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Background The accuracy of 18F-fluorodeoxygluocose positron emission tomography/computed tomography (PET/CT) in predicting immediate failure after radical chemoradiotherapy (CRT) for HNSCC is poorly characterized at present. The purpose of this study was to examine PET/CT as a predictive and prognostic gauge of immediate failure after CRT and determine the impact of these studies on clinical decision making in terms of salvage surgery. Methods Medical records of 78 consecutive patients receiving radical CRT for locally advanced HNSCC were reviewed, analyzing PET/CTs done before and 3 months after CRT. Immediate failure was defined as residual disease or locoregional and/or systemic relapse within 6 months after CRT. Results Maximum standard uptake value (SUV) of post CRT PET/CT (postSUVmax) was found optimal for predicting immediate failure at a cutpoint of 4.4. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were 90.0 %, 83.8 %, 98.3 %, and 45.0 %, respectively. Of 78 patients studied, postSUVmax ≥4.4 prevailed in 20 (25.6 %), with postSUVmax

Background Although adolescent and young adult (AYA) cancers are characterized by biological features and clinical outcomes distinct from those of other age groups, the molecular profile of AYA cancers has not been well defined. In this study, we analyzed cancer genomes from rare types of metastatic AYA cancers to identify driving and/or druggable genetic alterations. Methods Prospectively collected AYA tumor samples from seven different patients were analyzed using three different genomics platforms (whole-exome sequencing, whole-transcriptome sequencing or OncoScan™). Using well-known bioinformatics tools (bwa, Picard, GATK, MuTect, and Somatic Indel Detector) and our annotation approach with open access databases (DAVID and DGIdb), we processed sequencing data and identified driving genetic alterations and their druggability. Results The mutation frequencies of AYA cancers were lower than those of other adult cancers (median = 0.56), except for a germ cell tumor with hypermutation. We identified patient-specific genetic alterations in candidate driving genes: RASA2 and NF1 (prostate cancer), TP53 and CDKN2C (olfactory neuroblastoma), FAT1, NOTCH1, and SMAD4 (head and neck cancer), KRAS (urachal carcinoma), EML4-ALK (lung cancer), and MDM2 and PTEN (liposarcoma). We then suggested potential drugs for each patient according to his or her altered genes and related pathways. By comparing candidate driving genes between AYA cancers and those from all age groups for the same type of cancer, we identified different driving genes in prostate cancer and a germ cell tumor in AYAs compared with all age groups, whereas three common alterations (TP53, FAT1, and NOTCH1) in head and neck cancer were identified in both groups. Conclusion We identified the patient-specific genetic alterations and druggability of seven rare types of AYA cancers using three genomics platforms. Additionally, genetic alterations in cancers from AYA and those from all age groups varied by cancer type. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2209-1) contains supplementary material, which is available to authorized users.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that functions as a immuno-suppressive factor.[1] Tryptophan depletion inhibits proliferation and function of T cells and induc...

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 delays1 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.

Purpose This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. Results One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. Conclusion Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.

Objective We evaluated the characteristics of the gastrointestinal stromal tumors that showed discrepancies between their assessment using the Response Evaluation Criteria in Solid Tumor (RECIST) and Choi's criteria. We also investigated the clinical applicability of Choi's criteria to Korean gastrointestinal stromal tumor patients undergoing imatinib therapy. Methods Patients with advanced gastrointestinal stromal tumors treated with frontline imatinib were analyzed. Computed tomography images of these patients were reviewed and genotyping for the KIT and PDGFRA genes was performed. Immunohistochemical staining of c-KIT, CD34, platelet derived growth factor receptor-alpha, platelet derived growth factor receptor-beta, AKT, P-ERK and vascular endothelial growth factor was followed. Results Ninety-five patients were enrolled. When using Choi's criteria to evaluate the 61 patients who achieved at least partial response by Choi's criteria, 27 patients showed discrepancies in their response to treatment between these two sets of criteria. A lack of CD34 expression in tumors was found to be related to cystic degeneration after imatinib treatment (P=0.001). Patients who showed partial response by Choi's criteria but stable disease by RECIST criteria had a similar progression-free survival to cases who showed a partial response under both systems (P=0.951). Conclusions Gastrointestinal stromal tumors showing cystic degeneration after imatinib treatment lack CD34 expression. Choi's criteria have a clinical value in terms of the progression-free survival in Korean patients treated with imatinib.

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer (NSCLC) are mutually exclusive. However, several exceptional cases harboring both genetic alterations have been reported. In this study, a total of 444 patients with lung adenocarcinoma were examined for their EGFR and ALK status at Seoul National University Hospital between July 2008 and September 2011. EGFR mutations and ALK translocations were detected in 228 (51.4%) and 34 (7.7%) patients, respectively. Four patients (0.9%) had both genetic alterations and three underwent curative surgery. One patient who received both EGFR tyrosine kinase and ALK inhibitors, separately showed an objective response to the ALK inhibitor alone. Considering our and previous studies, patients harboring both EGFR mutation and ALK translocation showed differential sensitivities to both targeted therapies, suggesting a variable dependence on EGFR and ALK oncogenes.

PURPOSE Platinum-based chemotherapy has conferred a modest but significant survival benefit and the introduction of newer drugs has led to achieve higher response rate in patients with advanced non-small cell lung cancer (NSCLC). We performed a phase II trial in order to evaluate the efficacy and toxicity of combination chemotherapy with vinorelbine (Navelbine) and cisplatin in advanced NSCLC. MATERIALS AND METHODS Patients with previously untreated, unresectable stage IIIB or IV NSCLC with measurable lesion (s) were eligible for entry into the study. NP chemotherapy consisted of intravenous vinorelbine 25 mg/m2, on day 1 and 8, and intravenous cisplatin 80 mg/m2 on day 1; this cycle was repeated every three weeks. RESULTS A total of 33 patients were enrolled in the study between July 1999 and Feb 2000. Of the 30 patients deemed eligible for analysis, thirteen patients achieved a partial response and thirteen showed a stable disease. The overall response rate was 43.3%. The median duration of response was 5.7 months (95% CI: 2.8~8.5 months). The median time to progression was 7.6 months (95% CI: 5.5~9.7 months) and the overall median survival time was 15.1 months (95% CI: 9.8~20.4 months) in the intent-to-treat analysis. Chemotherapy-related grade 3 or 4 toxicities were anemia in 1.5%, leukopenia in 4.5%, nausea/vomiting in 2.3%, alopecia in 13.3%, and neurotoxicity in 3.3%. CONCLUSION The combination of vinorelbine and cisplatin chemotherapy seems to be active and fairly tolerable in patients with advanced NSCLC.

