Association of Nilotinib With Cardiovascular Diseases in Patients With Chronic Myelogenous Leukemia: A National Population-Based Cohort Study.

BACKGROUND: Tyrosine kinase inhibitor (TKI) treatment has been identified to be a risk factor for metabolic syndrome and cardiovascular diseases (CVDs) in patients diagnosed with chronic myeloid leukemia (CML). However, the specific contribution of post-TKI metabolic syndrome and the individual TKIs, including imatinib, nilotinib, and dasatinib, contribute to the development of CVDs remains unclear. METHODS: We conducted a nationwide database to investigate the incidence of post-TKI metabolic syndrome, including diabetes, hyperlipidemia, and hypertension, as well as their association with CVDs. To compare the risk of post-TKI comorbidities and CVDs among TKIs, we utilized the incidence rate ratio (IRR), and subdistribution hazard ratio (SHR) calculated from multiple Fine-Gray models. RESULTS: A total of 1211 patients without diabetes, 1235 patients without hyperlipidemia, and 1074 patients without hypertension were enrolled in the study. The incidence rate of post-TKI diabetes and hyperlipidemia was the highest in patients treated with nilotinib compared to imatinib and dasatinib (IRRs ≥ 3.15, Ps ≤ .047). After adjusting for confounders, nilotinib remained a significant risk factor for post-TKI diabetes and hyperlipidemia at an SHR of 3.83 (P < .001) and 5.15 (P < .001), respectively. Regarding the occurrence of CVDs, patients treated with nilotinib were more likely to develop CVDs than those treated with imatinib in non-hyperlipidemic group (IRR = 3.21, P = .020). Pre-existing and post-TKI hyperlipidemia were found to have a stronger association with CVDs, with SHR values of 5.81 (P = .034) and 13.21 (P = .001), respectively. CONCLUSION: The findings of this study indicate that nilotinib treatment is associated with increased risks of diabetes and hyperlipidemia, with hyperlipidemia being the most significant risk for CVDs. Therefore, we recommend that CML patients receiving nilotinib should undergo screening for diabetes and hyperlipidemia prior to initiating TKI treatment. Additionally, regular monitoring of lipid profiles during TKI therapy and implementing effective management strategies to control hyperlipidemia are crucial.

Virtual Screening and In Vitro Evaluation of PD-1 Dimer Stabilizers for Uncoupling PD-1/PD-L1 Interaction from Natural Products.

Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune response. PD-L1 is frequently overexpressed in many cancer cells, and its engagement with PD-1 on T cells diminishes the extent of cytotoxicity from the immune system. To resume immunity for fighting cancer, several therapeutic antibodies disrupting the PD-1/PD-L1 interaction have been introduced in clinical practice. However, their immunogenicity, low tissue penetrance, and high production costs rendered these antibodies beneficial to only a limited number of patients. PD-L1 dimer formation shields the interaction interface for PD-1 binding; hence, screening for small molecule compounds stabilizing the PD-L1 dimer may make immune therapy more effective and widely affordable. In the current study, 111 candidates were selected from over 180,000 natural compound structures through virtual screening, contact fingerprint analysis, and pharmacological property prediction. Twenty-two representative candidates were further evaluated in vitro. Two compounds were found capable of inhibiting the PD-1/PD-L1 interaction and promoting PD-L1 dimer formation. Further structure optimization and clinical development of these lead inhibitors will eventually lead to more effective and affordable immunotherapeutic drugs for cancer patients.

Accelerated Risk of Premature Ischemic Stroke in 5-Year Survivors of Nasopharyngeal Carcinoma.

