (PR), and one eventually exhibited progression. The overall response rate was 61%, the median time to PR was 8.0 months. Six patients achieved stable disease, although three developed progressions. Of the six patients with a PR, the median change in maximum diameter was −46%, and the median change in maximum volume was −84%. Three patients could have been diagnosed with progression at least 6 months earlier if the AV increment was considered. Conclusion: An AV assessment is essential for an accurate response assessment of DTs and radiotherapy seems feasible as a first-line treatment for DTs.

Case Presentation A 21-year-old man was admitted to our hospital with recurrent bilateral pneumothorax and hemoptysis. Three years earlier, he underwent coil embolization due to a subarachnoid hemorrhage caused by an intracerebral aneurysm rupture. Two months after the coil embolization, he underwent an emergent total colectomy due to a massive infarction of the colon. One year after the colectomy, he started to have recurrent hemoptysis, and a few months later, multiple episodes of bilateral pneumothorax that required a chest tube placement began to occur. Notably, he had a history of easy bruising. He was taking Depakote and aspirin to prevent seizure and thromboembolic complications, respectively, both of which he began taking after the coil embolization. He denied the use of any illicit drugs. The histories of his parents and sister were not remarkable.

Background: Hypersensitivity pneumonitis (HP) has various clinical courses and outcomes, but the prognostic factors are not well-defined. Vasakova et al. [Am J Respir Crit Care Med. 2017 Sep;196(6):680–9] have proposed a diagnostic algorithm that categorized suspected patients according to the level of confidence in the diagnosis. This study aimed to investigate whether the confidence level of clinical diagnosis has prognostic implication in patients with fibrotic HP. Methods: This study included 101 biopsy-proven fibrotic HP patients diagnosed between 2002 and 2017. The patients were retrospectively classified into confident, probable, possible, and unlikely chronic HP, according to the confidence level in the diagnostic criteria/algorithm. The survival and forced vital capacity (FVC) changes were compared between the groups. Risk factors for mortality were analysed using a Cox proportional hazard model. Results: The median follow-up duration was 67.6 months. The mean age was 60.4 years, and percentages of women were 60.4%. When classified based on the diagnostic criteria/algorithm, possible HP was the most common (51.5%), followed by probable (26.7%), confident (9.9%), and unlikely HP (6.9%). Distinctive survival curves were found according to the diagnostic confidence level, showing the worst outcome in unlikely chronic HP (median survival, 30.2 months). In a multivariable Cox analysis, unlikely HP was a significant predictor of poor survival (hazard ratio, 4.652; 95% confidence interval, 1.231–17.586; p = 0.023), after adjustment for age, body mass index, FVC, and diffusing capacity. Conclusions: The diagnostic confidence level may predict clinical outcomes in patients with HP. Unlikely HP was shown to have a significantly poorer survival than other diagnostic confidence levels.

There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model.Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, β-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization.OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51 vs. 5.76 ± 0.95 min in sham mice), increased non-voiding contractions (0.39 ± 0.11 vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, β2, β3, P2XContinuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

Aim This study was undertaken to investigate the role of postoperative radiotherapy (PORT) including post-breast conserving radiotherapy (PBCRT) and post-mastectomy radiotherapy (PMRT) in stage IV breast cancer patients who underwent planned primary tumor resection (PTR). Methods This study enrolled 112 patients diagnosed with de novo stage IV breast cancer who were treated with potentially curative PTR with or without PORT. The primary outcome was overall survival (OS), and the secondary outcomes were locoregional recurrence-free survival (LRRFS) and distant progression-free survival (DPFS). Results At a median follow-up of 48.9 months (range, 3.5-183.4 months), the median OS was 54.9 months (range, 5.3-185.9 months) with a 5 year OS rate of 59.6%. Lower clinical T stage, Luminal A or B type tumors and PBCRT were significantly predictive of longer OS. The 5 year LRRFS and DMFS rates were 79.0% and 34.3%, respectively. In multivariate analysis for LRRFS, the PBCRT arm demonstrated significant superiority compared to the No PORT arm. A comparison of patients who did and did not receive PORT showed that patients with disseminated metastasis more likely did not receive PORT and were excluded from the analysis. PBCRT arm demonstrated significantly superior LRRFS of 100% while PMRT and No PORT arm demonstrated 81.5% and 84.0%, respectively CONCLUSIONS: De novo stage IV breast cancer patients who received planned PTR showed favorable survival outcomes compared with historical cohorts. PTR may be predictive of a good prognosis, especially in patients with luminal A or B type tumors. PORT, especially PBCRT was predictive of LRRFS, suggesting that patients may benefit from this treatment.