PURPOSE Paclitaxel is a very effective agent in the treatment of breast cancer. Samyang Corporation has developed its own process to produce paclitaxel in a large volume using plant cell culture technology. To evaluate the efficacy and safety of Genexol(R) in patients with metastatic breast cancer who have failed to respond to standard therapy, we performed a prospective, multi- center phase II clinical trial. MATERIALS AND METHODS Patients with metastatic breast cancer were included in this study. Enrollees were required to have histologically confirmed breast cancer with bidimensionally measurable metastatic disease. Genexol(R) was administered at 175 mg/m2 as a 3-hour intravenous infusion every 3 weeks. All patients were premedicated with hydrocortisone, pheniramine maleate, and H2 blocker 30 minutes prior to paclitaxel. We planned to administer at least 4 courses of paclitaxel unless there was disease progression or unacceptable toxicity and to continue treatment up to a total of 6 courses in cases of objective response following 4 courses. RESULTS The median duration of follow-up was 8.9 (2.07~13.7) months. Forty-five patients were registered and 43 were eligible. The performance status of patients was ECOG 0~1 in 39 patients (90.7%) and 2 in 4 (9.3%). The location of metastases at the start of the study were the lung (15 patients), liver (8 patients), lymph nodes (22 patients), and other (7 patients). Among the 40 evaluable patients, 15 patients obtained partial responses (PRs) (37.5%, 95% CI: 22.5~52.5%). The median duration of response was 11.67 (4.1~11.7) months and the median time to progression was 7.73 (2.8~11.7) months. The median survival time was not reached at 13.7 months, and the overall survival rate at 13.7 months was 70.1%. The hematologic toxicity was primarily neutropenia with grade 3 or 4 in 10 patients (23.3%). The grade 3 or 4 non-hematologic toxicities included alopecia (17, 39.5%), myalgia (2, 4.7%), neuropathy (2, 4.7%), and pruritus (1, 2.3%). Mild hypersensitivity reaction was observed in 2 patients, although it did not cause withdrawal of the test drug. CONCLUSION The results suggest that the Genexol injection is an effective anticancer formulation for the treatment of metastatic breast cancer and toxicity is acceptable.

There is no specific marker to evaluate the immuno-suppressive status of cancer patients. Several markers, such as CD124, latency-associated peptide (LAP), arginase I, indole-amine-2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), are known to be associated with immune suppression. However, there is little research regarding the change in these parameters after chemotherapy. The present study enrolled 23 chemo-naive non-small cell lung cancer (NSCLC) patients and 19 healthy donors. From the 23 NSCLC patients, 11 post-chemotherapy samples were collected. Surface and functional markers were analyzed by flow-cytometry. The mean fluorescence intensities (MFI) of iNOS were higher and the MFI of LAP were lower in NSCLC patient than in healthy donors (P < 0.05). In a comparison of pre-chemotherapy and post-chemotherapy groups with NSCLC, the MFI of iNOS on granulocytes and monocytes and IDO on monocytes were significantly lower in the post-chemotherapy group than in the pre-chemotherapy group (P < 0.05). In a serial analysis with 10 patients who had paired samples and who showed clinical benefits from chemotherapy, the MFI of iNOS for both cell types, and of IDO and CD124 for monocytes decreased significantly after chemotherapy, compared with those before chemotherapy (iNOS, 4.79 ± 1.75 vs 2.83 ± 0.77, P = 0.005, for granulocytes and 6.15 ± 2.94 vs 2.76 ± 1.05, P = 0.005 for monocytes; IDO, 6.81 ± 3.43 vs 4.64 ± 1.55, P = 0.012 for monocytes; CD124, 2.31 ± 0.39 vs 1.94 ± 0.43, P = 0.008 for monocytes). The changes in arginase I and LAP expression were not significant. The changes in iNOS, IDO and CD124 expression were significant after chemotherapy in NSCLC. Further evaluation of the possibility of immune status monitoring using these parameters is needed.

Purpose We tested whether a decision aid explaining how to discuss the approach of death with a family member with cancer would help family caregivers decide to discuss a terminal prognosis. Patients and Methods We randomly assigned caregivers of terminally ill patients with cancer to a group that received a video and a companion workbook that showed either how they can discuss the prognosis with their patient (experimental arm) or how cancer pain can be controlled (control arm). At baseline and 1 month, we evaluated the decision to discuss terminal prognosis as the primary outcome. At 0, 1, 3, and 6 months, we assessed the caregivers' decisional conflict and satisfaction as secondary outcomes using a Decision Conflict Scale (DCS). Results We found no difference in changes in the decision to discuss terminal prognosis between the two groups. Conflict (P = .003), uncertainty (P = .019), and value clarity (P = .007) subscale scores and total DCS score (P = .008) improved from baseline to 1 month significantly more in the experimental arm than in the control arm. Over 6 months, the significant between-group differences continued for the conflict (P = .031), uncertainty (P = .014), and value clarity (P = .039) subscale scores and total DCS score (P = .040). Conclusion Decision aids can help caregivers, with the aid of trained professionals, to communicate with patients about their terminal illness.

Background: Many patients near death report an interest in knowing their prognoses. Patients’ awareness of disease status may lead to more appropriate care and maintained or improved quality of life. However, it is not known whether advanced cancer patients’ awareness of disease status is associated with patients’ quality of life. Aim: We aimed to examine the effect of patients’ awareness of disease status on the health-related quality of life (HRQOL) among advanced cancer patients undergoing palliative chemotherapy. Design: In this prospective cohort study, patients were followed-up at 4–6 weeks and 2–3 months after the initial palliative chemotherapy. Patients’ awareness of disease status, and demographic and clinical characteristics were assessed at baseline, and depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) and HRQOL using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were assessed three times. Setting / participants: In total, 100 patients with advanced cancer starting palliative chemotherapy were recruited from two tertiary university hospitals and from the Korea National Cancer Center. Results: Patients with advanced cancer undergoing palliative chemotherapy experienced deteriorated HRQOL. Of these, the patients who were aware of their disease status as incurable had significantly higher role ( p=0.002), emotional ( p=0.025), and social functioning ( p=0.002), and lower fatigue ( p=0.008), appetite loss ( p=0.039), constipation ( p=0.032), financial difficulties ( p=0.019), and anxiety ( p=0.041) compared with patients unaware of disease status. Conclusion: Our findings demonstrate the importance of patients’ awareness of disease status to HRQOL.

