Automated lung tumor segmentation robust to various tumor sizes using a consistency learning-based multi-scale dual-attention network.

BACKGROUND: It is often difficult to automatically segment lung tumors due to the large tumor size variation ranging from less than 1 cm to greater than 7 cm depending on the T-stage. OBJECTIVE: This study aims to accurately segment lung tumors of various sizes using a consistency learning-based multi-scale dual-attention network (CL-MSDA-Net). METHODS: To avoid under- and over-segmentation caused by different ratios of lung tumors and surrounding structures in the input patch according to the size of the lung tumor, a size-invariant patch is generated by normalizing the ratio to the average size of the lung tumors used for the training. Two input patches, a size-invariant patch and size-variant patch are trained on a consistency learning-based network consisting of dual branches that share weights to generate a similar output for each branch with consistency loss. The network of each branch has a multi-scale dual-attention module that learns image features of different scales and uses channel and spatial attention to enhance the scale-attention ability to segment lung tumors of different sizes. RESULTS: In experiments with hospital datasets, CL-MSDA-Net showed an F1-score of 80.49%, recall of 79.06%, and precision of 86.78%. This resulted in 3.91%, 3.38%, and 2.95% higher F1-scores than the results of U-Net, U-Net with a multi-scale module, and U-Net with a multi-scale dual-attention module, respectively. In experiments with the NSCLC-Radiomics datasets, CL-MSDA-Net showed an F1-score of 71.7%, recall of 68.24%, and precision of 79.33%. This resulted in 3.66%, 3.38%, and 3.13% higher F1-scores than the results of U-Net, U-Net with a multi-scale module, and U-Net with a multi-scale dual-attention module, respectively. CONCLUSIONS: CL-MSDA-Net improves the segmentation performance on average for tumors of all sizes with significant improvements especially for small sized tumors.

Lung tumor segmentation using dual-coupling net with shape prior based on lung and mediastinal window images from chest CT images.

BACKGROUND: Volumetric lung tumor segmentation is difficult due to the diversity of the sizes, locations and shapes of lung tumors, as well as the similarity in the intensity with surrounding tissue structures. OBJECTIVE: We propose a dual-coupling net for accurate lung tumor segmentation in chest CT images regardless of sizes, locations and shapes of lung tumors.METHODSTo extract shape information from lung tumors and use it as shape prior, three-planar images including axial, coronal, and sagittal planes are trained on 2D-Nets. Two types of window images, lung and mediastinal window images, are trained on 2D-Nets to distinguish lung tumors from the thoracic region and to better separate the boundaries of lung tumors from adjacent tissue structures. To prevent false-positive outliers to adjacent structures and to consider the spatial information of lung tumors, pairs of tumor volume-of-interest (VOI) and tumor shape prior are trained on 3D-Net.RESULTSIn the first experiment, the dual-coupling net had the highest Dice Similarity Coefficient (DSC) of 75.7%, considering the shape prior as well as mediastinal window images to prevent the leakage of adjacent structures while maintaining the shape of the lung tumor, with 18.23% p, 3.7% p, 1.1% p, and 1.77% p higher DSCs than in the 2D-Net, 2.5D-Net, 3D-Net, and single-coupling net results, respectively. In the second experiment with annotations for two clinicians, the dual-coupling net showed outcomes of 67.73% and 65.07% regarding the DSC for each annotation. In the third experiment, the dual-coupling net showed 70.97% for the DSC.CONCLUSIONSThe dual-coupling net enables accurate segmentation by distinguishing lung tumors from surrounding tissue structures and thus yields the highest DSC value.

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

BACKGROUND: This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC). METHODS: One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m2) or belotecan (0.5 mg/m2), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint. RESULTS: In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48-0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3-6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022). CONCLUSIONS: The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.

Interference with daily functioning by breakthrough pain in patients with cancer.

