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The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution. Post-translational modifications regulate tumorigenesis and cancer therapy sensitivity. Here, the authors show that N-glycosylation defective Interleukin-6 (deNG-IL6) switches downstream signalling pathway from JAK-STAT3 to SRC-YAP axis and lung cancer cells secrete deNG-IL6 to promote metastasis and tyrosine kinase inhibitor resistance. [ABSTRACT FROM AUTHOR]

Background: In RELAY, a randomized, double-blind, phase III trial investigating the efficacy and safety of ramucirumab+erlotinib (RAM+ERL) or ERL+placebo (PBO) in patients with untreated, stage IV, epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), RAM+ERL demonstrated superior progression-free survival (PFS) versus PBO+ERL, with no new safety signals. Objective: The aim of this paper was to report efficacy and tolerability findings for the Taiwanese participants of RELAY. Patients and Methods: Patients were randomized 1:1 to RAM+ERL or ERL+PBO. Primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and tolerability. Data for the current analysis are reported descriptively. Results: In RELAY, 56 Taiwanese patients were enrolled; 26 received RAM+ERL, 30 received ERL+PBO. The demographic profile of the Taiwanese subgroup was consistent with that of the overall RELAY population. Median PFS for RAM+ERL/ERL+PBO, respectively, was 22.05 months/13.40 months (unstratified hazard ratio 0.4; 95% confidence interval 0.2–0.9); ORR was 92%/60%; median DoR was 18.2 months/12.7 months. All patients experienced one or more treatment-emergent adverse events (TEAEs); those most commonly reported were diarrhea and dermatitis acneiform (58% each) for RAM+ERL and diarrhea (70%) and paronychia (63%) for PBO+ERL. Grade ≥ 3 TEAEs were experienced by 62%/30% of RAM+ERL/PBO+ERL patients, respectively, and included dermatitis acneiform (19%/7%), hypertension (12%/7%), and pneumonia (12%/0%). Conclusions: PFS for the Taiwanese participants of RELAY receiving RAM+ERL versus ERL+PBO was consistent with that in the overall RELAY population. These results, together with no new safety signals and a manageable safety profile, may support first-line use of RAM+ERL in Taiwanese patients with untreated EGFR-mutant stage IV NSCLC. Trial Registration: www.clinicaltrials.gov, NCT02411448. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov; NCT03255083. [ABSTRACT FROM AUTHOR]

The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial–mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan–Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results. [ABSTRACT FROM AUTHOR]

Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician's discretion based on patient's request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in real-world clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies. Objective: To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC. Patients and Methods: NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS). Results: 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9–15.9), and median PFS was 12.1 months (95% CI 11.0–13.6). Median TTSP (13.8 months, 95% CI 12.7–16.1) and PFS (11.4 months, 95% CI 10.9–13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075). Conclusions: Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit. Trial Registration Number and Date of Registration: NCT01953913 (1 October 2013). [ABSTRACT FROM AUTHOR]

S-1, an oral pyrimidine fluoride-derived agent, is effective against various cancers. Sorafenib, an oral multikinase inhibitor, was found to prolong the survival of various cancers and enhance the cytotoxicity of chemotherapeutic agents. We conducted a phase I dose escalation study to determine dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors. Eligible patients received escalating doses (30, 35, and 40 mg/m2 bid) of S-1 Day 1 (D1)–D14 and continuous sorafenib 400 mg bid from cycle 1 D8 every 21 days in a standard 3 + 3 study design. Primary endpoint was MTD. Thirteen patients were enrolled between May 2010 and Feb 2012. DLT developed in two (one grade 3 erythema and one prolonged grade 2 hand-foot-skin reaction) of the 6 patients at 35 mg/m2 dose level. One pancreatic neuroendocrine tumor (pNET) patient achieved a durable partial response (27.9 months). Four colon cancer patients had stable disease and 3 of them had progression-free survival greater than 6 months. This study determined the recommended (MTD) S-1 dose of 30 mg/m2 bid for this regimen. This result warrants further phase II studies for advanced pNET and colon cancer to evaluate the efficacy of this combination. [ABSTRACT FROM AUTHOR]