We intended to find predictive markers in advanced gastrointestinal stromal tumor patients treated with sunitinib. Korean patients who received sunitinib after imatinib failure for advanced gastrointestinal stromal tumor were studied. Genotyping for KIT and PDGFRA were performed. An immunohistochemical stain for PDGFR-α, PDGFR-β, and vascular endothelial growth factor (VEGF) was performed. A total of 22 patients were analyzed. Their median age was 55.1 years, and the male to female ratio was 12:10. The response rate of sunitinib was 30.4% and the median progression-free survival (PFS) was 10.1 months. In the sunitinib treatment, VEGF expression was related to a favorable response (P=0.002) and long PFS (P=0.020) in univariate analysis. CD34 (P=0.023) and PDGFR (P=0.022) expressions were also related to long sunitinib PFS in univariate analysis. However, the genotype did not affect either response rate or the PFS of sunitinib. In conclusion, expressions of VEGF, PDGFR, and CD34 may have predictive value in sunitinib treatments.

Purpose: We investigated prognostic implications of microRNAs in extranodal NK/T cell lymphoma (NKTL). Experimental Design: We measured miRNA expression in NKTL tissues and cell lines, using real-time PCR, and analyzed its role in NKTL, using cell lines. Results: Multivariate analysis showed low miR-146a expression (P < 0.001; HR = 13.110), primary non–upper aerodigestive tract lesion (non-UAT; P = 0.008; HR = 5.376) and high International Prognostic Index (IPI; ≥3; P = 0.013; HR = 3.584) to be independent poor prognostic factors. miR-146a expression could subdivide UAT-NKTL into 2 prognostic groups, resulting in the following prognostic groups: (i) UATLow-146a, (ii) UATHigh-146a, and (iii) non-UAT. Compared with UATHigh-146a, UATLow-146a showed distinctively poor prognosis (P < 0.001; HR = 15.620), similar to the non-UAT group. In vitro, miR-146a overexpression in NKTL cell lines, SNK6 and YT, inhibited nuclear factor κB (NFκB) activity, suppressed cell proliferation, induced apoptosis, and enhanced chemosensitivity. TNF receptor–associated factor 6, a target of miR-146a and a known NFκB activator, was downregulated by miR-146a in SNK6 and YT cells. Promoter methylation of miR-146a gene was observed in SNK6 and YT cells, as well as in NKTL tissues with low miR-146a expression, and miR-146a expression was induced by the conversion of methylation status with a demethylating agent in SNK6 and YT cells. Conclusions: These results suggest that miR-146a might function as a potent tumor suppressor in NKTL and be useful for patient assessment and therapeutic targeting. Clin Cancer Res; 17(14); 4761–71. ©2011 AACR.

Our purpose was to evaluate the effect of cancer patients’ awareness of their incurable disease status on decisional conflict and satisfaction with treatment choice. In this prospective cohort study, advanced cancer patients who were offered palliative chemotherapy completed questionnaires on their knowledge of their condition, their treatment decision conflicts, and their satisfaction with their treatment decisions. We enrolled 98 patients; 94 reported that they were aware of their advanced status and 50 were not. Decisional conflicts for all patients showed a significant decrease after treatment, but aware patients were significantly more satisfied with their decision (P = 0.02). Patients’ awareness of their incurable status was associated with greater satisfaction with their decision to receive palliative chemotherapy.

The aim of this study was to combine clinical pathologic variables that are associated with pathologic completer response (pCR) and relapse-free survival (RFS) after neoadjuvant chemotherapy into prediction nomograms.A total of 370 stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. We developed the nomograms using logistic regression model for pCR and Cox proportional hazard regression model for RFS.The nomogram for pCR based on initial tumor size, estrogen receptor (ER), human epidermal growth factor receptor 2, and Ki67 had good discrimination performance (AUROC = 0.830). Multivariate Cox model identified age less than 35, initial clinical stage, pathologic stage, ER, Ki67 as prognostic factors, and the nomogram for RFS was developed based on these covariates. The concordance index for the second nomogram was 0.781, and calibration was also good.We developed nomograms based on clinical and pathologic characteristics to predict the probability of pCR and RFS for patients receiving neoadjuvant docetaxel/doxorubicin chemotherapy.

Purpose We conducted this study to evaluate the validity of the perception that awareness of their terminal prognosis and use of palliative care or nonuse of an intensive care unit (ICU) causes patients to die sooner than they would otherwise. Patients and Methods In this prospective cohort study at 11 university hospitals and the National Cancer Center in Korea, we administered questionnaires to 619 consecutive patients immediately after they were determined by physicians to be terminally ill. We followed patients during 6 months after enrollment and assessed how their survival was affected by the disclosure of terminal illness and administration of palliative care or nonuse of the ICU. Results In a follow-up of 481 patients and 163.8 person-years, we identified 466 deceased patients. Nineteen percent of the patients died within 1 month, while 41.3% lived for 3 months, and 17.7% lived for 6 months. Once the cancer was judged terminal, the median survival time was 69 days. On multivariate analysis, neither patient awareness of terminal status at baseline (adjusted hazard ratio [aHR], 1.20; 95% CI, 0.96 to 1.51), use of a palliative care facility (aHR, 0.96; 95% CI, 0.76 to 1.21), nor general prostration (aHR, 1.23; 95% CI, 0.96 to 1.57) was associated with reduced survival. Use of the ICU (aHR, 1.47; 95% CI, 1.06 to 2.05) and poor Eastern Cooperative Oncology Group performance status (aHR, 1.37; 95% CI, 1.10 to 1.71) were significantly associated with poor survival. Conclusion Patients' being aware that they are dying and entering a palliative care facility or ICU does not seem to influence patients' survival.

It has recently been found that 5-lipoxygenase (5-LO) and cytochrome P450-2J2 (CYP2J2), molecules capable of arachidonic acid (AA) metabolism, might promote cancer cell viability through several mechanisms similar to those of cyclooxygenase-2 (COX-2). We found that not only COX-2 expression, but also the expression of 5-LO and CYP2J2 is up-regulated in head and neck squamous cell carcinoma (HNSCC) cell lines. From these observations, we hypothesized that AA metabolism by 5-LO and/or CYP2J2 may lower the efficacy of anti-cancer effect by COX-2 inhibition.Although COX-2 was highly expressed in all cell lines tested, COX-2-specific inhibition showed little growth-inhibitory effect in some cell lines. Inhibition of COX-2 resulted in increased production of LTB(4) and 14-15-DHET/EET, metabolites of 5-LO and CYP2J2, respectively. Combined knock-down of COX-2 and 5-LO or CYP2J2 by siRNA results in a decrease in cell proliferation and VEGF production. Furthermore, these results are dependent on 5-LO and CYP2J2 expression in cells.Therefore, combined inhibition of COX-2 and 5-LO or CYP2J2 may be one way to overcome low efficacy of single inhibition of COX-2 in cancer cells. In addition, combined therapies should be chosen based on the expression of members of other AA metabolism pathways.

