The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
...Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
Methylation of the MGMT gene promoter is associated with a favorable prognosis in adult patients with GBM treated with TMZ. We determined the incidence of pseudoprogression according to the MGMT ...methylation status and the potential value of DSC perfusion MR images for predicting pseudoprogression.
New or enlarged enhancing lesions after CCRT in adult patients with newly diagnosed GBMs were prospectively assessed by measuring their rCBV by using DSC perfusion MR images. Tumor tissue was assayed to determine MGMT promoter methylation status. All patients were regularly followed up at an interval of 2 months by MR images, including DSC perfusion MR images.
Ninety eligible patients were enrolled in this study. After CCRT, new or enlarged enhanced lesions were found in 59 of 90 patients, which were subsequently classified as pseudoprogression (26 patients, 28.9%) and real progression (33 patients, 36.7%). Overall, there was a significant difference in the mean rCBV between pseudoprogression and real tumor progression (P = .003). The ROC curve revealed that an rCBV ratio >1.47 had an 81.5% sensitivity and a 77.8% specificity. The unmethylated MGMT promoter group had a significant difference of mean rCBV between pseudoprogression and real progression (P = .009), though the methylated MGMT promoter group had no significant difference (P = .258).
The current study suggests that rCBV measured by DSC perfusion MR images has a differential impact on the predictability of pseudoprogression in patients with GBM.
Objective: To assess the effects of soybean-derived pinitol on glycaemic control and cardiovascular risk factors in Korean patients with type II diabetes mellitus. Design: Randomized, double-blind, ...placebo-controlled, parallel-group trial. Setting: Pusan Paik Hospital, Pusan, Republic of Korea. Interventions: A total of 30 patients with type II diabetes received an oral dose of 600 mg soybean-derived pinitol or placebo twice daily for 13 weeks. Results: Pinitol significantly decreased mean fasting plasma glucose, insulin, fructosamine, HbA1c, and the homeostatic model assessment insulin resistance index (HOMA-IR, P<0.001). Pinitol significantly decreased total cholesterol, LDL-cholesterol, the LDL/HDL-cholesterol ratio, and systolic and diastolic blood pressure and increased HDL-cholesterol (P<0.05). Conclusions: These data suggest that soybean-derived pinitol may be beneficial in reducing cardiovascular risk in Korean type II diabetes.
The recent manufacturing trend toward mass customization and further personalization of products requires factories to be smarter than ever before in order to: (1) quickly respond to customer ...requirements, (2) resiliently retool machinery and adjust operational parameters for unforeseen system failures and product quality problems, and (3) retrofit old systems with upcoming new technologies. Furthermore, product lifecycles are becoming shorter due to unbounded and unpredictable customer requirements, thereby requiring reconfigurable and versatile manufacturing systems that underpin the basic building blocks of smart factories. This study introduces a modular factory testbed, emphasizing transformability and modularity under a distributed shop-floor control architecture. The main technologies and methods, being developed and verified through the testbed, are presented from the four aspects of rapid factory transformation: self-layout recognition, rapid workstation and robot reprogramming, inter-layer information sharing, and configurable software for shop-floor monitoring.
We conducted a population-based retrospective cohort study to investigate the influence of hospital volume, delay of surgery, and both together on the long-term survival of postoperative cancer ...patients.
Using information from the Korea Central Cancer Registry from 2001 through 2005 and the National Health Insurance claim database, we determined survival for 147 682 patients who underwent definitive surgery for any of six cancers.
Regardless of cancer site, surgical patients in low- to medium-volume hospitals showed significantly worse survival adjusted hazard ratio (aHR) = 1.36–1.86 than those in high-volume hospitals in multivariable analyses. Among the latter, treatment delays > 1 month were not associated with worse survival for stomach, colon, pancreatic, or lung cancer but were for rectal aHR = 1.28; 95% confidence interval (CI), 1.17–1.40 and breast (aHR = 1.59; 95% CI, 1.37–1.84) cancer. For patients in low- to medium-volume hospitals, treatment delay was associated with worse survival for all types of cancer (aHR = 1.78–3.81).
Our findings suggest that the effect of hospital volume and surgical treatment delay on overall survival of cancer patients should be considered in formulating or revising national health policy.