Smoking tobacco is the major risk factor for developing lung cancer. However, most Han Chinese women with lung cancer are nonsmokers. Chinese cooking methods usually generate various carcinogens in fumes that may inevitably be inhaled by those who cook the food, most of whom are female. We investigated the associations of cooking habits and exposure to cooking fumes with lung cancer among non-smoking Han Chinese women. This study was conducted on 1,302 lung cancer cases and 1,302 matched healthy controls in Taiwan during 2002–2010. Two indices, "cooking time-years" and "fume extractor use ratio," were developed. The former was used to explore the relationship between cumulative exposure to cooking oil fumes and lung cancer; the latter was used to assess the impact of fume extractor use for different ratio-of-use groups. Using logistic models, we found a dose–response association between cooking fume exposure and lung cancer (odds ratios of 1, 1.63, 1.67, 2.14, and 3.17 across increasing levels of cooking time-years). However, long-term use of a fume extractor in cooking can reduce the risk of lung cancer by about 50%. Furthermore, we provide evidence that cooking habits, involving cooking methods and oil use, are associated with risk of lung cancer. [ABSTRACT FROM AUTHOR]

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers.Methods: In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics.Results: TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3-4 treatment-emergent adverse events occurred in 3.2-6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease.Conclusions: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued.Clinical Trial Registration Number: NCT02048488. [ABSTRACT FROM AUTHOR]

Purpose: This study attempted to compare changes in the Quality-of-Life (QoL) scores after three different first-line anti-cancer treatments for advanced non-small cell lung cancer (NSCLC) in a real-world clinical setting.Patients and Methods: From May 2011 to December 2013, we prospectively measured the QoL scores of patients with locally advanced or metastatic NSCLC using the World Health Organization Quality-of-Life-Brief (WHOQOL-BREF) questionnaire. Each QoL measurement was matched by age and sex with one healthy referent from the National Health Interview Survey. Dynamic changes in patients' QoL scores and major determinants were repeatedly assessed by construction of a mixed-effects model to adjust for possible confounders.Results: A total of 336 patients with 577 QoL measurements related to first-line anti-cancer treatments were enrolled. Performance status was the most important predictor of QoL scores in all domains after controlling for potential confounders. With age- and sex-matched healthy subjects as the reference, patients treated with gemcitabine + platinum showed significantly lower scores in multiple physical and psychological domain items in the WHOQOL-BREF. However, pemetrexed + platinum and gefitinib/erlotinib affected patients' QoL scores in 'energy/fatigue' and 'daily activities' with smaller magnitudes, and the scores appeared to improve after 3-4 months of treatment.Conclusions: Patients receiving gemcitabine + platinum as first-line anti-cancer treatment for advanced NSCLC experienced relatively poor QoL scores throughout treatment course. Studies to develop a real-time computerized system automatically updating the mixed-effects model for QoL to facilitate participatory clinical decision making by physicians, patients, and their families merit further research. [ABSTRACT FROM AUTHOR]