Background/aims Although re-evaluation of radiographic follow-up after 2 to 3 months of therapy is recommended for patients administered anti-tuberculosis medication owing to suspected pulmonary tuberculosis, reported findings are limited. Therefore, this study aimed to investigate changes in 1- and 2-month chest X-ray (CXR) findings after the treatment initiation and compared them according to the final diagnosis of tuberculosis or non-tuberculosis. Methods Patients who started anti-tuberculosis medication for suspected pulmonary tuberculosis were selected at a tertiary referral hospital in South Korea between January 2012 and December 2015. Changes in the 1- and 2-month CXR findings were classified as improved, unchanged, and aggravated. Results Among the 120 patients enrolled in the 1-month CXR group, 76 (63.3%) had the final diagnosis of tuberculosis. Comparison between the 1-month CXR changes and diagnosis showed that the final diagnosis was tuberculosis in 81.8% (45/55), 50.0% (26/52), and 38.5% (5/13) of patients whose 1-month CXR was improved, unchanged, and aggravated, respectively. In the 2-month CXR group, 167 patients were enrolled, and 139 (83.2%) of them were diagnosed with tuberculosis. Tuberculosis was the final diagnosis in 92.6% (100/108), 70.0% (35/50), and 44.4% (4/9) patients with improved, unchanged, and aggravated 2-month CXR findings, respectively. In patients with the final diagnosis of non-tuberculosis, nontuberculous mycobacteria and malignancy were the most common causes of improved and aggravated 1- and 2-month CXR findings, respectively. Conclusion Two-month CXR findings were of limited value for deciding on whether to continue anti-tuberculosis treatment. One-month CXR findings could help determine the need for further work-up.

ObjectiveThe aim of this study was to compare the clinical outcomes of chemoradiotherapy with or without bevacizumab in patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer.Methods41 patients with stage IVB cervical cancer who underwent chemoradiotherapy between August 2015 and December 2017 were retrospectively analyzed. This study included 11 patients who received bevacizumab before or after radiotherapy (group A) and 30 patients who received conventional chemoradiotherapy without bevacizumab (group B). We excluded the following patients: those with dual primary cancers; those whose pathologic diagnosis was neither squamous cell carcinoma nor adenocarcinoma; those who did not undergo radiotherapy; or those from whom follow-up data could not be collected. We analyzed the treatment responses, toxicities, progression-free survival, and overall survival rates.ResultsA total of 41 patients were included in the analysis. The median follow-up was 19 months (range 3–108). The response rates at 3 months after treatment were 90.9% in group A and 83.3% in group B (p=0.54). After completing all treatments, the complete response rates were 81.8% in group A and 47% in group B (p=0.04). Grade ≥3 gastrointestinal toxicities, including bleeding, fistula, perforation, and obstruction, were more frequent in group A (54.5%) than in group B (6.7%) (p=0.003). The 12 month progression-free survival and overall survival rates were similar in both arms (12 month progression-free survival: 45.5% vs 46.7%, respectively, p=0.22; 12 month overall survival: 81.8% vs 72.9%, respectively, p=0.57). Patients with node-only metastasis had better 12 month progression-free survival in group B than in group A (59.1% vs 42.9%, respectively, p=0.04). However, the responses to both treatments did not differ in patients with organ metastasis.ConclusionsBevacizumab for stage IVB cervical cancer is associated with higher complete response rates. However, patients treated with bevacizumab experienced more bowel toxicities. Bevacizumab did not improve progression-free survival among patients with node-only metastasis.

While many deep-learning-based computer-aided detection systems (CAD) have been developed and commercialized for abnormality detection in chest radiographs (CXR), their ability to localize a target abnormality is rarely reported. Localization accuracy is important in terms of model interpretability, which is crucial in clinical settings. Moreover, diagnostic performances are likely to vary depending on thresholds which define an accurate localization. In a multi-center, stand-alone clinical trial using temporal and external validation datasets of 1,050 CXRs, we evaluated localization accuracy, localization-adjusted discrimination, and calibration of a commercially available deep-learning-based CAD for detecting consolidation and pneumothorax. The CAD achieved image-level AUROC (95% CI) of 0.960 (0.945, 0.975), sensitivity of 0.933 (0.899, 0.959), specificity of 0.948 (0.930, 0.963), dice of 0.691 (0.664, 0.718), moderate calibration for consolidation, and image-level AUROC of 0.978 (0.965, 0.991), sensitivity of 0.956 (0.923, 0.978), specificity of 0.996 (0.989, 0.999), dice of 0.798 (0.770, 0.826), moderate calibration for pneumothorax. Diagnostic performances varied substantially when localization accuracy was accounted for but remained high at the minimum threshold of clinical relevance. In a separate trial for diagnostic impact using 461 CXRs, the causal effect of the CAD assistance on clinicians’ diagnostic performances was estimated. After adjusting for age, sex, dataset, and abnormality type, the CAD improved clinicians’ diagnostic performances on average (OR [95% CI] = 1.73 [1.30, 2.32]; p

