Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Local Ablative Therapy Combined With Pembrolizumab in Patients With Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Recursive Partitioning Analysis.

PURPOSE: This study aimed to evaluate the efficacy of local ablative therapy (LAT) combined with pembrolizumab in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) and to identify patients who would most benefit from LAT. METHODS AND MATERIALS: We retrospectively identified patients who received diagnosis of synchronous oligometastatic NSCLC (≤5 metastatic lesions and ≤3 organs involved) and were treated with first-line pembrolizumab between January 2017 and December 2022. Patients who underwent LAT, including surgery or radiation therapy at all disease sites, were compared with those who did not undergo LAT. A recursive partitioning analysis (RPA) model was developed using prognostic factors for progression-free survival (PFS). RESULTS: Among the 258 patients included, 78 received LAT with pembrolizumab, and 180 received pembrolizumab alone. The median follow-up duration was 15.5 months (range, 3.0-71.2 months). In the entire cohort, LAT was independently associated with significantly improved PFS (hazard ratio [HR], 0.64; P = .015) and overall survival (OS) (HR, 0.61; P = .020). In the propensity score-matched cohort (N = 74 in each group), the median PFS was 19.9 months and 9.6 months, respectively (P = .003), and the median OS was 42.2 months and 20.5 months, respectively (P = .045), for the LAT and non-LAT groups. Based on the RPA model, incorporating the number of metastatic lesions, performance status, and programmed cell death-ligand 1 expression level, patients were stratified into 3 risk groups with distinct PFS. LAT significantly improved PFS and OS in the low- and intermediate-risk groups; however, no difference was observed in the high-risk group. LAT was more effective as a consolidative treatment after pembrolizumab initiation than as an upfront therapy. CONCLUSIONS: LAT combined with pembrolizumab was associated with higher PFS and OS compared with pembrolizumab alone in selected patients with synchronous oligometastatic NSCLC. The RPA model could serve as a valuable clinical tool for identifying appropriate patients for LAT.

Diagnostic performance of a deep-learning model using 18F-FDG PET/CT for evaluating recurrence after radiation therapy in patients with lung cancer.

OBJECTIVE: We developed a deep learning model for distinguishing radiation therapy (RT)-related changes and tumour recurrence in patients with lung cancer who underwent RT, and evaluated its performance. METHODS: We retrospectively recruited 308 patients with lung cancer with RT-related changes observed on 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) performed after RT. Patients were labelled as positive or negative for tumour recurrence through histologic diagnosis or clinical follow-up after 18F-FDG PET/CT. A two-dimensional (2D) slice-based convolutional neural network (CNN) model was created with a total of 3329 slices as input, and performance was evaluated with five independent test sets. RESULTS: For the five independent test sets, the area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, and specificity were in the range of 0.98-0.99, 95-98%, and 87-95%, respectively. The region determined by the model was confirmed as an actual recurred tumour through the explainable artificial intelligence (AI) using gradient-weighted class activation mapping (Grad-CAM). CONCLUSION: The 2D slice-based CNN model using 18F-FDG PET imaging was able to distinguish well between RT-related changes and tumour recurrence in patients with lung cancer.

Safety and Efficacy of HL301 In Radiation Pneumonitis in Patients With Unresectable Non-Small Cell Lung Cancer Receiving Curative Concurrent Chemoradiotherapy: A Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Phase 2a Clinical Trial.