BACKGROUND: Research on cancer survivorship associated with nasopharyngeal carcinoma (NPC) is rare. We aimed to elucidate the risk of ischemic stroke in 5-year survivors of NPC following radiotherapy (RT) or concurrent chemoradiation therapy (CCRT). SUBJECTS, MATERIALS, AND METHODS: NPC survivors, defined as those who survived longer than 5 years after diagnosis, were identified and matched at a 1:5 ratio with normal controls from the Longitudinal Health Insurance Database 2005 of Taiwan. The stratified Cox regression models were used to access the risk of ischemic stroke, with adjustment for age, treatment modality, comorbidities, and socioeconomic characteristics. RESULTS: From 2000 to 2005, a total of 3,016 NPC survivors who had received RT (n = 959) or CCRT (n = 2,057) and 15,080 controls were matched for age, sex, income, and urbanization level. The risk of ischemic stroke was significantly higher in the NPC survivor cohort than in the control cohort. Stroke was positively related to death. Moreover, the age onset of stroke for NPC survivors was 10 years earlier than that for the general population. CONCLUSION: Not only was the stroke risk in NPC survivors higher than that in the general population, but the onset age was also 10 years earlier. Future survivorship care should include ischemic stroke as a late complication, for its proper prevention and management. IMPLICATIONS FOR PRACTICE: Nasopharyngeal carcinoma (NPC) is endemic in Taiwan, and its 5-year survival is 65.2%. With the increased 5-year cancer survivors, survivorship has become an important issue. However, research on NPC survivorship is very rare. To the authors' knowledge, this is the first population-based study on long-term NPC survivors. This study's results indicated that not only was the risk of ischemic stroke in NPC survivors at least triple that of the general population, but the onset age was also 10 years earlier. These results may provide solid evidence that survivorship care guidelines should include stroke as a late complication in 5-year NPC survivors, for its proper prevention and management.

Patients with head and neck cancer may need more intensive pain management to maintain daily functioning: a multi-center study.

PURPOSE: The purpose of this study is to investigate the prevalence of pain, pain management, and impact of recent pain on daily functioning in patients with head and neck cancer (HNC) and patients with other cancers. METHODS: This multi-center survey was conducted by using Brief Pain Inventory questionnaire to evaluate pain status and its impact on daily functioning. RESULTS: A total of 3289 patients were analyzed including 708 HNC patients and 2581 patients with other cancers. The overall pain prevalence was 69.17%. A higher percentage of HNC patients had recent pain (60.59 vs. 44.01%, P < 0.001), required pain management (86.29 vs. 72.03%, P < 0.001), and used any analgesics (53.81 vs. 34.52%, P < 0.001). HNC patients with pain management had a higher prevalence of recent pain (85.83 vs. 81.14%, P = 0.044) and a slightly lower satisfaction rate (74.00 vs. 79.70%, P = 0.070). Regarding the impact of pain on daily functioning, HNC patients had a lower mean interference score for general activity such as walking, normal work, sleep, and life enjoyment. CONCLUSIONS: The HNC patients may need more intensive pain management to achieve optimal pain control and maintain daily functioning.

Transcatheter arterial chemoembolization improves the resectability of malignant breast phyllodes tumor with angiosarcoma component: a case report.

BACKGROUND: A giant phyllodes tumor of the breast is a rare fibroepithelial lesion, and its treatment is controversial. Many case reports have reported performing skin graft reconstruction after tumor excision. Chest wall resection may be required if the tumor has invaded the chest muscle layer. We speculated that transcatheter arterial chemoembolization (TACE) can improve the resectability of malignant phyllodes tumor of the breast without requiring skin grafting. The English literature contains only one case report similar to our experience. CASE PRESENTATION: We report a rare case of a 51-year-old woman who had a giant malignant phyllodes tumor with heterologous sarcomatous differentiation in her right breast. The tumor was 19.43 × 12.98 × 21.47 cm. Whole-body computed tomography (CT) and bone scan did not reveal distant metastasis. Chest magnetic resonance imaging showed chest wall tumor invasion. Considering that skin defects after mastectomy can be extensive, we administered four courses of chemoembolization in the 5 weeks before surgery (30 mg of epirubicin and embozene microspheres [400, 500, and 700 µm]/week). Each process was well tolerated, with no serious complications. Only fever and local pain at the tumor site were noted, and these symptoms resolved with time. The follow-up CT scan showed a 45% reduction in tumor volume. Therefore, simple mastectomy was performed without skin grafting reconstruction. Wound healing was satisfactory, and the patient was discharged 1 week after surgery. Pathological and immunohistochemistry (IHC) findings showed a malignant phyllodes tumor with an angiosarcoma component. Because of tumor invasion of the chest wall, we recommended the patient receive radiotherapy, but she refused. Two months after surgery, recurrence of the malignant phyllodes tumor with right axillary lymph node involvement and lung metastasis was confirmed. CONCLUSION: Initial surgical resection of giant phyllodes tumors is often challenging. For initial presentation with unresectable giant phyllodes tumor, we recommend to perform TACE prior to surgery. In our patient, preoperative TACE was effective and safe. If the tumor has invaded the chest wall, early radiotherapy after surgery may be recommended for preventing recurrence.