Purpose: Some patients experience nausea and/or vomiting (NV) before receipt of chemotherapy. Our objective was to evaluate the impact of prior chemotherapy-induced NV (CINV) on the incidence of anticipatory NV in later cycles.Methods: This multicenter, prospective non-interventional study enrolled chemotherapy-naïve adults scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC) for cancer in six Asia Pacific countries, excluding those with emesis within 24 h before cycle 1 chemotherapy. On day 1 before chemotherapy, patients answered four questions regarding emesis in the past 24 h, nausea, expectation of post-chemotherapy nausea, and anxiety in the past 24 h, the latter three scored from 0-10 (none-maximum). Multivariate logistic regression was used to assess the impact of prior CINV on anticipatory NV in cycles 2 and 3.Results: Five hundred ninety-eight patients (59% female) were evaluable in cycle 2 (49% HEC, 51% MEC). The incidence of anticipatory emesis was low before cycles 2 and 3 (1.5-2.3%). The incidence of clinically significant anticipatory nausea (score of ≥3) was 4.8, 7.9, and 8.3% before cycles 1, 2, and 3, respectively, with adjusted odds ratio (OR), 3.95 (95% confidence interval (CI), 2.23-7.00; p < 0.001) for patients with clinically significant nausea in prior cycles, compared with none. The adjusted ORs for other anticipatory NV endpoints ranged from 4.54-4.74 for patients with prior CINV. The occurrence of clinically significant anxiety in the prior cycle also resulted in a significantly increased likelihood of anticipatory nausea.Conclusions: These findings highlight the importance of preventing CINV in cycle 1 to reduce anticipatory NV in subsequent cycles. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the safety and efficacy of biweekly capecitabine in combination with oxaliplatin in previously untreated patients with locally advanced or metastatic gastric cancer. Methods: Patients received oral capecitabine 1,000 mg/m twice daily on days 1-10 plus oxaliplatin 85 mg/m as a 2-h intravenous infusion on day 1, every 2 weeks (XELOX). The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, overall survival, and toxicity. Results: From March 2007 to October 2010, 46 patients were enrolled in this phase II study. The median age was 64 years (range 32-85). A total of 391 (median 7.5, range 1-29) cycles were delivered. Among the 41 patients evaluable for tumor response, 9 showed partial response and 25 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 22 % (95 % CI 10-42 %) and 20 % (95 % CI 9-34 %), respectively. In the ITT analysis, the progression-free survival and overall survival were 5.6 months (95 % CI 4.1-6.3 months) and 8.0 months (95 % CI 6.3-10.1 months), respectively. The most common hematological toxicities were thrombocytopenia (35 %) and leucopenia (34 %), whereas the most common non-hematological toxicities were neuropathy (35 %), fatigue (33 %), diarrhea (27 %), vomiting (26 %), and hand-foot syndrome (25 %). Major grade 3-4 toxicities were anemia (11 %), diarrhea (9 %), and hand-foot syndrome (7 %). No patient died of treatment-related toxicities. Conclusions: Although the biweekly XELOX regimen failed its primary response rate endpoint, it showed modest efficacy and an acceptable safety profile in the treatment of advanced gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to determine whether the increment in the maximal standardized uptake value (SUVmax) of the primary lung tumour between the initial and delayed imaging by dual-phase F-FDG PET has prognostic value in patients with non-small-cell lung cancer (NSCLC). Methods: We reviewed the records of patients with NSCLC who underwent pretreatment dual-phase F-FDG PET/CT scans acquired at 1 h and 2 h after injection. The SUVmax increment (SUVinc) of the primary lung tumour was the 2-h SUVmax minus the 1-h SUVmax. Univariate and multivariate analyses were used to assess the prognostic significance of SUVinc, retention index, whole-body total metabolic tumour volume, whole-body total lesion glycolysis (TLGwb), 1-h SUVmax, 2-h SUVmax, gender, age, performance status, histological subtype, T stage, N stage and clinical stage. Results: The records of 187 consecutive patients were reviewed. The median follow-up time was 3.9 years. The estimated median progression-free survival (PFS) and overall survival (OS) were 1.3 years and 4.4 years, respectively. An SUVinc cut-off value of >1 had the best discriminative yield for PFS. The 3-year PFS and OS were 61.6 % and 87.8 % in patients with SUVinc ≤1 versus 21.1 % and 46.2 % in patients with SUVinc >1 (all P < 0.01). Using the forward stepwise multivariate Cox proportional hazards model, SUVinc, TLGwb, and clinical stage were significant factors for PFS (all P < 0.01). A subgroup analysis of 117 patients treated with surgery showed that SUVinc ( P = 0.02) and clinical stage ( P < 0.01) were significant prognostic factors for PFS. Furthermore, in stage I patients treated with surgery alone, SUVinc was the only significant prognostic factor (HR 28.07; 95 % CI 2.42 - 326.41). Conclusion: SUVinc determined from dual-phase F-FDG PET is a promising prognostic factor for NSCLC. It adds to the value of dual-phase F-FDG PET. [ABSTRACT FROM AUTHOR]

Objective: Lung cancers that occur in never smokers differ from those that occur in smokers. We performed an analysis of potential epidemiological risk factors for lung cancer among never smokers. Methods: In this hospital-based matched case-control study, all 1,540 matched case-control pairs were Han Chinese in Taiwan. The data on demographic characteristics, smoking habit, exposure to environmental tobacco smoke, medical history of lung diseases, family history of lung cancer, and female characteristics were collected from a structured questionnaire. A multiple conditional logistic regression was used to estimate odds ratios and 95 % confidence intervals after adjusting for possible confounders. Results: Overall, several epidemiological factors of lung cancer in never smokers were different between males and females. For the female population, subjects who were exposed to environmental tobacco smoke (OR = 1.39, 95 % CI = 1.17-1.67) with a history of pulmonary tuberculosis and with family history of lung cancer in first-degree relatives (OR = 2.44, 95 % CI = 1.79-3.32) had higher risk of lung cancer, while subjects with a history of hormone replacement therapy and using fume extractors for those who cooked were protective. For the male population, only subjects with family history of lung cancer in first-degree relatives (OR = 2.77, 95 % CI = 1.53-5.01) were significantly associated with risk of lung cancer. Conclusion: This study provides insights about the epidemiological factors of lung cancer in never smokers, adding to existing evidence that family history of lung cancer and environmental tobacco smoke may moderate lung cancer risk. [ABSTRACT FROM AUTHOR]