PURPOSE: To investigate the association between quality of life (QOL) and breakthrough cancer pain (BTCP) intensity in patients who met the commonly accepted definition of BTCP. METHODS: This study was a subset analysis of a South Korean multicenter, non-interventional, cross-sectional, nationwide survey. Participants were recruited from March 2016 to December 2017. BTCP was defined as a controlled background pain of less than a numeric rating scale (NRS) of 3 and any flare-up pain intensity. Pain intensity data were collected using the Brief Pain Inventory (BPI), which includes an interference assessment of the affective and physical domains. Patients were categorized by BTCP intensity into mild (NRS 1-3), moderate (4-6), and severe (7-10) groups. RESULTS: Of the 969 screened patients with cancer, 679 had ≤ NRS 3 background pain, of whom 438 completed the BPI. Of these 438 patients, 40, 204, and 194 were in the mild, moderate, and severe BTCP groups, respectively. The median NRS of BTCP was 6.0 (interquartile range = 5.0-8.0). Patients with moderate-severe BTCP had significantly higher interference with daily functioning (IDF) scores than did mild BTCP patients (3.3 vs. 5.7; p < 0.01). Both domains of IDF were significantly hampered proportionally by increased BTCP intensity (p < 0.001). The median total IDF scores of the no, moderate, and severe BTCP groups were 3.3, 5.0, and 6.9, respectively. Furthermore, IDF depended on BTCP intensity, duration, and frequency (p < 0.01) but not on pain type and cause. CONCLUSION: An increase in BTCP intensity is likely to result in IDF, regardless of the cause or type of BTCP.

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07).

BACKGROUND: We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLC). METHODS: This study is a randomised, placebo-controlled, phase II study that enroled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum therapy. Eligible patients were randomly assigned (1 : 1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). RESULTS: 97 patients were enroled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n=48; placebo, n=47) and were included in the analyses. Grade 3 toxicities for pazopanib maintenance were thrombocytopenia (10.4%, including one case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (hazard ratio 0.44, 95% confidence interval: 0.29-0.69, P<0.0001). CONCLUSIONS: Pazopanib maintenance significantly prolonged PFS in patients with ED-SCLC. Given the toxicity profiles, however, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.

A combination of BR101801 and venetoclax enhances antitumor effect in DLBCL cells via c-Myc/Bcl-2/Mcl-1 triple targeting.

Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. In a recent phase I study, Venetoclax (ABT-199) targeting Bcl-2 also exhibited disappointing response rates in patients with relapsed/refractory DLBCL, suggesting that targeting only Bcl-2 is not sufficient for achieving successful efficacy due to the concurrent oncogenic function of c-Myc expression and drug resistance following an increase in Mcl-1. Therefore, co-targeting c-Myc and Mcl-1 could be a key combinatorial strategy to enhance the efficacy of Venetoclax. In this study, BR101801 a novel drug for DLBCL, effectively inhibited DLBCL cell growth/proliferation, induced cell cycle arrest, and markedly inhibited G0/G1 arrest. The apoptotic effect of BR101801 was also observed by increased Cytochrome C, cleaved PARP, and Annexin V-positive cell populations. This anti-cancer effect of BR101801 was confirmed in animal models, where it effectively inhibited tumor growth by reducing the expression of both c-Myc and Mcl-1. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL.

Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial.

BACKGROUND: Gefitinib was compared with pemetrexed as second-line therapy in a clinically selected population previously treated with platinum-based chemotherapy. METHODS: A phase 3 trial of gefitinib (250 mg/day) versus pemetrexed (500 mg/m(2) on day 1, every 3 weeks) was conducted in patients who had never smoked and who had advanced pulmonary adenocarcinoma treated with 1 previous platinum-based regimen. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 135 patients were analyzed. The gefitinib group had significantly longer PFS compared with the pemetrexed group, with a median PFS time of 9.0 versus 3.0 months (P = .0006). The objective response rates were 58.8% and 22.4% for gefitinib and pemetrexed, respectively (P < .001). However, there was no statistically significant difference in overall survival between the 2 groups (22.2 vs 18.9 months; P = .37). The difference of PFS was increased in a subgroup analysis of 33 patients with activating epidermal growth factor receptor mutation (15.7 vs 2.9 months; hazard ratio, 0.3; 95% confidence interval, 0.13-0.72; P = .005), with numerical superiority of gefitinib in the 38 patients testing negative for epidermal growth factor receptor mutation (5.9 vs 2.7 months; P = .099). Both regimens were well tolerated. There were no significantly different changes in quality of life between the 2 groups, except that symptom scores for dyspnea and diarrhea favored the gefitinib and pemetrexed arms, respectively. CONCLUSIONS: Gefitinib showed superior efficacy to pemetrexed as second-line therapy in Korean never-smokers with pulmonary adenocarcinoma.