PURPOSE: We aimed to investigate the safety and efficacy of HL301, a standardized combination product of 7 medicinal plants, in radiation pneumonitis in patients with unresectable non-small cell lung cancer undergoing curative concurrent chemoradiotherapy. METHODS AND MATERIALS: The target accrual was 87 and a total of 63 patients were enrolled due to poor accrual rate. We randomly assigned the 63 patients to receive a placebo (arm A), or 1200 mg HL301 (arm B), or 1800 mg HL301 (arm C). Patients received weekly paclitaxel and carboplatin concurrently with intensity-modulated radiation therapy at 60 to 66 Gy in conventional fractionation. Durvalumab was administered as a maintenance treatment according to standard clinical practice. HL301 was administered orally, daily for 12 weeks. The primary endpoint was incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy. RESULTS: The baseline characteristics of the patients were well balanced. The drug was tolerable with a compliance rate of 86.6%, 86.2%, and 88.8% in arms A, B, and C, respectively (P = .874). None of the patients experienced severe drug-related adverse events. No significant difference in the rate of adverse events were observed between the treatment arms. The incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy was 37.5% (95% CI, 18.5%-61.4%), 55.6% (95% CI, 33.7%-75.4%), and 52.4% (95% CI, 32.4%-71.7%) in arms A, B, and C, respectively (P = .535). CONCLUSIONS: This is the first exploratory clinical trial to test the safety and efficacy of HL301 in patients with non-small cell lung cancer. Safety and feasibility of HL301 were established but no signals of efficacy in reducing radiation pneumonitis was observed in this dose level.

Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

BACKGROUND: The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. METHODS: The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. RESULTS: A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55 months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. CONCLUSION: Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

Contribution of Enhanced Locoregional Control to Improved Overall Survival with Consolidative Durvalumab After Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: Insights from Real-World Data.

Purpose: This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. Materials and Methods: This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis free survival (DMFS), progression free survival (PFS), and overall survival (OS). Results: Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. Conclusion: The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care.

Application of surface-guided radiation therapy in prostate cancer: comparative analysis of differences with skin marking-guided patient setup.

PURPOSE: Surface-guided radiation therapy is an image-guided method using optical surface imaging that has recently been adopted for patient setup and motion monitoring during treatment. We aimed to determine whether the surface guide setup is accurate and efficient compared to the skin-marking guide in prostate cancer treatment. MATERIALS AND METHODS: The skin-marking setup was performed, and vertical, longitudinal, and lateral couch values (labeled as "M") were recorded. Subsequently, the surface-guided setup was conducted, and couch values (labeled as "S") were recorded. After performing cone-beam computed tomography (CBCT), the final couch values was recorded (labeled as "C"), and the shift value was calculated (labeled as "Gap (M-S)," "Gap (M-C)," "Gap (S-C)") and then compared. Additionally, the setup times for the skin marking and surface guides were also compared. RESULTS: One hundred and twenty-five patients were analyzed, totaling 2,735 treatment fractions. Gap (M-S) showed minimal differences in the vertical, longitudinal, and lateral averages (-0.03 cm, 0.07 cm, and 0.06 cm, respectively). Gap (M-C) and Gap (S-C) exhibited a mean difference of 0.04 cm (p = 0.03) in the vertical direction, a mean difference of 0.35 cm (p = 0.52) in the longitudinal direction, and a mean difference of 0.11 cm (p = 0.91) in the lateral direction. There was no correlation between shift values and patient characteristics. The average setup time of the skin-marking guide was 6.72 minutes, and 7.53 minutes for the surface guide. CONCLUSION: There was no statistically significant difference between the surface and skin-marking guides regarding final CBCT shift values and no correlation between translational shift values and patient characteristics. We also observed minimal difference in setup time between the two methods. Therefore, the surface guide can be considered an accurate and time-efficient alternative to skin-marking guides.

Outcome of dose-escalated intensity-modulated radiotherapy for limited disease small cell lung cancer.

PURPOSE: An optimal once-daily radiotherapy (RT) regimen is under investigation for definitive concurrent chemoradiotherapy (CCRT) in limited disease small cell lung cancer (LD-SCLC). We compared the efficacy and safety of dose escalation with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Between January 2016 and March 2021, patients treated with definitive CCRT for LD-SCLC with IMRT were retrospectively reviewed. Patients who received a total dose <50 Gy or those with a history of thoracic RT or surgery were excluded. The patients were divided into two groups (standard and dose-escalated) based on the total biologically effective dose (BED, α/ß = 10) of 70 Gy. The chemotherapeutic regimen comprised four cycles of etoposide and cisplatin. RESULTS: One hundred and twenty-two patients were analyzed and the median follow-up was 27.8 months (range, 4.4 to 76.9 months). The median age of the patients was 63 years (range, 35 to 78 years) and the majority had a history of smoking (86.0%). The 1- and 3-year overall survival rates of the escalated dose group were significantly higher than those of the standard group (93.5% and 50.5% vs. 76.7% and 33.3%, respectively; p = 0.008), as were the 1- and 3-year freedom from in-field failure rates (91.4% and 66.5% vs. 73.8% and 46.9%, respectively; p = 0.018). The incidence of grade 2 or higher acute and late pneumonitis was not significantly different between the two groups (p = 0.062, 0.185). CONCLUSION: Dose-escalated once-daily CCRT with IMRT led to improved locoregional control and survival, with no increase in toxicity.