Background Over 90% of patients with cancer experience 1 or more symptoms caused directly by cancer or its treatment. These symptoms negatively impact on the completion of planned treatment as well as patients’ health-related quality of life (HRQoL). It often results in serious complications and even life-threatening outcomes. Thus, it has been recommended that surveillance of symptom burden should be performed and managed during cancer treatment. However, differences in symptom profiles in various patients with cancer have not been fully elucidated for use in performing surveillance in the real world. Objective This study aims to evaluate the burden of symptoms in patients with various types of cancers during chemotherapy or radiation therapy using the PRO-CTCAE (Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events) and its impact on quality of life. Methods We performed a cross-sectional study of patients undergoing outpatient-based chemotherapy, radiation therapy, or both at the National Cancer Center at Goyang or at the Samsung Medical Center in Seoul, Korea between December 2017 and January 2018. To evaluate cancer-specific symptom burden, we developed 10 subsets for using the PRO-CTCAE-Korean. To measure HRQoL, we used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Participants answered questions prior to their clinic appointments on tablets. Multivariable linear regression was used to analyze symptoms based on cancer type and to evaluate the association between the PRO-CTCAE items and the EORTC QLQ-C30 summary score. Results The mean age (SD) of the patients was 55.0 (11.9) years, and 39.94% (540/1352) were male. Overall, symptoms in the gastrointestinal category were the most dominant in all cancers. Fatigue (1034/1352, 76.48%), decreased appetite (884/1352, 65.38%), and numbness and tingling (778/1352, 57.54%) were the most frequently reported. Patients reported more local symptoms caused by a specific cancer. In terms of nonsite-specific symptoms, patients commonly reported concentration (587/1352, 43.42%), anxiety (647/1352, 47.86%), and general pain (605/1352, 44.75%). More than 50% of patients with colorectal (69/127, 54.3%), gynecologic (63/112, 56.3%), breast (252/411, 61.3%), and lung cancers (121/234, 51.7%) experienced decreased libido, whereas 67/112 (59.8%) patients with gynecologic cancer and lymphoma/myeloma reported pain during sexual intercourse. Patients with breast, gastric, and liver cancers were more likely to have the hand-foot syndrome. Worsening PRO-CTCAE scores were associated with poor HRQoL (eg, fatigue: coefficient –8.15; 95% CI –9.32 to –6.97), difficulty in achieving and maintaining erection (coefficient –8.07; 95% CI –14.52 to –1.61), poor concentration (coefficient –7.54; 95% CI –9.06 to –6.01), and dizziness (coefficient –7.24; 95% CI –8.92 to –5.55). Conclusions The frequency and severity of symptoms differed by cancer types. Higher symptom burden was associated with poor HRQoL, which suggests the importance of appropriate surveillance of PRO symptoms during cancer treatment. Considering patients had comprehensive symptoms, it is necessary to include a holistic approach in the symptom monitoring and management strategies based on comprehensive patient-reported outcome measurements.

Although the combination of radiotherapy and immunotherapy has proven to be effective in lung cancer treatment, it may not be sufficient to fully activate the antitumor immune response. Here, we investigated whether entinostat, a histone deacetylase inhibitor, could improve the efficacy of radiotherapy and anti-PD-1 in a murine syngeneic LL/2 tumor model. A total of 12 Gy of X-rays administered in two fractions significantly delayed tumor growth in mice, which was further enhanced by oral entinostat administration. Flow cytometry-aided immune cell profiling revealed that entinostat increased radiation-induced infiltration of myeloid-derived suppressor cells and CD8+ T cells with decreased regulatory T-cells (Tregs). Transcriptomics-based immune phenotype prediction showed that entinostat potentiated radiation-activated pathways, such as JAK/STAT3/interferon-gamma (IFN-γ) and PD-1/PD-L1 signaling. Entinostat augmented the antitumor efficacy of radiation and anti-PD-1, which may be related to an increase in IFN-γ-producing CD8+ T-cells with a decrease in Treg cells. Comparative transcriptomic profiling predicted that entinostat increased the number of dendritic cells, B cells, and T cells in tumors treated with radiation and anti-PD-1 by inducing MHC-II genes. In conclusion, our findings provided insights into how entinostat improves the efficacy of ionizing radiation plus anti-PD-1 therapy and offered clues for developing new strategies for clinical trials.

