Determinants of clinical outcomes of gastric cancer patients treated with neoadjuvant chemotherapy: a sub-analysis of the PRODIGY study.

BACKGROUND: In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment strategies for gastric cancer patients receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed. RESULTS: The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (P < 0.01). PFS and OS were also different according to the ypStage (P < 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (P < 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively. CONCLUSIONS: Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage.

Early diagnosis of Gaucher disease in Korean patients with unexplained splenomegaly: a multicenter observational study.

Background: Gaucher disease (GD) is an autosomal recessive disorder characterized by excessive accumulation of glucosylceramide in multiple organs. This study was performed to determine the detection rate of GD in a selected patient population with unexplained splenomegaly in Korea. Methods: This was a multicenter, observational study conducted at 18 sites in Korea between December 2016 and February 2020. Adult patients with unexplained splenomegaly were enrolled and tested for ß-glucosidase enzyme activity on dried blood spots (DBS) and in peripheral blood leukocytes. Mutation analysis was performed if the test was positive or indeterminate for the enzyme assay. The primary endpoint was the percentage of patients with GD in patients with unexplained splenomegaly. Results: A total of 352 patients were enrolled in this study (male patients, 199; mean age, 48.42 yr). Amongst them, 14.77% of patients had concomitant hepatomegaly. The most common sign related to GD was splenomegaly (100%), followed by thrombocytopenia (44.32%) and, anemia (40.91%). The ß-glucosidase activity assay on DBS and peripheral leukocytes showed abnormal results in sixteen and six patients, respectively. Eight patients were tested for the mutation, seven of whom were negative and one patient showed a positive mutation analysis result. One female patient who presented with splenomegaly and thrombocytopenia was diagnosed with type 1 GD. The detection rate of GD was 0.2841% (exact 95% CI, 0.0072‒1.5726). Conclusion: The detection rate of GD in probable high-risk patients in Korea was lower than expected. However, the role of hemato-oncologists is still important in the diagnosis of GD.

Dose Modification of Etoposide plus Platinum in Elderly Patients with Extensive-Disease Small-Cell Lung Cancer.

BACKGROUND: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. METHODS AND PATIENTS: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. RESULTS: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269-1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. CONCLUSIONS: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer.

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

The prevalence and clinical characteristics of restless legs syndrome in patients with iron deficiency anemia in Korea.

STUDY OBJECTIVES: While the prevalence and clinical characteristics of restless legs syndrome (RLS) are known to vary according to ethnicity, a detailed evaluation of this condition among patients with iron deficiency anemia (IDA) has not yet been reported in an Asian population. We investigated the prevalence and clinical characteristics of RLS in patients with IDA in Korea compared with age- and sex-matched patients diagnosed with idiopathic RLS. METHODS: This prospective single-center study was performed at a regional university hospital. Consecutive patients with IDA were enrolled over a 4-year period. Clinical interviews and laboratory tests were conducted at the first visit. RLS diagnosis was confirmed through face-to-face interviews. We randomly selected patients with idiopathic RLS without comorbid medical disorders from our sleep center dataset as control patients. The clinical characteristics of both groups were compared. RESULTS: We enrolled 124 patients with IDA. Fifty (40.3%) patients were diagnosed with RLS, with 82% exhibiting severe to very severe symptoms. Patients with IDA and RLS were older and reported more sleep deterioration than patients with IDA without RLS. Patients with IDA and RLS also had a more depressed mood and higher periodic limb movement index scores than patients with idiopathic RLS. CONCLUSIONS: The prevalence of RLS among patients with IDA in Korea was high, with the majority having severe to very severe symptoms. Patients with IDA and RLS had poorer sleep quality and more emotional problems than patients with IDA without RLS. Therefore, patients with IDA should be screened for RLS to prevent adverse effects on the quality of sleep and life.