Targeting phosphomevalonate kinase enhances radiosensitivity via ubiquitination of the replication protein A1 in lung cancer cells.

Radiotherapy (RT) plays an important role in localized lung cancer treatments. Although RT locally targets and controls malignant lesions, RT resistance prevents RT from being an effective treatment for lung cancer. In this study, we identified phosphomevalonate kinase (PMVK) as a novel radiosensitizing target and explored its underlying mechanism. We found that cell viability and survival fraction after RT were significantly decreased by PMVK knockdown in lung cancer cell lines. RT increased apoptosis, DNA damage, and G2/M phase arrest after PMVK knockdown. Also, after PMVK knockdown, radiosensitivity was increased by inhibiting the DNA repair pathway, homologous recombination, via downregulation of replication protein A1 (RPA1). RPA1 downregulation was induced through the ubiquitin-proteasome system. Moreover, a stable shRNA PMVK mouse xenograft model verified the radiosensitizing effects of PMVK in vivo. Furthermore, PMVK expression was increased in lung cancer tissues and significantly correlated with patient survival and recurrence. Our results demonstrate that PMVK knockdown enhances radiosensitivity through an impaired HR repair pathway by RPA1 ubiquitination in lung cancer, suggesting that PMVK knockdown may offer an effective therapeutic strategy to improve the therapeutic efficacy of RT.

ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

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.

Deep learning proton beam range estimation model for quality assurance based on two-dimensional scintillated light distributions in simulations.

BACKGROUND: Many studies have utilized optical camera systems with volumetric scintillators for quality assurances (QA) to estimate the proton beam range. However, previous analytically driven range estimation methods have the difficulty to derive the dose distributions from the scintillation images with quenching and optical effects. PURPOSE: In this study, a deep learning method utilized to QA was used to predict the beam range and spread-out Bragg peak (SOBP) for two-dimensional (2D) map conversion from the scintillation light distribution (LD) into the dose distribution in a water phantom. METHODS: The 2D residual U-net modeling for deep learning was used to predict the 2D water dose map from a 2D scintillation LD map. Monte Carlo simulations for dataset preparation were performed with varying monoenergetic proton beam energies, field sizes, and beam axis shifts. The LD was reconstructed using photons backpropagated from the aperture as a virtual lens. The SOBP samples were constructed based on monoenergetic dose distributions. The training set, including the validation set, consisted of 8659 image pairs of LD and water dose maps. After training, dose map prediction was performed using a 300 image pair test set generated under random conditions. The pairs of simulated and predicted dose maps were analyzed by Bragg peak fitting and gamma index maps to evaluate the model prediction. RESULT: The estimated beam range and SOBP width resolutions were 0.02 and 0.19 mm respectively for varying beam conditions, and the beam range and SOBP width deviations from the reference simulation result were less than 0.1 and 0.8 mm respectively. The simulated and predicted distributions showed good agreement in the gamma analysis, except for rare cases with failed gamma indices in the proximal and field-marginal regions. CONCLUSION: The deep learning conversion method using scintillation LDs in an optical camera system with a scintillator is feasible for estimating proton beam range and SOBP width with high accuracy.

Challenges and Opportunities With the Use of Hypofractionated Radiation Therapy in Cancer Care: Regional Perspectives From South Korea, Japan, Singapore, and Australia.