A phase II trial of erlotinib in combination with gemcitabine and capecitabine in previously untreated metastatic/recurrent pancreatic cancer: combined analysis with translational research.

BACKGROUND: To confirm the efficacy and toxicity of Erlotinib in combination with Gemcitabine and Capecitabine when used as a first-line therapy in metastatic/recurrent pancreatic cancer (PC). METHODS: Locally advanced PC was excluded. Erlotinib was given at a dose of 100 mg daily from D1 to D28. 1000 mg/m(2) of gemcitabine was given on D1,8,15 and 1660 mg/m(2)/day of capecitabine was given from D1 to 21, repeated every 4 weeks. Response was assessed every 8 weeks. RESULTS: A total of 47 patients were enrolled. Response rate and disease control rate was 32.6% (95% CI, 18.6-46.6%) and 83.7% (95% CI, 72.7-94.7%) respectively. The PFS was 6.5 months (95% CI, 3.4-9.7) and OS was 12.0 months (95% CI, 8.6-15.9). The Gr 3/4 toxicities were: neutropenia (6.8%), thrombocytopenia (3.2%), anemia (1.6%). nausea (1.6%), vomiting (1.6%), anorexia (5.3%), rash (2.4%). The EGFR expression was associated with shorter OS and ERCC2 expression was associated with longer PFS and OS. PFS and OS were not different according to K-RAS mutation or polymorphism of RRM1 and CDA. CONCLUSIONS: Erlotinib, gemcitabine and capecitabine combination showed promising efficacy and good tolerability in metastatic PC. This efficacy was observed irrespective of K-RAS mutation, and EGFR expression was poor prognostic factor for OS.

Prediction of Two-Year Recurrence-Free Survival in Operable NSCLC Patients Using Radiomic Features from Intra- and Size-Variant Peri-Tumoral Regions on Chest CT Images.

To predict the two-year recurrence-free survival of patients with non-small cell lung cancer (NSCLC), we propose a prediction model using radiomic features of the inner and outer regions of the tumor. The intratumoral region and the peritumoral regions from the boundary to 3 cm were used to extract the radiomic features based on the intensity, texture, and shape features. Feature selection was performed to identify significant radiomic features to predict two-year recurrence-free survival, and patient classification was performed into recurrence and non-recurrence groups using SVM and random forest classifiers. The probability of two-year recurrence-free survival was estimated with the Kaplan-Meier curve. In the experiment, CT images of 217 non-small-cell lung cancer patients at stages I-IIIA who underwent surgical resection at the Veterans Health Service Medical Center (VHSMC) were used. Regarding the classification performance on whole tumors, the combined radiomic features for intratumoral and peritumoral regions of 6 mm and 9 mm showed improved performance (AUC 0.66, 0.66) compared to T stage and N stage (AUC 0.60), intratumoral (AUC 0.64) and peritumoral 6 mm and 9 mm classifiers (AUC 0.59, 0.62). In the assessment of the classification performance according to the tumor size, combined regions of 21 mm and 3 mm were significant when predicting outcomes compared to other regions of tumors under 3 cm (AUC 0.70) and 3 cm~5 cm (AUC 0.75), respectively. For tumors larger than 5 cm, the combined 3 mm region was significant in predictions compared to the other features (AUC 0.71). Through this experiment, it was confirmed that peritumoral and combined regions showed higher performance than the intratumoral region for tumors less than 5 cm in size and that intratumoral and combined regions showed more stable performance than the peritumoral region in tumors larger than 5 cm.