Ventriculoperitoneal Shunt for CNS Metastasis in Breast Cancer: Clinical Outcomes Based on Intrinsic Subtype.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with a grave prognosis in breast cancer (BC) and can be controlled with a ventriculoperitoneal shunt (VPS). Information regarding LM and VPS based on intrinsic subtype is limited; thus, we investigated the clinical outcomes of BC treated with VPS. PATIENTS AND METHODS: The present retrospective study comprised 70 patients diagnosed with LM who received a VPS. The patients were divided into 4 groups based on BC subtype: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+, and triple negative BC (TNBC). RESULTS: The most common indications for VPS were uncontrolled intracranial pressure (57.1%) and uncontrolled headache (55.7%), which improved in 54 (77.1%) of 70 patients after VPS. The median overall survival (OS) after brain or LM and overall survival after VPS were 7.6 and 2.3 months, respectively. Anti-HER2 treatment was a significant prognostic factor for better OS after brain or LM based on multivariate analysis (hazard ratio, 0.15; 95% confidence interval, 0.04-0.57; P = .005), whereas TNBC was correlated with shorter OS after central nervous system metastasis (hazard ratio, 2.82; 95% confidence interval, 1.46-5.48; P = .002). CONCLUSIONS: There were significant differences in clinical outcome based on the intrinsic subtype of patients with BC with LM who received a VPS. Anti-HER2 treatment in patients with HER2+ BC was associated with better survival in patients with metastatic BC with VPS insertion compared with those without. Survival of metastatic BC with VPS remained poor, especially in the TNBC subgroup.

A retrospective analysis of etiology and outcomes of hemophagocytic lymphohistiocytosis in children and adults.

BACKGRUOUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe, life-threatening inflammatory condition if untreated. We aimed to investigate the etiologies, outcomes, and risk factors for death in children and adults with HLH. METHODS: The medical records of patients who met the HLH criteria of two regional university hospitals in Korea between January 2001 and December 2019 were retrospectively investigated. RESULTS: Sixty patients with HLH (35 children and 25 adults) were included. The median age at diagnosis was 7.0 years (range, 0.1-83 years), and the median follow-up duration was 8.5 months (range, 0-204 months). Four patients had primary HLH, 48 patients had secondary HLH (20 infection-associated, 18 neoplasm-associated, and 10 autoimmune-associated HLH), and eight patients had HLH of unknown cause. Infection was the most common cause in children (14/35, 40.0%), whereas neoplasia was the most common cause in adults (13/25, 52.0%). Twenty-eight patients were treated with HLH-2004/94 immunochemotherapy. The 5-year overall survival (OS) rate for all HLH patients was 59.9%. The 5-year OS rates for patients with primary, infection-associated, neoplasm-associated, autoimmune-associated, and unknown cause HLH were 25.0%, 85.0%, 26.7%, 87.5%, and 62.5%, respectively. Using multivariate analysis, neoplasm-induced HLH (p=0.001) and a platelet count <50×109/L (p=0.008) were identified as independent risk factors for poor prognosis in patients with HLH. CONCLUSION: Infection was the most common cause of HLH in children, while it was neoplasia in adults. The 5-year OS rate for all HLH patients was 59.9%. HLH caused by an underlying neoplasm or a low platelet count at the time of diagnosis were risk factors for poor prognosis.

Correction to: Comparison of the effects of adjuvant concurrent chemoradiotherapy and chemotherapy for resected biliary tract cancer.

An amendment to this paper has been published and can be accessed via the original article.

Comparison of the effects of adjuvant concurrent chemoradiotherapy and chemotherapy for resected biliary tract cancer.