Background: Whereas most studies have focused on euthanasia and physician-assisted suicide, few have dealt comprehensively with other critical interventions administered at the end of life. We surveyed cancer patients, family caregivers, oncologists and members of the general public to determine their attitudes toward such interventions. Methods: We administered a questionnaire to four groups about their attitudes toward five end-of-life interventions — withdrawal of futile life-sustaining treatment, active pain control, withholding of life-sustaining measures, active euthanasia and physician-assisted suicide. We performed multivariable analyses to compare attitudes and to identify sociodemographic characteristics associated with the attitudes. Results: A total of 3840 individuals — 1242 cancer patients, 1289 family caregivers and 303 oncologists from 17 hospitals, as well as 1006 members of the general Korean population — participated in the survey. A large majority in each of the groups supported withdrawal of futile life-sustaining treatment (87.1%–94.0%) and use of active pain control (89.0%–98.4%). A smaller majority (60.8%–76.0%) supported withholding of life-sustaining treatment. About 50% of those in the patient and general population groups supported active euthanasia or physician-assisted suicide, as compared with less than 40% of the family caregivers and less than 10% of the oncologists. Higher income was significantly associated with approval of the withdrawal of futile life-sustaining treatment and the practice of active pain control. Older age, male sex and having no religion were significantly associated with approval of withholding of life-sustaining measures. Older age, male sex, having no religion and lower education level were significantly associated with approval of active euthanasia and physician-assisted suicide. Interpretation: Although the various participant groups shared the same attitude toward futile and ameliorative end-of-life care (the withdrawal of futile life-sustaining treatment and the use of active pain control), oncologists had a more negative attitude than those in the other groups toward the active ending of life (euthanasia and physician-assisted suicide).

IntroductionThe purpose of this study was to analyze the clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase (ALK)-positive advanced pulmonary adenocarcinoma and to devise an effective screening strategy to identify such patients.MethodsWe screened advanced pulmonary adenocarcinoma patients to identify ALK-positive cases. The presence of ALK rearrangements was confirmed by fluorescence in situ hybridization.ResultsOf the 221 screened patients, 45 demonstrated ALK rearrangements, and these individuals were younger than the ALK-negative patients (p < 0.001). The proportion of never smokers and light smokers was found not to differ according to the ALK status (p = 0.537). Epidermal growth factor receptor (EGFR) mutations and ALK rearrangements were found to be mutually exclusive. Thyroid-transcription factor-1 (TTF-1) expression was observed in all ALK-positive tumors for which immunohistochemistry data were available. The objective response rate and progression-free survival to first-line platinum-based chemotherapy showed no significant differences between ALK-positive and ALK-negative patients. On the other hand, no patient with ALK-positive tumors achieved objective tumor responses to EGFR tyrosine kinase inhibitors (TKIs). ALK rearrangements were not found among individuals who had EGFR mutations, an objective response to a previous EGFR TKI treatment or TTF-1-negative tumors.ConclusionThe clinical outcomes of platinum-based chemotherapy were found not to differ according to the ALK status. Both smokers and never/light smokers should be candidates for ALK screening. We suggest that the exclusion of patients with activating EGFR mutations, an objective response to previous EGFR TKIs, or TTF-1-negative tumors from ALK screening could be an effective enrichment strategy for ALK-positive cases.

Therapeutic plasma exchange (TPE) has been used for the treatment of patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). We report the 10-year treatment results along with the risk factors analyses.Retrospective analyses were performed on patients who were treated with TPE for TTP-HUS.Fifty-two patients were included. Secondary causes were identified in 38 patients (73·1%). The others were classified as idiopathic. After a median five sessions of TPE, 26 patients (50·0%) achieved remission. Remission rate in patients with idiopathic and secondary TTP-HUS was 71·4 and 42·1%, respectively. Overall 30-day mortality rate was 34·6% and median overall survival was 5·2 months. Patients with hematopoietic stem cell transplantation-associated TTP-HUS did not respond and had poor overall survival. Males had a lower remission rate than females (P = 0·009).TPE was an effective treatment in patients with idiopathic TTP-HUS. Treatment results were various according to etiology and gender.

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPARγ protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPARγ ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPARγ ligands may have applications for the treatment of ovarian cancer.

Objective: The purpose of our study was to define the prognostic impact of increased copies of epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma patients receiving adjuvant chemotherapy after surgery. Methods: The study included 95 adenocarcinoma patients who received curative resection for non-small cell lung cancer. Patients received adjuvant chemotherapy composed of paclitaxel and carboplatin. We performed fluorescent in situ hybridization on tissue microarray in duplicate to detect EGFR copy number change. Results: The EGFR fluorescent in situ hybridization result was available in 93 patients with a positive rate of 32.6%. EGFR copy number change did not correlate with age, gender or smoking history. However, EGFR copy number gain was related to high tumor standardized uptake value at diagnosis (P ¼ 0.042). An increase in EGFR copy number was a negative prognostic factor in terms of disease-free survival (median disease-free survival not reached versus 23.6 months, P ¼ 0.037) and overall survival (median overall survival 74.6 versus 43.5 months, P ¼ 0.032). An increase in EGFR copy number was independently related to short disease-free survival in multivariate analysis (hazard ratio 2.039, P ¼ 0.025). Conclusions: EGFR copy number gain is associated with aggressive tumor biology and is a poor prognostic factor for tumor relapse in resected lung adenocarcinoma patients receiving adjuvant chemotherapy of paclitaxel and carboplatin.

This study was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in patients with advanced pulmonary adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations and to explore the molecular factors affecting the efficacy of gefitinib. Tumor tissue, derived from either the original tumor or the metastatic or recurrent site was taken from chemo-naïve pts with advanced (stage IIIB, IV, and recurrent) pulmonary adenocarcinoma. Tumor genomic DNA underwent direct sequencing for EGFR exons 18, 19, 20, and 21. Patients with EGFR mutations received 250 mg of gefitinib daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and tolerability. Out of 147 screened patients, 45 pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (29 pts, 64%) and L858R point mutation in exon 21 (15 pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR was 53.3% (95% CI, 38.6-67.9) and disease control rate (DCR) including stable disease was 86.7%. The median progression free survival (PFS) was 398 days and the median overall survival (OS) was 819 days. Treatment was well tolerated. Grade 3/4 adverse events (AEs) were reported by 6 patients and treatment-related Grade 3 AEs by 3 patients. There were no treatment-related Grade 4 AEs. Exploratory subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in patients with exon 19 deletions than those with L858R (62.1% vs 33.3%; P=0.0705 and 96.6% vs 66.7%; P=0.0062, respectively). All 4 patients with progressive disease had a L858R mutation. No secondary resistant mutations such as T790M mutation or insertions in exon 20 were found in those patients. In addition, OS was significantly better in patients with exon 19 deletions than those with L858R (24-month OS rate was 72.1% vs 32.0%, P=0.0148). Gefitinib as the first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations was effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in patients with the exon 19 deletion mutations (ClinicalTrials.gov number, NCT00344773).