Comparative efficacy and safety of fimasartan in patients with hypertension: A network meta-analysis of randomized controlled trials.

Hypertension is a prevalent risk factor for cardiovascular disease. Angiotensin II receptor blockers are widely prescribed to patients with hypertension, while new drugs are continuously developed. However, data on comparative efficacy and safety of novel agents, such as fimasartan, are scarce. Here, we aimed to collect clinical evidence on different angiotensin II receptor blockers using a network meta-analysis. Randomized controlled trials whose follow-up time is within 12 weeks were identified from eight databases via a systematic literature review. Of the 7909 possibly relevant studies, 61 studies with 14,249 adult patients were included in the analysis. These studies were further subjected to quality appraisal using Cochran's Risk of Bias, and sitting systolic blood pressure was considered the primary endpoint. A Bayesian random effect generalized linear model was used for the network meta-analysis, and the treatment rank probability was determined. Olmesartan (standardized mean difference -0.987 [-1.29, -0.729]) and fimasartan (standardized mean difference -0.966 [-1.21, -0.745]) showed the highest rank probabilities (37% and 35%) in the 4-week group, considering the primary endpoint. Furthermore, the odds ratio of adverse events for all agents did not differ significantly from that of the placebo. The treatment rank of angiotensin II receptor blockers varied depending on the outcome type and follow-up period considerably. Fimasartan rapidly lowered blood pressure in 4 weeks, which was further maintained until 12 weeks, indicating its competent efficacy and tolerability. Our findings may help medical practitioners and patients to select the best angiotensin II receptor blocker against hypertension.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Bortezomib, doxorubicin, and dexamethasone combination therapy followed by thalidomide and dexamethasone consolidation as a salvage treatment for relapsed or refractory multiple myeloma: analysis of efficacy and safety.

We conducted a phase 2 study with bortezomib, doxorubicin, and dexamethasone (PAD) followed by thalidomide and dexamethasone (TD) in patients with relapsed multiple myeloma (MM). Forty patients were enrolled between November 2005 and October 2007, with follow-up continuing until January 2009. Efficacy could be assessed in 37 patients. The overall response rate to PAD followed by TD was 83.6%: complete response 51.4%, near-complete response 13.4%, very good partial remission 5.4%, and partial response 13.4%. The median follow-up was 27 months (range 13-39). The median progression-free survival (PFS) from the start of treatment was 18 months (95% CI, 9.7-26.2 months), with a 1-year PFS rate of 56.9% and 3-year PFS rate of 25.7%. Median overall survival was 35.1 months (95% CI, 18.5-51.7), with a 1-year survival rate of 75% and 3-year survival rate of 27.3%. One hundred seventy-eight PAD cycles (median 6, range 1-6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3-4 in 35.8%. Sensory neuropathy occurred at grade 2 in 26.3% and grade 3 in 10.3%. Two hundred TD treatment cycles (median 4, range 0-12 cycles) were administered. Most adverse events were of mild degree and manageable. PAD followed by TD in patients with relapsed MM is very effective and tolerable.

Perspectives on Professional Burnout and Occupational Stress among Medical Oncologists: A Cross-sectional Survey by Korean Society for Medical Oncology (KSMO).