BACKGROUND: Biliary tract cancers (BTC) have a poor prognosis even after curative resection because of frequent local and distant recurrences. Therefore, the importance of adjuvant therapy in BTC has been advocated to improve outcomes. However, the choice of adjuvant therapy is still controversial. The aim of this study was to compare the effects of adjuvant concurrent chemoradiotherapy (CCRT) and chemotherapy on resected BTC. METHODS: We analyzed 92 patients who had curatively resected BTC and had received adjuvant CCRT or chemotherapy from January 2000 to December 2017 at Keimyung University Dongsan Medical Center. RESULTS: Of the patients, 46 received adjuvant CCRT and 46 received adjuvant chemotherapy. The median recurrence-free survival (RFS) for the adjuvant CCRT and chemotherapy groups were 13.8 and 11.2 months (p = 0.014), respectively. The median overall survival (OS) for the adjuvant CCRT and chemotherapy groups were 30.1 and 26.0 months (p = 0.222), respectively. Adjuvant CCRT had significantly better RFS and numerically higher OS than did chemotherapy. For subgroups with no lymph node (LN) involvement (RFS p = 0.006, OS p = 0.420) or negative resection margins (RFS p = 0.042, OS p = 0.098), adjuvant CCRT led to significantly longer RFS and numerically higher OS than did chemotherapy. For multivariate analysis, the pattern of adjuvant treatment (chemotherapy vs. CCRT, p = 0.004, HR 2.351), histologic grade (poor vs. well, p = 0.023, HR 4.793), and LN involvement (p = 0.028, HR 1.912) were the significant prognostic factors for RFS. CONCLUSIONS: Our study demonstrated the superiority of adjuvant CCRT over chemotherapy for improving RFS in curatively resected BTC.

Clinical activity of fulvestrant in metastatic breast cancer previously treated with endocrine therapy and/or chemotherapy.

BACKGROUND/AIMS: We conducted a retrospective analysis of the clinical activity of fulvestrant in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with endocrine therapy and/or chemotherapy. METHODS: We reviewed the medical records of all patients with MBC treated at Samsung Medical Center between January 2009 and August 2016. Patients received fulvestrant 250 mg intramuscularly every 28 days (from January 2009 to November 2010) or 500 mg intramuscularly every 28 days (from December 2010 to August 2016). Tumor responses were assessed every 8 weeks and at the end of treatment, as well as when disease progression was suspected. RESULTS: A total of 84 patients were included in this study. A median of two previous endocrine treatments had been performed; 79% of the patients had received two or more endocrine treatments. Forty-five patients (54%) had been treated with chemotherapy for MBC before the fulvestrant treatment course. Visceral metastasis was found in 49 patients (58%). The estimated median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI], 3.4 to 5.5) and 32.5 months (95% CI, 17.6 to 47.4), respectively. The disease control rate was 40.5% (95% CI, 30.5 to 51.5); partial response was observed in 16% of the patients and stable disease was observed in 25% of the patients. The most frequently reported adverse reactions were mild-to-moderate grade myalgia (10.5% of the patients), injection site pain (7%), and fatigue (7%). Fulvestrant was generally well tolerated. CONCLUSION: Fulvestrant showed encouraging clinical activity and favorable feasibility in postmenopausal women with MBC who had been treated with multiple endocrine therapies and/or cytotoxic chemotherapies.

The prognostic factors influencing overall survival in uterine cervical cancer with brain metastasis.

BACKGROUND/AIMS: The occurrence of brain metastasis (BM) has increased due to improved overall survival (OS) in uterine cervical cancer. However, research about prognostic factors and therapeutic guidelines for BM in uterine cervical cancer remains scarce due to the rarity of BM in this type of cancer. The present study evaluated the clinical characteristics and prognostic factors influencing OS in patients with BM from uterine cervical cancer. METHODS: A total of 19 BM patients of uterine cervical cancer were analyzed retrospectively from January 1995 to December 2016. RESULTS: The median and mean OS of all patients was 9.6 and 15.4 months. Treatment (vs. palliative care, p < 0.001), fewer than three regimens of chemotherapy before BM (vs. ≥ 3, p < 0.013), and chemotherapy after BM (vs. absence, p < 0.001) significantly increased the OS time. The Karnofsky performance status ≥ 70 (vs. < 70, p = 0.213), single BM (vs. multiple BM, p = 0.157), and small cell carcinoma (vs. others, p = 0.351) had numerically higher OS than others. Dual therapy (vs. single therapy, p = 0.182; vs. no therapy, p = 0.076) were associated with a longer OS time, but the difference did not reach statistical significance. In addition, the graded prognostic assessment (GPA) appeared to be a better prognostic tool than the recursive partitioning analysis. CONCLUSION: The results of the present study suggest active multimodal treatment including neurosurgery, radiotherapy, and chemotherapy for BM of uterine cervical cancer with single BM, good performance status, histology of small cell carcinoma, and a better GPA.

Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01).

BACKGROUND: Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC. METHODS: DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2. RESULTS: The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were TP53 (151, 93.2%), KDR (104, 64.2%), and epidermal growth factor receptor (EGFR; 69, 42.6%). We also observed coexistence of EGFR and other oncogene (such as KRAS, PIC3CA, PTEN, and STK11) mutations. Given that 69.6% (48/69) of EGFR mutant patients were treated with EGFR tyrosine kinase inhibitors, EGFR mutant status had higher prognostic ability in this study. CONCLUSIONS: These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.

Isolated pachymeningeal metastasis from breast cancer: Clinical features and prognostic factors.

PURPOSE: To evaluate the clinical features and prognoses of patients with isolated pachymeningeal metastasis (IPM) from breast cancer. METHODS: We reviewed the medical records of all patients with metastatic breast cancer (MBC) treated from January 2009 to August 2016. Eligibility criteria included diagnosis of pachymeningeal metastasis based on brain magnetic resonance imaging and histologic diagnosis of primary breast cancer. We excluded patients with concomitant parenchymal or leptomeningeal metastases. RESULTS: Thirty-eight patients who matched our inclusion criteria were included in this study. The incidence of IPM in breast cancer was 1.5% of all patients with MBC. The molecular subtype distribution was: triple negative, 29.0%; ER+/HER2-, 44.7%; ER+/HER2+, 18.4%; and ER-/HER2+, 7.9%. All isolated pachymeningeal involvement resulted from the direct extension of skull metastases. The median time to IPM from systemic metastasis was 28.6 (95% CI: 23.6-33.6) months. The median time to IPM from skull metastasis was 5.2 (95% CI: 0-10.9) months. The median overall survival (OS) from IPM was 4.0 (95% CI: 2.5-5.5) months. In patients who received chemotherapy the OS was longer than for those who received radiotherapy or supportive care only [median OS 8.9 (95% CI: 0.0-18.4), 2.8 (95% CI: 0.5-5.0), and 0.8 (95% CI: 0.6-1.1) months, respectively (p = 0.006)]. Multivariate analysis revealed that good performance status and chemotherapy were associated with better survival outcomes. CONCLUSION: Stratified evaluation is required for patients with skull metastasis from breast cancer, as pachymeningeal involvement can develop and be associated with unsuspected outcomes.

Comparison of RECIST to immune-related response criteria in patients with non-small cell lung cancer treated with immune-checkpoint inhibitors.

PURPOSE: Given that immune-related response in non-small cell lung cancer (NSCLC) has not been well evaluated, we assessed tumor response using the response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related response criteria (irRC) to identify atypical responses in patients with advanced NSCLC treated with immunotherapeutic agents. METHODS: Patients received immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed platinum-based chemotherapy. Tumor response was assessed according to both RECIST v1.1 and irRC. RESULTS: Responses by 41 patients were analyzed. The overall response rate (ORR) was 29.2% (95% CI 17.6-44.5) assessed by RECIST v1.1 and 34.1% (95% CI 21.6-49.4) by irRC, showing similar results from the two methods (p = 0.923). Two patients (4.9%) were defined as having progressive disease as assessed by RECIST but not by irRC. The patients eventually experienced tumor regression, suggesting delayed pseudoprogression. For all patients, the median PFS was 5.1 months (95% CI 3.4-6.7) and OS was 18.3 months (95% CI 6.7-29.8). In multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer PFS. CONCLUSION: Our study found that pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC.