Introduction: NKTCLs are rare, Epstein-Barr virus-associated distinct subtypes of peripheral T-cell lymphoma that are predominantly extranodal and of the nasal type, and are more common in Asia and Central/South America (Tse and Kwong. Blood 2013. 121:4997-5005). There is no standard therapy for R/R NKTCL and patient (pt) outcomes are very poor. Thus, there exists a highly unmet medical need for R/R NKTCL pts. Clinical data from NKTCL pts suggest CD38 as a new prognostic biomarker and novel target for therapy (Wang et al. Ann Hematol 2015. 94:1381-8). Daratumumab (DARA) is a human CD38 monoclonal antibody approved across all stages of multiple myeloma (MM). DARA has a direct on-tumor and immunomodulatory mechanism of action, and has been associated with significant treatment-related reduction of NK cells that does not impact drug efficacy or safety in MM (Casneuf et al. Blood Adv 2017. 1:2105-2114). DARA monotherapy induced a sustained remission in a single extranodal NKTCL pt (Hari et al. New Engl J Med 2016. 375:1501-2). A phase 2 study (NCT02927925) with Simon's 2-stage design was conducted to evaluate DARA monotherapy in pts with R/R NKTCL. Interim data from the stage 1 of the study are presented. Methods: Pts had histologically confirmed extranodal NKTCL nasal type, per WHO classification, that was refractory to or relapsed after ≥1 line of chemotherapy and were not candidates for other treatment modalities. Pts without fresh or archived tumor samples for biomarker determination were excluded. DARA 16 mg/kg was administered by IV infusion once weekly for 8 weeks, every other week for 16 weeks, and every 4 weeks thereafter until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) based on blinded independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Other endpoints included progression-free survival (PFS) and duration of response based on BICR, overall survival (OS), and safety. A protocol-specified futility analysis was planned after approximately 15 pts received ≥1 dose of DARA and had ≥1 post-baseline disease evaluation; futility criterion for ORR was defined as at most 1 of 15 pts with complete response (CR)/partial response (PR). Results: A total of 16 pts were treated in Korea (n = 13) and Taiwan (n = 3) at the time of clinical cut-off for the interim analysis (March 1, 2018). Median age was 58 years, and median time from initial NKTCL diagnosis was 35.9 months. Most pts had CD38 expression values ≥50% (n = 9). The median number of lines of prior therapy was 2 (range: 1-6), and 13 pts received prior radiotherapy. Median number of DARA cycles received was 2 (range: 1-11). At clinical cut-off, 81% of pts discontinued treatment (disease progression [56%], physician decision [13%], pt withdrawal [13%]). At a median follow-up of 3.1 months, 14 pts were response evaluable. ORR based on BICR was 35.7% (Table 1). Response rates were slightly higher for pts who received The most common (>20%) all-grade treatment-emergent adverse events (TEAEs) are summarized in Table 2. Nine (56%) pts had grade 3/4 TEAEs; neutropenia, thrombocytopenia, and hypotension were most common (19% each). No pt discontinued treatment due to TEAEs. Infusion-related reactions (IRRs) occurred in 69% of pts, all during the first infusion, and all pts recovered and IRRs were resolved on the same day. Three (19%) pts died within 30 days of last treatment dose, 2 of which were due to adverse events (both pneumonia) unrelated to DARA and 1 due to progressive disease. There was no clear association between CD38 expression and DARA response. NK cell reductions in peripheral blood were observed in all pts after 1 cycle of DARA. Conclusions: DARA 16 mg/kg was well tolerated with no new or unexpected safety signals and no treatment discontinuations due to TEAEs. DARA demonstrated a promising response rate (ORR: 35.7%) in pts with R/R NKTCL. The interim results did not meet pre-specified futility criteria in this poor prognosis pt population, and stage 2 of the study is ongoing. Disclosures Kim: Takeda: Research Funding; Roche: Honoraria, Research Funding; Merck: Research Funding; Celgene: Research Funding; J&J: Research Funding; Novartis: Research Funding; Mundipharma: Research Funding; Kyowa-Kirin: Research Funding; Eisai: Honoraria, Research Funding; Celltrion: Honoraria, Research Funding. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Gao:Janssen: Employment. Zhang:Janssen: Employment. Qi:Janssen Research & Development, LLC: Employment. Kwong:Bayer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

The objective of this study was to evaluate cost-reduction efficacy of a palliative care unit (PCU) by analyzing medical expenses of terminal cancer patients.Hospital bills and medical records of 656 patients who died of cancer from January to December 2007 at one university hospital in Seoul were analyzed.Of the total 656 patients, 126 died in the PCU. Compared to non-PCU patients, PCU patients were more likely to permit do-not-resuscitate (DNR), visit the emergency room (ER), and receive palliative chemotherapy (P0.001, P = 0.045, P = 0.002). The non-PCU patients were admitted to the intensive care unit (ICU), used a ventilator, and received hemodialysis more often (P0.001, P0.001, P0.001). Total medical cost per all patients within 6 months of death averaged $27,863. There was a significant difference in medical costs starting at 2 months before death between PCU and non-PCU patients. The medical cost of the PCU group was 32.8% lower 1 month before death and 33.0% lower 2 months before death than the non-PCU group (P0.001, P0.001). Patients using PCU services, those with solid cancers, and those with less than a high school education paid lower medical expenses (P0.05)Cost savings of the PCU were verified. It was also determined that specific factors were tied to increased medical expenses during the last 6 months of life. If these parameters are controlled properly, additional cost savings, associated with palliative care could be realized.

It is well known that tumor-surrounding stromal tissues support tumor development through secreting soluble factors such as various cytokines, chemokines, and growth factors. It has also been suggested that tumor-associated fibroblast and immune cells have a high expression of cyclooxygenase-2 (COX-2) and produce and secrete several prostaglandins (PGs) to adjacent cancer tissues. From these findings, we assumed that COX-2 inhibition might have an anticancer effect on cancer cells even without COX-2 expression in COX-2-dependent mechanisms through blocking the effect of stroma-derived PGs. Here, because of the complex involvement of various factors in vivo, we investigated this possibility with an in vivo-mimicking model using a Transwell system. To test our hypothesis, we used COX-2-transfected cell lines as stromal cells in our model. When we cocultured cancer cells (LS174T cells without COX-2 expression) with COX-2-high stromal cells in the Transwell membrane system, we observed that the proliferation of cancer cells was promoted and vascular endothelial growth factor synthesis was up-regulated significantly. These effects were blocked completely by COX-2 inhibitors and phosphoinositide-3-kinase inhibitors and partially by the PG E(2) receptor 4 antagonist. Even if some cancer cells did not express COX-2, they were found to have expression of PG receptors and PG-related downstream signaling molecules associated with cell viability. Our observation suggests that these cells can be influenced by PGs derived from stromal tissues. These findings also suggest that COX-2 inhibitors can be used to control the interaction between cancer and surrounding stromal tissues and suppress the proliferation of cancer cells regardless of the expression of COX-2 in cancer cells.