L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate ...is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant ...chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC.
The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146).
A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable.
In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
•In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy.•The addition of radiotherapy to chemotherapy did not significantly reduce the rate of recurrence after D2 gastrectomy.•DFS between patients treated with adjuvant chemotherapy and chemoradiotherapy was similar across all subgroups, including Lauren classification.
In this study, we undertook a randomized phase III trial of 105 NSCLC patients with oligo (one to four) -brain metastases. Patients were randomly assigned (1:1) to receive either stereotactic ...radiosurgery (SRS) followed by chemotherapy or upfront chemotherapy alone. The results demonstrated that SRS followed by chemotherapy did not improve overall survival compared with upfront chemotherapy only.
It is unclear whether treating brain metastasis before starting systemic chemotherapy can improve survival compared with upfront chemotherapy in non-small-cell lung cancer (NSCLC) with asymptomatic cerebral oligo-metastases.
We undertook a randomized, controlled trial of 105 patients with one to four brain metastases, admitted to Samsung Medical Center between 2008 and 2013. Patients were randomly assigned to receive stereotactic radiosurgery (SRS) (49 patients) followed by chemotherapy or upfront chemotherapy (49 patients). The primary end point was overall survival (OS) and secondary end points included central nervous system (CNS) progression-free survival, progression to symptomatic brain metastasis and brain functional outcome.
The median age was 58 years (range, 29–85) with ECOG 0–1 performance status, and 40% of patients were never smokers. Most patients had adenocarcinoma, and about half of patients had only one brain metastasis, while the rest had multiple cerebral metastases. The median OS time was 14.6 months 95% confidence interval (CI), 9.2–20.0 in the SRS group and 15.3 months (95% CI, 7.2–23.4) for the upfront chemotherapy group (P = 0.418). There was no significant difference in time to CNS disease progression median, 9.4 months (SRS) versus 6.6 months (upfront chemotherapy),P = 0.248. Symptomatic progression of brain metastases was observed more frequently in the upfront chemotherapy group (26.5%) than the SRS group (18.4%) but without statistical significance.
Although this study included smaller sample size than initially anticipated due to early termination, SRS followed by chemotherapy did not improve OS in oligo-brain metastases NSCLC patients compared with upfront chemotherapy. Further study with large number of patients should be needed to confirm the use of upfront chemotherapy alone in this subgroup of patients.
NCT01301560.
Traditionally, neuromyelitis optica (NMO) was known to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti-aquaporin-4 (AQP4) antibody for NMO enabled us to ...identify more diverse clinical manifestations. Here, we describe the demographic and clinical characteristics of patients who were anti-AQP4-antibody positive, represented by CNS AQP4 autoimmunity.
In total, 388 consecutive patients with inflammatory demyelinating CNS diseases were tested for the anti-AQP4 antibody and 106 seropositive patients who were positive by ELISA or cell-based assay were included.
Ninety-seven patients were women, and 9 men. The median age at onset was 32 years. The median annualized relapse rate was 1.14 during the median follow-up of 7.0 years. When the 2006 revised diagnostic criteria for NMO were applied, 72% of patients met the criteria, and 28% had a limited form of NMO. Brain symptoms were observed in 51% of patients, and 24% of patients presented with brain symptoms as their first manifestation. Severe residual visual impairment or ambulatory disability was observed in 42% of patients. The median intervals to Expanded Disability Status Scale (EDSS) 6 and severe visual impairment in at least one eye were 12 and 11 years, respectively. A multivariate analysis revealed a delay of more than 4 years before appropriate immunotherapy was independently associated with reaching severe disability of more than EDSS 6.
The spectrum of neurologic manifestations and the disease course associated with CNS AQP4 autoimmunity is broader than previously recognized.
Summary Background The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned ...interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. Methods CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II–IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m2 twice daily on days 1–14 plus intravenous oxaliplatin 130 mg/m2 on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov , NCT00411229. Findings We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54–70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio HR 0·58, 95% CI 0·47–0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63–73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47–58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51–0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74–82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64–73) in the observation group. Adverse event data were not collected after the primary analysis. Interpretation Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. Funding F Hoffmann La-Roche and Sanofi.
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