Hypofractionated radiotherapy schedules provide higher per-fraction radiation doses delivered in fewer fractions than conventional schedules. This novel delivery method is supported by a large body of clinical trial evidence across various cancer sites in both curative and palliative settings. Hypofractionation is associated with benefits such as lower costs, improved patient access and increased treatment precision, which has led to its inclusion in various treatment guidelines. Despite this, utilization is not uniform across cancer sites and geographic regions due to reasons such as reimbursement models, nuances in healthcare systems, and professional culture. Key factors to ensure patients benefit from access to high quality radiotherapy include publishing clinical evidence, cross-country collaboration to fill knowledge gaps, reviewing reimbursement models, and improving patient advocacy in treatment decision-making.

Efficacy of lazertinib for symptomatic or asymptomatic brain metastases in treatment-naive patients with advanced EGFR mutation-positive non-small cell lung cancer: Protocol of an open-label, single-arm phase II trial.

INTRODUCTION: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has a higher incidence of brain metastases than wild-type EGFR mutations. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), targets both EGFR-TKI sensitizing and T790M-resistance mutations and has a higher brain penetration rate relative to first- and second-generation EGFR-TKIs. Therefore, osimertinib has become a preferred first-line therapy for advanced EGFR mutation-positive NSCLC. However, lazertinib, an emerging EGFR-TKI, has shown higher selectivity toward EGFR mutations and improved penetration of the blood-brain barrier compared to osimertinib in preclinical studies. This trial will evaluate the efficacy of lazertinib as a first-line therapy in patients with EGFR mutation-positive NSCLC who have brain metastases, with or without additional local therapy. METHODS: This is a single-center, open-label, single-arm phase II trial. A total of 75 patients with advanced EGFR mutation-positive NSCLC will be recruited. Eligible patients will receive oral lazertinib 240 mg, once daily until disease progression or intolerable toxicity is detected. Patients with moderate to severe symptoms related to brain metastasis will simultaneously receive local therapy for the brain. The primary endpoints are progression-free survival and intracranial progression-free survival. DISCUSSION: Lazertinib, in combination with local therapy for the brain, if necessary, is expected to improve the clinical benefit in advanced EGFR mutation-positive NSCLC with brain metastases, as a first-line treatment.

Korean Real-World Data on Patients With Unresectable Stage III NSCLC Treated With Durvalumab After Chemoradiotherapy: PACIFIC-KR.

INTRODUCTION: This study aimed to investigate real-world evidence for efficacy and safety of durvalumab consolidation (DC) after chemoradiotherapy (CRT) in patients with unresectable stage III NSCLC. METHODS: Patients with stage III NSCLC who started DC after CRT between September 2018 and December 2020 and were treated at five tertiary hospitals in the Republic of Korea were included. The primary end point was real-world progression-free survival (rwPFS). Secondary end points were overall survival, objective response rate, and adverse events including radiation pneumonitis (RP) and immune-related adverse events (irAEs). RESULTS: A total of 157 patients were enrolled. At the median follow-up of 19.1 months, median rwPFS of DC was 25.9 months (95% confidence interval: 16.5-35.4) and the 1-, 2-, and 3-year rwPFS rates were 59.4%, 51.8%, and 43.5%, respectively. The median overall survival was not mature, and objective response rate of DC was 51.0%. High programmed death-ligand 1 expression (≥50%) and development of RP requiring steroid treatment were significantly associated with longer (p = 0.043) and shorter rwPFS (p = 0.036), respectively. RP, RP requiring steroid treatment, and irAEs developed in 57 (36.3%), 42 (26.8%), and 53 (33.8%) patients, respectively. Among peripheral blood cell counts at the initiation of DC, a high derived monocyte-to-lymphocyte ratio was the most significant risk factor for the development of RP requiring steroid treatment (OR 44.76, 95% CI: 8.89-225.43, p < 0.001) and irAEs (OR 2.85, 95% CI: 1.27-6.41, p = 0.011). CONCLUSIONS: Compared with the outcome of the PACIFIC trial, these real-world data revealed favorable survival benefits of DC after CRT in patients with unresectable stage III NSCLC. Blood-based biomarkers could predict higher-grade RP and irAEs before the initiation of DC.