Background: Although EGFR exon 20 insertion mutation is the third most common among EGFR-mutant NSCLC, this mutation has not been well studied and the first-generation EGFR TKIs are ineffective. In addition, the efficacy of the third-generation EGFR TKIs is controversial. Methods: Various EGFR exon 20 insertion mutation models were developed using Ba/F3 system as follows: C-helix (n=1, A763_Y764insFQEA) and loop following C-helix (n=7). In addition, SNU-3173 cell line was derived from NSCLC patient with EGFR exon 20 insertion mutation. Cell viability assays were performed using EGFR TKIs (gefitinib, erlotinib, dacomitinib, afatinib, rociletinib, olmutinib, nazartinib, and osimertinib). Immunoblotting was performed to evaluate the downstream signals of EGFR pathway. Additionally, the docking homology models of EGFR exon 20 insertion mutations with osimertinib were developed with SWISS-Model and SwissDock for estimation of the structural appropriateness. Results: Cell viability assay showed that EGFR exon 20 insertion mutants are resistant to the first-generation EGFR TKIs, except for A763_Y764insFQEA mutant Ba/F3 cells. IC50 values of second-generation EGFR TKIs are five- to hundreds-folds lower than gefitinib and erlotinib. Dacomitinib and afatinib have good efficacy for the most of them, and regulated down signaling pathways. The third-generation TKIs showed moderate efficacy against EGFR exon 20 insertion mutants. Overall, osimertinib has the most successful inhibition of EGFR exon 20 insertion mutants (IC50 values for C-helix and loop following C-helix mutants for afatinib, Conclusions: Osimertinib showed an outstanding effectiveness against various EGFR exon 20 insertion mutations. In addition, docking simulation of in silico homology models corresponded with the in vitro results. Consequently, osimertinib is effective against EGFR exon 20 insertion mutant models. Citation Format: Yusoo Lee, Tae Min Kim, Dong-Wan Kim, Yong-Oon Ahn, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dae Seog Heo. Osimertinib (AZD9291) is sensitive and bound with affinity to EGFR exon 20 insertion mutant models [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B27.

Background: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. Methods: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells. Results: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P=0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P=0.078), CD8+ (P=0.055), FOXP3+ (P=0.016), and PD-1+ (P=0.016) TILs. Conclusions: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM. Citation Format: Ryul Kim, Bhumsuk Keam, Sehui Kim, Miso Kim, Se Hyun Kim, Jin Wook Kim, Yu Jung Kim, Tae Min Kim, Yoon Kyung Jeon, Dong-Wan Kim, Doo Hyun Chung, Jong Seok Lee, Dae Seog Heo. Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: Therapeutic implications for immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5201.

Background : Clinical practice guidelines are an increasingly familiar part of clinical practice. Moreover, rigorously developed evidence based guidelines has been widely used. However, in Korea, some of published documents as clinical practice guidelines have shown considerable disparity in structure, contents and quality. This is mainly because there is no consensus on the definition and quality standard of clinical practice guidelines. The purpose of this study was to draw consensus on the definition and the quality standard about clinical practice guidelines. Method : We developed a questionnaire about the definition of clinical practice guidelines with inclusion criteria(23 items) and the quality standard(30 items). We selected 9 experts who had prior experience in developing and implementing guidelines. Rating methods for appropriateness of items were adopted from the RAND method. Consensus was drawn in three rounds. Results : Of the 47 items agreed, 40 items were determined to be appropriate. Clinical practice guidelines were defined as "scientifically and systematically developed statements to assist practitioners and patients on making decisions about appropriate health care for specific clinical circumstances." Narrative reviews, systematic reviews or health technology assessment without recommendations, translation of foreign guidelines, guidelines for patients only and training manuals were not considered as clinical practice guidelines. For the quality standard of clinical practice guidelines, 27 items were deemed necessary. Conclusions : The consensus on the definition with inclusion criteria and the quality standard of clinical practice guidelines carries an important meaning as the first attempt to draw a general agreement in our society. The unique achievement of the consensus reflects the current status of clinical practice guidelines that there has been a high tendency to adapt foreign guidelines. We hope efforts of this kind will continue to bring improvement in clinical practice guidelines.

7570Background: Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity recently approved in the US for treatment of relapsed follicul...

8575Background: Patients with platinum refractory extensive disease (ED) small cell lung cancer (SCLC) have a poor prognosis and a little progress have been made. We aimed to investigate the effica...

Background We analyzed the significance of class III beta-tubulin (TUBB3) expression in curatively resected non-small cell lung cancer as a prognostic marker along with previously reported excision repair cross complementation group 1 (ERCC1). Methods One hundred and thirty-six consecutive patients were included in this retrospective study. Patients who received adjuvant chemotherapy were excluded. We used immunohistochemistry to evaluate TUBB3 and ERCC1 expression on tissue microarray in duplicate. Semiquantitative H score was used for the scoring of tumor staining. Results Sixty percent of patients had stage I disease, 17% stage II, 18% stage IIIA, and 5% stage IIIB. TUBB3 H score showed bimodal distribution with the minimum at the value of 4, which was used as a cutoff value for determination of TUBB3 positivity. TUBB3 was expressed in 60 patients (44%). Patients with a positive TUBB3 expression survived shorter than did the patients with a negative expression (5-year overall survival [OS] rate was 40% versus 61%; p = 0.005/5-year disease-free survival rate was 34% versus 55%; p = 0.024). ERCC1 expression showed tendency for prolonged OS without reaching statistical significance. A multivariate analysis that incorporated covariates including TUBB3 expression, age, stage, EGFR mutation status, histology, and ERCC1 expression showed that TUBB3 was an independent unfavorable prognostic factor for OS (hazard ratio 2.083; p = 0.008) and relapse free survival (hazard ratio 1.978; p = 0.020). Conclusions TUBB3 expression is an independent unfavorable prognostic marker in patients with curatively resected non-small cell lung cancer who did not receive adjuvant chemotherapy.