PurposeTo evaluate the role of postmastectomy radiation therapy (PMRT) in patients with node-negative breast cancer of 5cm or larger tumors undergoing mastectomyMaterials and MethodsMedical records of 274 patients from 18 institutions treated with mastectomy between January 2000 and December 2016 were retrospectively reviewed. Among these, 202 patients underwent PMRT, while 72 did not. Two hundred and forty-one patients (88.0%) received systemic chemotherapy, and 172 (62.8%) received hormonal therapy. Patients receiving PMRT were younger, more likely to have progesterone receptor-positive tumors, and received adjuvant chemotherapy more frequently compared with those without PMRT (p

PurposeThis study was to evaluate anti-tumor efficacy of osimertinib in patients positive for acquired epidermal growth factor receptor (EGFR) T790M mutation in liquid biopsy using plasma, bronchoalveolar lavage fluid (BALF) or bronchial washing fluid (BWF), and pleural effusion.Materials and MethodsAmong patients benefited from previous EGFR‒tyrosine kinase inhibitor treatment followed by treatment failure, patients in whom T790M mutations are detected in at least one of the samples including tumor tissues, BALF/BWF, plasma, and pleural effusion were enrolled. T790M mutation was detected by extracting cell free DNA from liquid biopsy samples, using PANA Mutyper. Objective response rate (ORR) and progression-free survival (PFS) with osimertinib treatment were evaluated.ResultsBetween January 2018 and December 2019, 63 patients were enrolled and received osimertinib. Mean age was 63 years, and 38 (60.3%) were female. Twenty-six patients had T790M mutation in both liquid and tissue samples (group A), 19 patients had only in tissue biopsy samples (group B), and 18 patients had T790M mutation only in liquid biopsy samples (group C). ORR in overall population was 63.5%, and was 61.5% in group A, 68.4% in group B, and 61.1% in group C, respectively. Median PFS in overall patients was 15.6 months (95% confidence interval, 10.7 to 24.2). There was no significant difference in ORR or PFS between groups. ConclusionOsimertinib showed favorable efficacy in lung cancer patients with acquired resistance to prior EGFR-TKI therapies, who screened positive for harboring T790M mutation detected from cell free DNA extracted from plasma, BALF/BWF, and pleural effusion.