Clinical Outcome of Stereotactic Body Radiotherapy in Patients with Early-Stage Lung Cancer with Ground-Glass Opacity Predominant Lesions: A Single Institution Experience.

PURPOSE: The detection rate of early-stage lung cancer with ground-glass opacity (GGO) has increased, and stereotactic body radiotherapy (SBRT) has been suggested as an alternative to surgery in inoperable patients. However, reports on treatment results are limited. Therefore, we performed a retrospective study to investigate the clinical outcome after SBRT in patients with early-stage lung cancer with GGO-predominant tumor lesions at a single institution. MATERIALS AND METHODS: This study included 89 patients with 99 lesions who were treated with SBRT for lung cancer with GGO-predominant lesions that had a consolidation-to-tumor ratio of ≤0.5 at Asan Medical Center between July 2016 and July 2021. A median total dose of 56.0 Gy (range, 48.0-60.0) was delivered using 10.0-15.0 Gy per fraction. RESULTS: The overall follow-up period for the study was median 33.0 months (range, 9.9 to 65.9 months). There was 100% local control with no recurrences in any of the 99 treated lesions. Three patients had regional recurrences outside of the radiation field, and three had distant metastasis. The 1-year, 3-year, and 5-year overall survival rates were 100.0%, 91.6%, and 82.8%, respectively. Univariate analysis revealed that advanced age and a low level of diffusing capacity of the lungs for carbon monoxide were significantly associated with overall survival. There were no patients with grade ≥3 toxicity. CONCLUSION: SBRT is a safe and effective treatment for patients with GGO-predominant lung cancer lesions and is likely to be considered as an alternative to surgery.

NCK-associated protein 1 regulates metastasis and is a novel prognostic marker for colorectal cancer.

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 TGFß1, 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.

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in patients with recurrent non-small cell lung cancer after definitive concurrent chemoradiation or radiotherapy.

PURPOSE: Whether prior radiotherapy (RT) affects the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitor (TKI) remains elusive. METHODS: Patients with EGFR-mutated NSCLC treated with EGFR TKIs who recurred after curative treatment at Asan Medical Center, Seoul, Korea were included. The progression-free survival (PFS) and overall survival (OS) from the initiation of EGFR TKI in patients who recurred after definitive RT were analyzed and compared to the outcomes of RT-naïve patients with advanced NSCLC treated with EGFR TKIs from previously reported prospective clinical trial results. RESULTS: A total of 60 patients who recurred after definitive RT were included. The median age was 70 years (range, 38-88), with 24 patients (40.0%) being males. Among the 60 patients, 52 patients (86.7%) had exon 19 deletion or L858R mutation, with 49 patients (81.7%) receiving gefitinib as the first-line EGFR TKI. The median PFS and OS from the initiation of EGFR TKI were 10.4 months (95% confidence interval [CI], 7.4-13.2) and 21.3 months (95% CI, 13.4-28.8), respectively. CONCLUSION: The EGFR TKI efficacy in EGFR-mutated patients with NSCLC who recurred after RT was comparable with that in historic controls of RT-naïve patients with advanced NSCLC treated with EGFR TKIs, indicating that RT may not affect EGFR TKI efficacy.

A study of quantitative indicators for slice sorting in cine-mode 4DCT.

The uncertainties of four-dimensional computed tomography (4DCT), also called as residual motion artefacts (RMA), induced from irregular respiratory patterns can degrade the quality of overall radiotherapy. This study aims to quantify and reduce those uncertainties. A comparative study on quantitative indicators for RMA was performed, and based on this, we proposed a new 4DCT sorting method that is applicable without disrupting the current clinical workflow. In addition to the default phase sorting strategy, both additional amplitude information from external surrogates and the quantitative metric for RMA, investigated in this study, were introduced. The comparison of quantitative indicators and the performance of the proposed sorting method were evaluated via 10 cases of breath-hold (BH) CT and 30 cases of 4DCT. It was confirmed that N-RMSD (normalised root-mean-square-deviation) was best matched to the visual standards of our institute's regime, manual sorting method, and could accurately represent RMA. The performance of the proposed method to reduce 4DCT uncertainties was improved by about 18.8% in the averaged value of N-RMSD compared to the default phase sorting method. To the best of our knowledge, this is the first study that evaluates RMA indicators using both BHCT and 4DCT with visual-criteria-based manual sorting and proposes an improved 4DCT sorting strategy based on them.