Intratumoral heterogeneity has been suggested to be an important resistance mechanism leading to treatment failure. We hypothesized that radiologic images could be an alternative method for identification of tumor heterogeneity. We tested heterogeneity textural parameters on pretreatment FDG-PET/CT in order to assess the predictive value of target therapy. Recurred or metastatic non-small cell lung cancer (NSCLC) subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory data set (n = 161) and a validation data set (n = 21) were evaluated, and eight parameters were selected for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and the predictive value was calculated using Harrell's C-index. Univariate analysis revealed that all eight parameters showed an increased hazard ratio (HR) for progression-free survival (PFS). The highest HR was 6.41 (P

To overcome the low efficiency of gene therapy, we combined a conditionally replicating adenovirus (CRAd) and an adenoviral vector with a therapeutic gene. CRAd has an oncolytic activity in cancer cells with abnormal Rb activity and helps the replication of therapeutic genes incorporated in the E1-deleted adenovirus. We investigated the anticancer effect of a combination of CRAd and adenovirus carrying tumor necrosis factor-related apoptosis inducing ligand (ad-TRAIL). We expected to see increased gene expression in cancer cells as well as an antitumor effect. With the combined application of CRAd and ad-luciferase in head and neck cancer cell lines, we observed considerably increased luciferase activity that was 10- to 50-fold greater than with ad-luciferase alone. The combination of CRAd and ad-TRAIL showed significant suppression of growth in cell lines and increased the sub-G1 portion of cells 30-fold compared to any single treatment. The expression of TRAIL was highly amplified by the combined treatment and was accompanied by expression of molecules related to apoptosis. In a xenograft animal model, mice treated with CRAd and ad-TRAIL showed complete regression of established tumors, whereas mice treated with CRAd or ad-TRAIL alone did not. In conclusion, this combined strategy using CRAd and adenovirus carrying a therapeutic gene increased the gene transfer rate and enhanced antitumor effects. We expect that this combination strategy could be extended to a multitarget cancer gene therapy by combining multiple adenoviruses and CRAd. (Cancer Sci 2009)

Objectives Nivolumab is used at 3 mg/kg or fixed doses of 240 mg every 2 weeks. There was no dose–response/toxicity relationship of nivolumab. This study evaluated the efficacy of low-dose nivolumab as an alternative to the financial toxicity of standard-dose nivolumab in treatment of non-small cell lung cancer (NSCLC). Methods Outcomes of patients with NSCLC treated with nivolumab as a routine practice at two tertiary hospitals in Korea were retrospectively analysed. Patients who could not afford standard nivolumab treatment received low-dose nivolumab (20 or 100 mg fixed dose every 3 weeks). Others received standard dose of 3 mg/kg every 2 weeks. Progression-free survival (PFS) and overall survival (OS) were measured and compared between low-dose and standard-dose groups in overall and stratified analyses according to programmed death-ligand 1 (PD-L1) status. Results Among the 47 patients with NSCLC, 18 received low-dose nivolumab. PD-L1 positivity was observed in 13 (27.7%) patients and did not differ between the groups. During 5.2 months of follow-up, the objective response rate was 13.8% in the standard-dose group and 16.7% in the low-dose group (p=0.788). Dosing of nivolumab or PD-L1 expression did not significantly affect PFS or OS. Conclusion Low-dose nivolumab can be effective in NSCLC and is worth considering as an alternative option to reducing financial toxicity. The efficacy of low-dose nivolumab requires study.

Background: Extranodal natural killer/T-cell lymphoma (NKTCL) is a clinically heterogeneous disease with a poor prognosis, requiring risk-stratified management in affected patients. Recently, tumor microenvironment including regulatory T cells (Tregs) has been implicated as a prognostic marker in certain types of lymphoma. Patients and methods: We collected 64 NKTCL cases and numerically quantified the amount of tumor-infiltrating FOXP3-positive Tregs by automated slide scanning and image analysis program after immunohistochemical staining using anti-FOXP3 antibody. Results: Patients were able to be classified into two end groups by their level of Tregs. Twenty-eight (44%) patients had Tregs

Our aim was to evaluate the feasibility and efficacy of intensity-modulated radiation therapy (IMRT) with simultaneous integrated boost (SIB) technique following neoadjuvant chemotherapy for locoregionally advanced nasopharyngeal cancer (NPC).Between April 2004 and December 2006, 25 patients with stage IIB to IVB NPC underwent 3 cycles of neoadjuvant chemotherapy followed by IMRT using SIB technique. Neoadjuvant chemotherapeutic regimens were 5-fluorouracil and cisplatin in 11 patients; docetaxel, 5-fluorouracil, and cisplatin in 8; and paclitaxel and cisplatin in 6. Dose prescription of IMRT was as follows: 67.5 Gy at 2.25 Gy/fraction to postchemotherapy gross tumor, 54 to 60 Gy at 1.8 to 2 Gy/fraction to subclinical disease, and 48 Gy at 1.6 Gy/fraction to elective neck. Seventeen patients received weekly cisplatin during the course of radiation therapy as well.With a median follow-up of 29 months for survivors (range, 14-39), the 3-year local progression-free, regional progression-free, and distant metastasis-free survival rates were 89.6%, 87.2%, and 80.4%, respectively. Treatment was well tolerated despite the grade 3 mucositis (16%) and/or pharyngitis (16%). With follow-up, the frequency of xerostomia decreased. At 3 months after IMRT, the proportions of Radiation Therapy Oncology Group grades 0, 1, and 2 xerostomia were 13%, 38%, and 50%, respectively. At 24 months, the corresponding figures were 36%, 46%, and 18%, respectively.IMRT with SIB technique for locoregionally advanced NPC was feasible and effective regarding locoregional control and development of xerostomia, even after neoadjuvant chemotherapy. Definition of gross tumor volume by postchemotherapy extent of disease was also feasible.

Extranodal NK/T-cell lymphoma (NTCL) is characterized by clinical heterogeneity based on clinical prognostic factors and survival outcome. NTCL subsets are classified as upper aerodigestive tract (UAT) NTCL or non-UAT NTCL; non-UAT has pathologic similarity to UAT-NTCL but is a clinically distinct subtype. Due to the clinical heterogeneity of NTCL, optimal treatment modalities and prognostic factors have been difficult to determine. Ann Arbor staging for lymphomas and the International Prognostic Index (IPI) have been used to predict prognosis for UAT-NTCL; however, local tumor invasiveness (bony invasion or perforation or invasion of the overlying skin) is the most significant factor for poor outcomes in localized UAT-NTCL. Thus, a new staging system is proposed: limited disease (stage I/II UAT-NTCL without local tumor invasiveness) and extensive disease (stage I/II with local invasiveness or stage III/IV disease of UAT NTCL, and non-UAT NTCL) based on treatment outcomes. NTCL is resistant to anthracycline-based chemotherapy, whereas non-anthracycline combination chemotherapy (such as ifosfamide, methotrexate, etoposide, and prednisolone) has an activity against NTCL as either a front-line or as a second-line treatment. The effectiveness of radiotherapy is evident in limited disease, but questionable in extensive disease.