자율주행자동차의 등장은 과학기술의 비약적 발전을 과시하기 위함이 아니라 교통사고의 감소 및 원활한 운전에 따른 교통체증의 완화와 환경부화 경감, 고령자 등과 인구 과밀지역에 있어서 이동수단의 확보라고 하는 여러 가지의 사회적 편익을 기대하기 위함이고, 상용화의 현실을 향해 각각의 검토가 각국에서 진행되고 있다. 이에 일본 경찰청에서 국회에 제출한 일본도로교통법 개정안은 우리 도로교통법에게 시사점을 안겨준다고 할 수 있다. 다른 법에서도 유사성이 있을 수 있지만 도로교통법의 경우 한국과 일본은 그 입법목적부터 상당한 유사성을 지닌 특성이 있다. 따라서 일본의 개정방향은 우리에게 상당한 검토 자료로서의 역할을 할 수 있다. 일본 도로교통법 개정의 경우 우선 그 특징을 세 가지로 나누어 볼 수 있다. 첫째, 일본의 경우 자율주행자동차에 대한 개념에 대해서 자동화된 기계로 인식하였다. 따라서 용어 또한 자동운전차라고 하여 기존에 이름만 자동차이지 타동차인 자동차가 좀 더 진전된 자동기술을 보유한 채로 관리주체인 사람의 역할이 필요한 용어로 정리한 것으로 보이며 이에 따라 자율주행장치를 사용하는 것을 인간운전자가 운전하는 행위의 범주에 포함시키고 이에 따른 관리의무 등을 제시하였다. 둘째, 도로교통법 개정에 있어 다른 유관기관 및 관ㆍ민ㆍ학ㆍ연과의 협의 및 논의가 보다 더 안정적으로 활성화 된 것으로 보인다. 자율주행시대에 있어서는 이제 더이상 교통과 유관한 법들이 독자적 개정이 아닌 다양한 접근 및 논의를 통한 타법과의 개정을 수반할 필요가 있게 된 것이다. 셋째, 우선 상용화될 Lv.3수준의 자율주행자동차에 대한 개정안을 바탕으로 향후 진전될 기술에 탄력적으로 대응하기 위한 개정안인 것을 특징으로 하고 있다. 이를 바탕으로 우리 도로교통법의 개정방향을 고민해본다면, 우선 인간이 편리하고 안전하기 위해 존재하는 자율주행자동차의 필요성을 적절히 인식한 채 인간의 선택권을 염두에 두고 인간에서 자동차로의 역할변화가 아닌 인간의 역할과 자동차의 역할을 분리하여 고민할 필요가 있다. 또한 자율주행자동차의 등장은 이제 더 이상 차량과 도로교통과의 논의가 분리되던 시대를 지나 차량 및 도로인프라등의 융합이 필요한 시점이 도래된 것이기에 법개정에 있어서도 다양한 접근 및 논의 등이 바탕이 되어야 한다. 나아가 기술개발 수준에 맞추어 법ㆍ제도적 정비가 이루어지는 것이 타당하기에 아직 미완성된 기술수준에 대한 법의 반영의 난점이 될 수 있겠지만 단계적 실현을 위한 논의 및 법ㆍ제도적 측면의 정비는 필요로 할 것이다. 이에 기술 발전에 대한 예정이 명확하지 않은 입장에서 우선 개정이 필요한 사항부터 순차적으로 진행하는 것이 보다 더 적절할 것으로 보인다. 따라서 이러한 관점으로부터 우리의 개정 역시 완전자율주행자동차를 바라보고 상상하는 것이 아니라 일단 우선적으로 상용화될 혹은 필요한 사항에 대한 개정안을 바탕으로 하여 향후 이어질 발전의 현실을 살펴가며 탄력적인 대응을 도모하는 것이 보다 더 적절할 것으로 보인다.

Purpose BRAF mutations are found in 1-5% of non-small cell lung cancers, particularly adenocarcinomas. However, information regarding this mutation is limited in patients without EGFR/ALK aberrations, who have limited treatment options. Patients and methods The medical records of 224 stage III/IV adenocarcinoma patients without EGFR/ALK aberrations and with available pathologic tissue, were retrospectively reviewed. BRAF mutations were evaluated using a PNAClampTM BRAF mutation detection kit (Panagene, Daejeon, Korea). The outcomes in the study population were compared with stage III/IV adenocarcinoma patients harboring an EGFR mutation. A case report of targeted therapy against BRAF mutations was also presented. Results A cohort of 222 adenocarcinoma patients with adequate pathologic tissue samples was analyzed. The median patient age was 63 years, 68.8% of the patients were male and 68.7% were ever-smokers. The V600E BRAF mutation was detected in 4 patients (1.8%). The 222 study patients had a poorer survival outcome compared to stage III/IV adenocarcinoma patients with an EGFR mutation (median, 12 vs 67 months, P

Electrochemical oxidative radical sulfonylation/semipinacol rearrangement sequences of alkenylcyclobutanols have been developed. The reaction proceeds in an undivided electrochemical cell equipped with platinum plate electrodes employing sodium iodide as a redox catalyst and a supporting electrolyte. This approach is environmentally benign by using shelf-stable arylsulfonyl hydrazides as arylsulfonyl radical precursor and electrons as oxidizing reagents. The present protocol offers a facile way to prepare β-sulfonated cyclic ketone derivatives.

Electrochemical oxidative selenylation of imidazo[1,2–a]pyridines has been developed. The reaction proceeds in an undivided electrochemical cell equipped with glassy carbon electrodes employing LiClO4 as a supporting electrolyte. This approach is environmentally benign by using shelf-stable diselenides as selenium source and electrons as oxidizing reagents. The present protocol offers a facile way to prepare 3-selenylated imidazopyridine derivatives.

Electrochemical oxidative radical selenylation/1,2-carbon migration and Dowd-Beckwith-type ring-expansion sequences of alkenylcyclobutanols were developed in this study. This approach is environmentally benign and uses shelf-stable diselenides as selenium radical precursors and electrons as oxidizing reagents. The present protocol offers a facile way to prepare β-selenated cyclic ketone derivatives. Under Dowd-Beckwith-type rearrangement, it can afford the corresponding one-carbon ring-expanded ketones.