The Clinical Impact of c-MET Over-Expression in Advanced Biliary Tract Cancer (BTC).

Background: c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic biliary tract cancer (BTC). Methods: We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC. Results: The BTC subtype distribution (N=44) was as follows: intrahepatic cholangiocarcinoma (IHCC, n=7), extrahepatic cholangiocarcinoma (EHCC, n=25) and gallbladder cancer (GBC, n=12). Liver (52.3%) was the predominant metastatic site, followed by lymph nodes (36.4%) and bone (15.9%). Among the 44 patients analyzed for c-MET expression, 15 (34.1%) exhibited c-MET overexpression in tumor tissues. There was no significant difference in the prevalence of c-MET overexpression among primary sites in EHCC (7/25, 28.0%), IHCC (3/7, 42.9%), and GBC (5/12, 41.7%). There was also no significant correlation between specific clinicopathologic variables and c-MET expression. Comparing the tumor-response to GC according to c-MET expression (overexpression vs. non-overexpression), there was no significant difference in either RR or DCR (p=0.394 and p >0.999, respectively). The median PFS for all 44 patients was 9.00 months (95% CI, 7.5-10.5 months) and there was no significant difference for PFS between patients with c-MET overexpression and those without (p=0.917). The median OS was 14.4 months (95% CI, 11.9-16.9 months). There was no significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708). Conclusions: c-MET overexpression was detected in 34.1% of advanced BTC patients irrespective of tumor location. c-MET overexpression did not predict response to GC or survival. Further studies are needed to fully elucidate the value of c-MET overexpression as a novel biomarker in these patients.

Clinical significance of systemic chemotherapy after curative resection of metachronous pulmonary metastases from colorectal cancer.

PURPOSE: The use of systemic chemotherapy after resection remains controversial in patients with resectable metachronous pulmonary metastases from colorectal cancer (CRC). This retrospective study compared systemic chemotherapy with observation alone after resection of pulmonary metastases from CRC. METHODS: Between 2001 and 2015, 91 patients with metachronous pulmonary metastases underwent curative surgical resection at five centers. Patients with stage IV at diagnosis were excluded. Overall survival (OS) was defined as the time from pulmonary resection until death. The disease-free interval (DFI) was defined as the time from pulmonary resection until recurrence or death. RESULTS: Among the 91 patients, 63 were in the chemotherapy group, while 28 were in the observation alone group. The characteristics were similar between the two groups, except for the carcinoembryonic antigen level after pulmonary metastases and the use of adjuvant treatment after resection of the primary tumor. With a median follow-up duration of 46 months (11-126), the estimated 5-year DFI and OS rates were 32.8 and 61.4%, respectively. The chemotherapy following pulmonary resection was not significantly associated with the DFI (p = 0.416) and OS (p = 0.119). CONCLUSION: Systemic chemotherapy after pulmonary resection was not found to have a significant effect on survival.

IRF4/MUM1 expression is associated with poor survival outcomes in patients with peripheral T-cell lymphoma.

Background: Interferon regulatory factor 4 (IRF4)/multiple myeloma oncogene-1 (MUM1) is a member of the interferon regulatory factor family of transcriptional factors. Although IRF4/MUM1 expression is associated with aggressiveness of B-cell lymphoma and multiple myeloma, the prognostic value of IRF4/MUM1 expression in peripheral T-cell lymphoma (PTCL) is unclear. Methods: We analyzed a tissue array from 69 patients diagnosed with PTCL. The expression levels of IRF4/MUM1 and associated proteins such as MYC and Ikaros were analyzed by immunohistochemistry. Samples were classified by IRF4/MUM1 expression into a negative group (less than 5% of all tumor cells staining positive) or a positive group (≥ 5% of all tumor cells staining positive). Results: IRF4/MUM1 expression was observed in 33% of all patients (23/69), most frequently in patients with anaplastic large cell lymphoma (ALCL, 78%, 7/9). Patients with PTCL, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) showed expression rates of 33% (9/28) and 50% (4/8), respectively, whereas only 3 patients with extranodal NK/T-cell lymphoma (12%, 3/24) showed positive staining. The percentage of IRF4-positive tumor cells was significantly associated with the percentage of MYC-positive tumor cells (R: 0.410, P=0.013). Comparison of survival outcomes revealed that the IRF4/MUM1-positive group exhibited worse survival than the IRF4/MUM1-negative group; moreover, IRF4/MUM1-positive patients with a high level of MYC expression had the worst survival of all patients with nodal PTCL (PTCL-NOS, AITL, and ALCL; n=45) (P < 0.05).Conclusions: IRF4/MUM1 expression was associated with poor survival outcomes in PTCL, implying that this gene is a potential therapeutic target.