The activity of erlotinib after gefitinib failure in non-small cell lung cancer patients with all four favorable clinical factors including female, never smoker, Asian, and adenocarcinoma histology for tyrosine kinase inhibitors (TKIs) is not well known. Treatment efficacy of erlotinib (150 mg daily) after progression on gefitinib (250 mg daily) was analyzed in patients exhibiting the four clinically favorable factors. Sixteen consecutive female, never smoker, Korean (Asian), adenocarcinoma patients who received erlotinib after gefitinib failure were analyzed. The disease control rate for gefitinib was 68.8% (95% CI, 0.44–0.86) while the disease control rate for erlotinib following gefitinib failure was 25.0% (95% CI, 0.10–0.50) comprised of one partial response and three stable disease patients. The median progression free survival was 6.3 months for gefitinib treatment and 1.7 months for erlotinib treatment following gefitinib failure. The efficacy of erlotinib after progression on gefitinib is unsatisfactory in patients with four favorable clinical factors for TKIs. Novel treatment approaches such as the use of irreversible TKIs or anti-cMET agents for those patients are warranted.

Despite recent progress in palliative chemotherapy for advanced non-small cell lung cancer (NSCLC), the prognosis is still poor. Aside from multiple lines of chemotherapy, many patients need palliative procedures due to disease-related events. The patterns of events requiring palliative procedures and their impact on the clinical course have not been well described.We evaluated 162 patients who were diagnosed with stage IIIB (with malignant effusion) or IV NSCLC at Seoul National University Hospital in 2005. The patterns of disease-related events requiring palliative procedures, the palliative procedures given, and the clinical outcomes were retrospectively analyzed.Of the 162 patients, 107 were male (66%) and 55 were female (34%) with a median age of 61 years (range 31-90). Among these patients, 108 patients (66%) received palliative procedures due to disease-related events. Forty-nine patients (30%) needed a palliative procedure at the time of diagnosis, and 59 patients (36%) required palliative procedure later during the course of their treatment. The events requiring palliative procedures were thoracic events (malignant effusion or severe pneumonia requiring intensive care unit care not related to treatment) in 32 (30%), CNS events (brain metastasis or leptomeningeal metastasis) in 37 (34%), skeletal events (bone metastasis requiring radiation, spinal cord compression, hypercalcemia) in 29 (27%), and other events in 10 (9%). The patients who had events at the time of diagnosis showed comparable overall survival to the patients without events at the time of diagnosis (14.6 months vs. 13.3 months, p=0.65). The patients with later events during their course of treatment had a short median survival after the event requiring palliative procedures (median 2.7 months, 95% CI 2.19-3.21).A considerable proportion of patients with advanced NSCLC receive palliative procedures apart from chemotherapy. These interventions should be taken into consideration for comprehensive cancer care and timely cooperation with palliative care team.

The aim of this study was to analyse the impact of epidermal growth factor receptor (EGFR), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), aurora kinase (ARK) A/B, and excision repair cross-complementing gene 1 (ERCC1) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III–IV (M0) who subsequently treated with adjuvant FP chemotherapy. TS, DPD, TP, ERCC1, and ARK proteins were measured by immunohistochemistry (IHC). EGFR expression was investigated using a standardized IHC with the EGFR PharmDx assay. Amplification of EGFR gene was analysed using fluorescent in situ hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and EGFR expression were significant prognostic factors for overall survival. Patients with higher EGFR expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282–0.791, P=0.005). Low EGFR expression might be a predictive marker for relapse in curative resected stage III–IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.

Although several studies have described the prognostic implication of bone marrow (BM) involvement (BMI) in lymphoma, studies focused on BM-involved diffuse large B-cell lymphoma (DLBCL) are very rare and small-sized. This study was performed to examine the prognostic impact of morphologic findings of BMI by lymphoma and risk factors for central nervous system (CNS) relapse in BM-involved DLBCL. Between 1993 and 2005, 675 patients were diagnosed with DLBCL, and 88 patients who had BMI at initial diagnosis were eligible for this study. The median overall survival (OS) and failure-free survival (FFS) of 88 patients were 36.6 and 20.1 months, respectively. When three variables from BM morphologic findings (the pattern of BM infiltration, extent of BMI by lymphoma, and percentage of large cells in the infiltrate) were simultaneously included into multivariate model, the increased extent of BMI by lymphoma (or =10%) in BM area was the only negative prognostic factor, independent of the International Prognostic Index (IPI). Patients with both lower IPI scores and less extent of BMI showed an excellent prognosis with chemotherapy alone (5-year OS and FFS rates, 80% and 69%). However, morphologic BM features were not independent predictive factors for CNS recurrences. An increased lactate dehydrogenase (LDH) level at initial diagnosis was the only independent predictive factor for CNS relapse. Further efforts should be directed toward finding optimal treatment modalities based on the IPI and the extent of BMI by lymphoma. CNS prophylaxis may be considered only in patients with initial elevated LDH levels.

Background: Many patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy. Patients and methods: This was single-institutional, phase II study. The primary end point was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Patients with relapsed or refractory NTCL were eligible. They received the chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone and it was repeated every 3 weeks. Results: Thirty-two patients were enrolled and 15 patients had achieved partial remission (PR) or complete remission (CR) after the front-line chemotherapy. The International Prognostic Index scores were 0–1 in thirteen, 2 in five, 3 in five, and 4–5 in nine patients. Twelve and two patients achieved CR and PR, respectively. Median OS and TTF of all patients were 8.2 and 3.7 months, respectively. Non-hematologic toxic effects were well tolerated, but grade 3/4 leukopenia occurred in 11.7% of all cycles. Four patients developed febrile neutropenia and one patient died due to pneumonia. Conclusions: This chemotherapy regimen was moderately effective for relapsed/refractory extranodal NTCL, nasal type. Toxic effects were moderate, but caution should be exercised to prevent severe infection.

The purpose of this study was to demonstrate the prevalence of and risk factors for pneumonia after cytotoxic chemotherapy in advanced lung cancer patients. We retrospectively reviewed 193 out of 215 advanced lung cancer patients who were consecutively treated with cytotoxic chemotherapy at Seoul National University Hospital in 2005. The mean age was 61 years (range, 31-85 years). A total of 41 patients (21%) had Eastern cooperative oncology group (ECOG) performance status 2-3. Among 135 patients with pulmonary function test (PFT), 34% (n=46) of patients demonstrated an obstructive pattern of lung function. Pneumonia occurred in a total of 10 patients (5%). Occurrence rate was significantly higher in older patients (>70 years) than in younger ones (13% vs. 4%, p=0.05), higher in patients with ECOG 2-3 compared with those with ECOG 0-1 (15% vs. 3%, p