A missense mutation from arginine to tryptophan at residue 849 in the kinase domain of Tie2 (Tie2-R849W) is commonly identified in familial venous malformations. The mechanistic action of Tie2-R849W variant expression on angiogenic cascades including smooth muscle cell recruitment, however, remains elusive. To avoid confounding factors from endogenous Tie2 expression, Tie2-depleted endothelial cells (ECs) were used to study the effects of ectopic shRNA-resistant Tie2 variant expression, Tie2-WT* and Tie2-R849W*, on vascular cell proliferation, migration, tube formation, and smooth muscle cell (SMC) recruitment. Tie2-R849W* induced STAT1 phosphorylation at Tyr701. Tie2-R849W*-expressing cells had reduced ability to migrate and form tubes on Matrigel than their wildtype counterparts. STAT1 phosphorylation attenuated VEGF-A-induced STAT3 tyrosine phosphorylation in Tie2-R849W*-expressing HUVECs. The induced STAT1 activation also decreased VEGF-A-induced bFGF mRNA expression by competing with activated STAT3 for a direct binding to the consensus STAT-binding site at positions −997 to −989 bp from transcription start site in the bFGF promoter. Depleting STAT1 expression rescued the inability of Tie2-R849W expression to mediate angiogenesis. Moreover, bFGF neutralization or constitutive STAT1 activation, reminiscence of Tie2-R849W* expression, suppressed the smooth muscle cell recruiting ability of endothelial conditioned medium. This work reveals an anti-angiogenic role of STAT1 activation that acts in Tie2-R849W-expressing ECs to impair VEGF-A-mediated STAT3 signaling, bFGF production, and smooth muscle cell recruitment. A balancing activity of STAT1 and STAT3 may be important for Tie2-mediated vascular homeostasis. [ABSTRACT FROM AUTHOR]

Thromboembolism (TE) is a common complication in patients with multiple myeloma (MM). Immunomodulatory agents, e.g., thalidomide, have expanded the therapeutic options for treating myeloma; however, Western countries report a high incidence of thrombosis in thalidomide-treated MM patients who lack thromboprophylaxis. A Korean trial reported low TE incidence in thalidomide-treated myeloma patients (39 % were given aspirin prophylactically). We aimed to elucidate the TE frequency in MM patients in Taiwan who were treated with thalidomide without TE prophylaxis. We retrospectively collected the records of MM patients who had used thalidomide from a single institute between 2004 and 2010, combined these records with two other Taiwanese studies, and compared all three with the Korean trial. In the current Taiwanese series, five of 144 patients (3.5 %) developed TE as follows: three (2.1 %) were venous and two (1.3 %) were arterial. Only 6.1 % of the patients had undergone TE prophylaxis, which is less than in the Korean trial (38.9 %, p < 0.05). Of the patients in the relapsed/refractory cohort ( n = 114) who were given thalidomide alone, none (0/52) developed venous TE (VTE); however, two patients (2/35, 5.7 %) who were given thalidomide-dexamethasone as a salvage treatment developed VTE. In the thrombosis cohort, four patients (80 %) were treated with thalidomide plus dexamethasone. In conclusion, the frequency of thalidomide-related TE in myeloma patients without effective TE prophylaxis was low in Taiwan. In relapsed/refractory myeloma patients, the VTE frequency was slightly lower compared with Western patients irrespective of treatment with thalidomide alone or combined with dexamethasone. Even in low TE incidence areas, thalidomide combined with dexamethasone was more thrombogenic compared with others. [ABSTRACT FROM AUTHOR]