PURPOSE: This study aimed to investigate the prevalence and risk factors of burnout and occupational stress among medical oncologists in Korea. MATERIALS AND METHODS: A survey was conducted of medical oncologists who were members of Korean Society for Medical Oncology (KSMO) using the Korean Occupational Stress Scale, the validated Maslach Burnout Inventory (MBI) and supplemental questions about work and lifestyle factors. RESULTS: Among 220 active KSMO members, 111 responses were collected. The median age was 42 years (range, 32 to 63 years). Two-thirds of responders worked 6 days per week and half of them worked a total of 60-80 hours per week. Each medical oncologist treated a median of 90-120 patients per week in outpatient clinics and 20-30 patients per week in patient practices. MBI subscales indicated a high level of emotional exhaustion in 74%, a high level of depersonalization in 86%, and a low level of personal accomplishment in 65%: 68% had professional burnout according to high emotional exhaustion and high depersonalization scores. The risk of burnout was higher for medical oncologists aged from 30-39 than 40-49 years, and unmarried than married. Considering personal accomplishment, females had a higher risk of burnout. The median score of occupational stress was 63 (range, 43 to 88). Having night-duty call was the strongest risk factor on more stress. A higher stress score was associated with a higher prevalence of burnout. CONCLUSION: Burnout and occupational stress are quite common amongst Korean medical oncologists. Achieving a healthy work-life balance, ensuring balanced workload distribution, and engaging in proper stress relief solutions are necessary.

Practice patterns of multidisciplinary team meetings in Korean cancer care and patient satisfaction with this approach.

BACKGROUND/AIMS: The multidisciplinary team (MDT) approach is a cornerstone of clinical oncology. This study investigated the current state of MDT care, including patient satisfaction, in Korea. METHODS: We obtained the annual number of cancer patients who have received MDT care since 2014 from the registry of the Health Insurance Review and Assessment Service (HIRA). In addition, patients who received MDT care from August 2014 to May 2017 at four university hospitals were further characterized, and patient satisfaction was measured prospectively using a patient-reported questionnaire. RESULTS: The total number of patients who received MDT care increased from 2014 to 2016 (2,113 to 9,998 patients, respectively) in the HIRA Cohort. The type of cancer that most often required MDT was breast cancer (23.8%), followed by colorectal cancer (19.1%). In the Representative Cohort (n = 1,032), MDT was requested by the surgeon more than half the time (55.7%). The main focus of MDT was decision making for further treatment planning (99.0%). The number of doctors participating in the MDT was usually five (70.0%). After initiating an MDT approach, the treatment plan changed for 17.4% of patients. Among these patients, 359 completed a prospective satisfaction survey regarding their MDT care. The overall satisfaction with the MDT approach was very high, with an average score of 9.6 out of 10 points. CONCLUSION: The application of MDT care is a rapidly growing trend in clinical oncology, and shows high patient satisfaction. Further research is needed to determine which types of cancer patients could benefit most from MDT, and to enable MDT care to operate more efficiently so that it may expand successfully throughout Korea.

Geriatric Nutritional Risk Index as a prognostic marker in patients with extensive-stage disease small cell lung cancer: Results from a randomized controlled trial.

BACKGROUND: Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive-stage disease small cell lung cancer (ED-SCLC) have not previously been reported. METHODS: This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first-line therapy for ED-SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92-98, and <92 were grouped into no, low, and moderate/major risk groups, respectively. RESULTS: The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression-free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012-1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069-2.216; P = 0.020). CONCLUSIONS: This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED-SCLC.Key points SIGNIFICANT FINDINGS OF THE STUDY: The lower GNRI group had a low response rate to chemotherapy for ED-SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92. WHAT THIS STUDY ADDS: Low GNRI is associated with poor prognosis in ED-SCLC.

Gemcitabine plus carboplatin versus gemcitabine plus oxaliplatin in cisplatin-unfit patients with advanced urothelial carcinoma: a randomised phase II study (COACH, KCSG GU10-16).