We evaluated the clinical outcome of patients with stage III to IV thymomas (Ts) or stage II to IV thymic carcinomas (TCs) treated with complete thymectomy and local radiation therapy (LRT, targeting the tumor bed and anterior mediastinal areas only) or elective nodal irradiation (ENI, targeting the entire mediastinal and supraclavicular regions).Data from 47 patients diagnosed with Ts or TCs and treated with surgery and adjuvant RT from May 2002 to May 2015 were analyzed. The standard RT dose was 50.4 Gy in 28 fractions; patients with a positive resection margin received a further 4 to 10 Gy. Survival outcomes determined at 5 years included local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, and overall survival.Five-year local recurrence-free survival was similar in both groups (LRT, 94.7% vs. ENI, 96.2%; P = .849). Significant differences were seen in 5-year regional recurrence-free survival (LRT, 55.1% vs. ENI, 83.7%; P = .006); however, tumor size was seen to be a significant factor (7 cm, 95.2% vs. ≥ 7 cm, 48.9%; P .001), and the LRT group contained a greater proportion of patients with ≥ 7-cm tumors (70% vs. 33%). Multivariate analysis demonstrated that tumor size was the only significant prognostic factor (P .001). No differences in 5-year overall survival were seen (LRT, 91.7% vs. ENI, 100%; P = .106).ENI may not be indicated in all cases, as additional benefit in reducing recurrence or improving survival was not predominant. LRT seems to be a feasible option with favorable patient outcomes.

Background/aim To present the variations in the target delineation and the planning results of intensity-modulated radiation therapy (IMRT) for breast cancers. Patients and methods We requested the target volumes and organs at risk delineation for two cases of left breast cancers, and evaluated the IMRT plans including the supraclavicular and internal mammary node irradiation. Results Twenty-one institutions participated in this study. Differences in the planning target volume among institutions reached up to three-times for breast-conserving surgery (BCS) case and five-times for mastectomy case. Mean heart doses ranged from 3.3 to 24.1 Gy for BCS case and from 5.0 to 26.5 Gy for mastectomy case. Ipsilateral lung volumes receiving more than 20 Gy ranged from 4.7 to 57.4% for BCS case and from 16.4 to 55.5% for mastectomy case. Conclusion There were large variations in the target delineation and planning results of IMRT for breast cancers among institutions. Considering the increased use of breast IMRT, more standardized protocols are needed.

In 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system of uterine cervix cancer, size criteria of primary tumor has been revised. This study aimed to evaluate the validity of this new size criteria (2, 2-4, and ≧4 cm) in patients who underwent radical hysterectomy and adjuvant radiation therapy (RT) for early cervical cancer.We retrospectively examined 312 patients who underwent radical hysterectomy and adjuvant RT for early cervical cancer (IB-IIA) from 2001 to 2014. The effects of clinical and pathological factors on disease-free survival (DFS) and overall survival (OS) were evaluated in univariate and multivariate analyses.After a median follow-up of 71.5 months, the 5-year DFS and OS rates were 89.5% and 94.7%, respectively. The primary tumor size was not a significant factor for DFS (p = 0.382) or OS (p = 0.725) in all patients.Primary tumor size was not a significant factor for survival in patients who received hysterectomy and adjuvant RT for early cervical cancer. Adequacy of new tumor size criteria (2, 2-4, and ≧4 cm) in new 2018 FIGO stage needs to be validated in further studies.

Objective External beam radiation therapy (EBRT) with concurrent chemotherapy followed by intracavitary brachytherapy is the standard treatment in locally advanced cervical cancer. This study examined the brachytherapy utilization rate and evaluated the effect of brachytherapy on survival in cervical cancer patients in Korea. Methods In this study, data from the Korea Central Cancer Registry and Korean National Health Insurance Service and data on mortality from Statistics Korea were linked and used. Patients with other cancers, distant metastasis at diagnosis, or unknown stage or who underwent hysterectomy were excluded. A total of 12,721 cervical cancer patients were analyzed in this study. Results The brachytherapy utilization rate (%) was calculated as the proportion of patients who received brachytherapy among those who received curative EBRT. The brachytherapy utilization rate decreased from 84% in 2005 to 78% in 2013 (p, Synopsis This study examined the brachytherapy utilization rate and evaluated the effect of brachytherapy on survival in cervical cancer patients in Korea. We used data from the Korea Central Cancer Registry and Korean National Health Insurance Service. Brachytherapy use is independently associated with significantly higher survival.