Analgesic effect of quetiapine in a mouse model of cancer-induced bone pain.

BACKGROUND/AIMS: Cancer-induced bone pain (CIBP) is one of the most common pains in patients with advanced neoplasms. Because of treatment-associated side effects, more than half of cancer patients are reported to have inadequate and undermanaged pain control. New mechanism-based therapies must be developed to reduce cancer pain. Quetiapine is a commonly used atypical antipsychotic drug. We report a study of the potential analgesic effects of quetiapine in a mouse model of CIBP and examine the mechanism of bone pain by analyzing the expression of various nociceptors. METHODS: Fifteen male C3H/HeN mice were arbitrarily divided into five groups: control and, CIBP with no treatment, quetiapine treatment, opioid treatment, and melatonin treatment. The mice were tested for mechanical hyperalgesia by determining the nociceptive hind paw withdrawal pressure threshold. Tissues from tibia were removed and subjected to quantitative and qualitative evaluations of transient receptor potential vanilloid 1 (TRPV1), TRPV4, acid-sensing ion channel 1 (ASIC1), ASIC2, and ASIC3 expression. RESULTS: Paw withdrawal pressure threshold was improved in the quetiapine treatment group compared with the CIBP group. Expression of TRPV1, TRPV4, ASIC1, ASIC2, and ASIC3 in the CIBP with quetiapine treatment group was significantly lower than that in the CIBP group. CONCLUSIONS: Our results suggest an analgesic effect of quetiapine in the CIBP animal model and implicate TRPV and ASICs as potential targets for cancer pain management.

Efficacy of BRAF Inhibitors in Asian Metastatic Melanoma Patients: Potential Implications of Genomic Sequencing in BRAF-Mutated Melanoma.

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mucosal subtypes, the efficacy of BRAF inhibitors for this subset of patients has not been extensively investigated. Acquired resistance generally appears 6 to 8 months after treatment with a BRAF inhibitor, and the mechanism of resistance is not well established. METHODS: We examined treatment outcomes for patients diagnosed with metastatic melanoma and treated with BRAF inhibitors at Samsung Medical Center between April 2013 and December 2015. We analyzed genomic alterations in selected patients using targeted sequencing. RESULTS: Twenty-seven patients with a median age of 49 years (range 23-82 years) with metastatic melanoma and treated with a BRAF inhibitor were identified. Of these patients, 19 (70.3%) had noncutaneous melanoma, including acral and mucosal melanoma. All patients had BRAFV600E mutations. The median progression-free survival of all patients was 9.2 months (95% confidence interval, 1.6-16.7), and the objective response rate was 78.9% in the mucosal/acral melanoma group and 75.0% in the cutaneous melanoma group. Three (11.1%) patients achieved complete response, and 19 (70.4%) showed a partial response. Targeted sequencing in five patients demonstrated NF1 mutations in three patients who did not respond to BRAF inhibitors. CONCLUSION: BRAF inhibitors were an effective therapeutic option for Korean patients with metastatic melanoma harboring a BRAF V600 mutation regardless of melanoma subtype (acral/mucosa versus cutaneous).