Sex differences in the characteristics and survival of patients with non-small-cell lung cancer: A retrospective analytical study based on real-world clinical data of the Korean population.

PURPOSE: This study aimed to investigate the differences in characteristics, clinical stages, treatment modalities, and survival outcomes in patients with non-small-cell lung cancer (NSCLC) based on sex differences using Korean nationwide registry data. METHODS: We analyzed the data of 8650 patients diagnosed with NSCLC between 2014 and 2017, obtained from the Korean Association for Lung Cancer Registry (KALC-R). The Cox proportional hazard model was used to define the differences in survival based on sex. Propensity score matching was used to adjust for differences between men and women. RESULTS: Of a total of 10 943 patients, 8650 (79.1%) were diagnosed with NSCLC, of whom 68.7% were men and 31.3% were women. For NSCLC, the median age was higher (69.0 vs. 67.0, p < 0.001) and the proportion of ever-smokers (84.5% vs. 10.8%, p < 0.001) was higher in men. Adenocarcinoma (55.5% vs. 90.4%, p < 0.001) and stage I NSCLC (26.3% vs. 41.3%, p < 0.001) were more common in women. Survival was significantly lower in men with NSCLC (hazard ratio [HR] 1.493 [95% confidence interval, CI 1.238-1.800], p < 0.001) even after adjusting for meaningful clinical variables, and in the matched cohort (HR 1.339 [1.075-1.667], p = 0.009). Similarly, survival was significantly lower in men with stage IV adenocarcinoma after adjusting for other clinical variables (HR 1.493 [1.238-1.800], p < 0.001) and in the matched cohort (HR 1.339 [1.075-1.667]; p = 0.009). CONCLUSIONS: Male patients with NSCLC had poorer prognosis, not only after variable adjustments for prognostic factors, but also in the matched cohort.

Clinicopathologic Characteristics and Clinical Outcome of Localized Liposarcoma: A Single-Center Experience over 25 Years and Evaluation of PD-L1 Expression.

PURPOSE: For liposarcoma (LPS), clinical course and proper treatment strategies have not been well-established. Recently, immune-checkpoint inhibitors have shown potential efficacy in LPS. We aimed to describe the clinical course of LPS and evaluate the clinical impact of programmed death-ligand 1 (PD-L1). MATERIALS AND METHODS: We reviewed all consecutive patients (n=332) who underwent curative-intent surgery for localized LPS at Asan Medical Center between 1989 and 2017. PD-L1 testing was performed in well-differentiated and dedifferentiated LPS. RESULTS: The median age was 56 years with males comprising 60.8%. Abdomen-pelvis (47.6%) and well-differentiated (37.7%) were the most frequent primary site and histologic subtype, respectively. During a median follow-up of 81.2 months, recurrence was observed in 135 (40.7%), and 86.7% (117/135) were loco-regional. Well-differentiated subtype (hazard ratio [HR], 0.38), abdomen-pelvis origin (HR, 2.43), tumor size larger than 5 cm (HR, 1.83), positive resection margin (HR, 2.58), and postoperative radiotherapy (HR, 0.36) were significantly related with recurrence-free survival as well as visceral involvement (HR, 1.84) and multifocality (HR, 3.79) in abdomen-pelvis LPS. PD-L1 was positive in 31.5% (23/73) and 51.3% (39/76) of well-differentiated and dedifferentiated LPS, respectively, but had no impact on survival outcomes. CONCLUSION: Clinical course of LPS was heterogeneous according to histology and anatomic location. Clear resection margin was important to lower recurrence and postoperative radiotherapy might have additional benefit. A decent portion of well-differentiated and dedifferentiated LPS were positive for PD-L1, but its prognostic role was unclear. Further research is needed to determine clinical implications of PD-L1, especially for advanced-stage LPS with unmet needs for effective systemic treatment.