Purpose: To test the efficacy and safety of a triweekly reduced-dose docetaxel (60 mg/m) regimen combined with a standard dose of cisplatin in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Patients and methods: Patients with R/M HNSCC were enrolled. All eligible patients received intravenous docetaxel 60 mg/m combined with cisplatin 75 mg/m on day 1 and then every 3 weeks thereafter. Treatment was continued until disease progression, patient intolerance, or death. Results: In total, 58 patients were enrolled and 41 patients were evaluated. Among the evaluated population, one patient achieved a complete response (2.4%) and nine patients achieved a partial response (22%), resulting in an overall response rate of 24.4%. Furthermore, 17 patients had stable disease (41.5%), which corresponds to a disease control rate of 65.9%. With a median follow-up of 24 months (1-43 months), progression-free survival was 170 days (95% confidence interval 97.9-242.1) and the median overall survival was 265 days (95% confidence interval 89.0-441.0) in evaluable population. The most common toxicities (≥grade III) were leucopenia (66.7%) and anemia (33.3%). Conclusions: Triweekly reduced-dose docetaxel 60 mg/m combined with cisplatin is effective and feasible for Taiwanese patients with R/M HNSCC. However, the hematologic toxicity of this regimen should be carefully monitored and managed. [ABSTRACT FROM AUTHOR]

Hypoxia and acidosis are microenvironmental selection forces during somatic evolution in breast carcinogenesis. The effect of cobalt chloride (CoCl(2))-induced hypoxia on the expression of hypoxia-inducible factor (HIF)-1alpha, glucose transporter 1 (GLUT1), and carbonic anhydrase IX (CAIX) was assessed in breast cancer cells derived from primary sites (HCC1395 and HCC1937) and metastatic sites (MCF-7 and MDA-MB-231) by reverse transcriptase-polymerase chain reaction and immunoblotting. We analyzed these proteins' expression in tissue samples from normal breast tissue, usual ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) using immunohistochemistry. CAIX mRNA was expressed constitutively in MDA-MB-231 cells but not in the other three cell lines. CAIX mRNA expression was increased after CoCl(2)-induced hypoxia in all four breast cancer cell lines. The expression of HIF-1alpha and GLUT1 proteins was increased after CoCl(2)-induced hypoxia in all breast cancer cell lines tested. Hypoxia significantly increased CAIX protein expression in primary cancer cells but not in metastatic ones. HIF-1alpha was not expressed in benign breast tissue, whereas it was significantly expressed in DH, ADH, DCIS, and IDC (p < 0.001). GLUT1 and CAIX were expressed only in DCIS (56.8% and 25.0%) and IDC (44.1% and 30.5%), with higher expression in high grade DCIS than low/intermediate grade DCIS (79.2% vs. 30.0%, p = 0.001 and 37.5% vs. 10.0%, p = 0.036, respectively). High CAIX expression was significantly associated with poor histological grade of IDC (p = 0.005). During breast carcinogenesis, the role of HIF-1alpha changes from response to proliferation to tumor progression. GLUT1 expression (glycolytic phenotype) and CAIX expression (acid-resistant phenotype) may result in a powerful adaptive advantage and represent an aggressive phenotype. [ABSTRACT FROM AUTHOR]

The hepatitis B virus (HBV) reactivation rate among hepatitis B virus surface antigen (HBsAg)-positive patients undergoing chemotherapy ranges from 21 to 35% with a mortality rate of 4–41%. The risk is significantly evident in patients with aggressive lymphoma, which is highly responsive to standard chemotherapy with cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) achieving a complete response rate of 60–80% and 5-year survival rate of 30–50% with only 1% of treatment-related mortality. α-Interferon and lamivudine were given as preemptive treatment for HBV reactivation in HBsAg-positive patients treated for aggressive lymphoma consecutively from 1994 to 1997 and 1998 to 2001, respectively, in our institution. The outcome of 77 HBsAg-positive patients treated for aggressive lymphoma at our institution from 1990 to 2001 was studied. Of these patients, 53 did not receive prophylaxis while 13 received subcutaneous α-interferon 3×106 U thrice weekly and 11 received oral lamivudine 100 mg/day simultaneously with chemotherapy. Seventeen patients in the non-prophylactic group experienced HBV reactivation (32%), seven of whom progressed to fatal fulminant hepatitis (41%), which is associated with 13.2% of the mortality rate among the non-prophylactic patients. None of the 24 patients in the prophylactic group had grade III or IV toxicity or elevated ALT level greater than fivefold exceeding 200 IU/l suggestive of clinical hepatitis that required dose reduction or delayed chemotherapy. Thus, preemptive use of α-interferon or lamivudine in HBsAg-positive lymphoma patients undergoing chemotherapy may be a promising approach to prevent HBV reactivation that carries a risk of delayed treatment or even fatal outcome. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the characteristics of implantable venous port-related infections in patients with malignancies.Patients and Methods: This was a 6-year study in which all the records of cancer patients who were diagnosed with port-related infections were retrospectively analyzed.Results: The analysis included 36 episodes of port-related infections. The median period from port implantation to the episode of port-related infection was 164 days (21 to 1650 days). Of the 36 episodes, 15 (42%) were polymicrobial infections, and 21 (58%) were gram-negative pathogens. If only the port-related bacteremia was taken into consideration, gram-negative bacilli and gram-positive cocci accounted for 39 and 7 pathogens of the total 53 isolated microorganisms (74% and 13%, respectively). Stenotrophomonas maltophilia and Acinetobacter baumanii were the predominant causal microorganisms. All except two infectious catheters were removed. No infection-related mortality developed.Conclusions: Gram-negative bacilli, especially the glucose-non-fermenting pathogens, tend to be the major microorganisms that account for port-related infections, and the infections run a benign course, even those developed in septicemia. [ABSTRACT FROM AUTHOR]