PURPOSE: Gemcitabine-oxaliplatin (GEMOX) demonstrated mild toxicity and promising effectiveness in patients with advanced urothelial cell cancer (UCC). We investigated the activity and safety of first-line GEMOX compared with gemcitabine-carboplatin (GCb) in cisplatin-ineligible patients with advanced UCC. METHODS: Treatment-naive, cisplatin-ineligible patients with advanced UCC were randomly assigned to GEMOX (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2 on day 1 [D1] every 2 weeks) or GCb (1000 mg/m2 of gemcitabine on D1 and D8 and carboplatin area under the curve of 4.5 mg/mL/min on D1 every 3 weeks). We evaluated the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Between January 2011 and March 2017, 80 patients were enrolled; 39 and 40 patients were allocated to GCb and GEMOX arms, respectively. The ORR was 48.7% in the GCb arm and 55.0% in the GEMOX arm. The median follow-up duration was 37.8 months; the median PFS and OS in the GCb and GEMOX arms were 5.5 months (95% confidence interval [CI], 4.8-6.2) vs. 4.4 months (95% CI, 2.7-6.1) and 9.1 months (95% CI, 5.2-13.0) vs. 11.0 months (95% CI, 6.9-15.0), respectively. ≥Leucopenia, neutropenia and fatigue of ≥ grade III were significantly more common in the GCb arm (26% vs. 3%, P = 0.003; 33% vs. 10%, P = 0.014; 15% vs. 3%, P = 0.012), whereas any-grade neuropathy was more common in the GEMOX arm (8% vs. 60%). CONCLUSIONS: GEMOX showed similar efficacy with GCb and a favourable haematologic toxicity profile. GEMOX may be an additional chemotherapy option for patients with UCC ineligible for cisplatin-containing chemotherapy (NCT01487915).

Real-World Experience of Nivolumab in Non-small Cell Lung Cancer in Korea.

PURPOSE: The introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti-programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program. MATERIALS AND METHODS: Previously treated patients with advanced nonsquamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected. RESULTS: Two hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression-free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data. CONCLUSION: This real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age.

Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation.

Evaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients' diagnoses were essential thrombocythemia (ET n = 146), polycythemia vera (PV n = 120), primary myelofibrosis (n = 12), and unclassifiable MPN (MPNu n = 5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p = 0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p = 0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.

Depletion of L-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes.

PURPOSE: L-ascorbic acid (LAA) modifies the in vitro growth of leukemic cells from approximately 50% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). To test the hypothesis that depletion of LAA, alternating with supplementation to prevent scurvy, would provide therapeutic benefit, a single-arm pilot trial was conducted (ClinicalTrials.gov identifier: NCT00329498). Experimental results: During depletion phase, patients with refractory AML or MDS were placed on a diet deficient in LAA; during supplementation phase, patients received daily intravenous administration of LAA. An in vitro assay was performed pretherapy for LAA sensitivity of leukemic cells from individual patients. RESULTS: Of 18 patients enrolled, eight of 16 evaluable patients demonstrated a clinical response. Responses were obtained during depletion (four patients) as well as during supplementation (five patients) but at a pharmacologic plasma level achievable only with intravenous administration. Of nine patients for whom the in vitro assay indicated their leukemic cells were sensitive to LAA, seven exhibited a clinical response; compared with none of six patients who were insensitive to LAA. CONCLUSIONS: The clinical benefit, along with a conspicuous absence of significant adverse events, suggests that further testing of LAA depletion alternating with pharmacologic dose intravenous supplementation in patients with these and other malignancies is warranted.

Clinical features and survival outcomes in patients with multiple myeloma: analysis of web-based data from the Korean Myeloma Registry.

AIM: The Korean Multiple Myeloma Working Party performed a nationwide registration of multiple myeloma patients via a web-based data bank system. METHODS: We retrospectively analyzed registered data from 3,209 patients since 1999. RESULTS: The median overall survival (OS) was 50.13 months (95% confidence interval: 46.20-54.06 months). Patients < or =40 years demonstrated a longer OS than patients >65 years of age (median OS 71.13 vs. 36.73 months, p < 0.001). Patients who received novel agents at any time during their treatments showed a longer OS than patients who did not (median OS 42.23 vs. 55.50 months, p < 0.001). Response to treatment was associated with OS, with tandem autologous stem cell transplantation (SCT) producing longer OS than single autologous SCT. CONCLUSIONS: We demonstrated associations between survival outcomes and treatment modalities as well as baseline disease characteristics in a registry of multiple myeloma patients using a web-based data analysis.