Immunosuppression (IS) therapy with antilymphocyte globulin (ALG) is currently the treatment of choice for patients with aplastic anemia who do not have histocompatible sibling donors or who are not candidates for allogeneic bone marrow transplantation. Thirty-eight patients with aplastic anemia who received ALG-based therapy at a single institute in Taiwan were analyzed, and 28 were followed up for more than 6 months. Four patients (10.5%) had a complete response, and 11 (28.9%) had a partial response. The overall response rate was 39.4%. The significant prognostic factor that affected the response to IS therapy was a positive test result for antibodies to the hepatitis C virus. The rate of early mortality (death within 90 days after initiation of ALG-based therapy) was 15.8%, and most deaths were secondary to infection. Factors influencing the risk of early mortality were old age, hypotension, and bacteremia. In conclusion, ALG-based IS therapy was effective for aplastic anemia in Chinese patients. The role of hepatitis C associated with aplastic anemia and its relationship to IS need to be clarified by further investigations. [ABSTRACT FROM AUTHOR]

The expression of several growth factors and K-ras gene mutation in bile were studied to better understand the pathogenesis and improve early diagnosis of bile duct cancers. Bile samples were collected from 12 cholangiocarcinomas (CLC), 10 ampullary cancers (APC), 3 gallbladder cancers (GBC), 7 pancreatic cancers (PNC), 9 biliary tract infection (BTI), 8 biliary stone disease (ST), and 5 normal controls (NC). The highest mean value of TGF-beta in bile was in patients with BTI; the mean levels of bFGF and PDGF were highest in CLC, and patients with APC and CLC had higher expression of HER2/Neu than other groups. In bile, a K-ras gene codon 12 mutation was found in 5 of 6 (83%) cases of CLC by the PCR-RFLP method. The results suggest overexpression of bFGF, PDGF, and HER2/Neu and the presence of K-ras mutation are important for carcinogenesis of bile duct cancers, and detection of the above abnormalities in bile is helpful for early diagnosis. [ABSTRACT FROM AUTHOR]

Demonstrates that mutant thanatophoric dysplasia type II (TDII) fibroblast growth-factor receptor FGFR3 has a constitutive tyrosine kinase activity which can specifically activate the transcription factor Stat1. The role of Stat1 as signal transducer and activator of transcription; Other aspects of TDII FGFR3 expression; The possible cause for FGFR3-related bone disease.

This study was performed to examine the immunohistochemical expression of fibroblast growth factor-1 and fibroblast growth factor-2 in normal liver and a total of 31 cases of hepatocellular carcinoma (HCC). Reactivity for both types of angiogenic factor did not exist in any cellular component of normal liver. For HCC, variable amounts of fibroblast growth factor-1 were detected in 6 of 31 cases (19.4%). There was no apparent relationship between the expression pattern and clinicopathologic factors (P > 0.1, respectively), except a positive correlation with histologic grading (P = 0.04). No tumor showed reactivity for fibroblast growth factor-2 in their cancer cells. However, both types of peptide could be demonstrated in the pericellular stroma of HCC. With a mean follow-up at 60 months, fibroblast growth factor-1 expression did not correlate with patients' outcome (P > 0.1). Our study suggested that fibroblast growth factor-1 appears to play a certain role in hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]