Antrodia cinnamomea extract inhibits the proliferation of tamoxifen-resistant breast cancer cells through apoptosis and skp2/microRNAs pathway.

BACKGROUND: Breast cancer is the most common cancer in women and affects 1.38 million women worldwide per year. Antiestrogens such as tamoxifen, a selective estrogen receptor (ER) modulator, are widely used in clinics to treat ER-positive breast tumors. However, remissions of breast cancer are often followed by resistance to tamoxifen and disease relapse. Despite the increasing understanding of the resistance mechanisms, effective regimens for treating tamoxifen-resistant breast cancer are limited. Antrodia cinnamomea is a traditional medicinal mushroom native only to Taiwan. In this study, we aimed to examine in vitro effect of antrodia cinnamomea in the tamoxifen-resistant cancer. METHODS: Antrodia cinnamomea was studied for its biological activity against proliferation of tamoxifen-resistant breast cancer by XTT assay. Next, the underlying mechanism was studied by flow cytometry, qPCR and Western's blotting assay. RESULTS: Our results revealed that the ethanol extract of antrodia cinnamomea (AC) can inhibit the growth of breast cancer cells, including MCF-7 cell and tamoxifen-resistant MCF-7 cell lines. Combination treatment with AC and 10- 6 M tamoxifen have the better inhibitory effect on the proliferation of tamoxifen-resistant MCF-7 cells than only AC did. AC can induce apoptosis in these breast cancer cells. Moreover, it can suppress the mRNA expression of skp2 (S-phase kinase-associated protein 2) by increasing the expressions of miR-21-5p, miR-26-5p, and miR-30-5p in MCF-7 and tamoxifen-resistant MCF-7 cells. CONCLUSIONS: These results suggest that the ethanol extract of antrodia cinnamomea could be a novel anticancer agent in the armamentarium of tamoxifen-resistant breast cancer management. Moreover, we hope to identify additional pure compounds that could serve as promising anti-breast cancer candidates for further clinical trials.

HIC1 and RassF1A Methylation Attenuates Tubulin Expression and Cell Stiffness in Cancer.

Cell stiffness is a potential biomarker for monitoring cellular transformation, metastasis, and drug resistance development. Environmental factors relayed into the cell may result in formation of inheritable markers (e.g., DNA methylation), which provide selectable advantages (e.g., tumor development-favoring changes in cell stiffness). We previously demonstrated that targeted methylation of two tumor suppressor genes, hypermethylated in cancer 1 (HIC1) and Ras-association domain family member 1A (RassF1A), transformed mesenchymal stem cells (MSCs). Here, transformation-associated cytoskeleton and cell stiffness changes were evaluated. Atomic force microscopy (AFM) was used to detect cell stiffness, and immunostaining was used to measure cytoskeleton expression and distribution in cultured cells as well as in vivo. HIC1 and RassF1A methylation (me_HR)-transformed MSCs developed into tumors that clonally expanded in vivo. In me_HR-transformed MSCs, cell stiffness was lost, tubulin expression decreased, and F-actin was disorganized; DNA methylation inhibitor treatment suppressed their tumor progression, but did not fully restore their F-actin organization and stiffness. Thus, me_HR-induced cell transformation was accompanied by the loss of cellular stiffness, suggesting that somatic epigenetic changes provide inheritable selection markers during tumor propagation, but inhibition of oncogenic aberrant DNA methylation cannot restore cellular stiffness fully. Therefore, cell stiffness is a candidate biomarker for cells' physiological status.

The survival impact of delayed surgery and adjuvant chemotherapy on stage II/III rectal cancer with pathological complete response after neoadjuvant chemoradiation.

Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1,914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p < 0.001). The cumulative rate of pCR rose up to 83.4% in the 9th week and slowly reached a plateau after the 11th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p = 0.52). By subgroup analysis, those younger than 70-year old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p = 0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70-year old, but further prospectively randomized controlled trials are warranted to validate these findings.

JAK2V617F influences epigenomic changes in myeloproliferative neoplasms.

Negative valine (V) to phenylalanine (F) switch at the Janus kinase (JAK2) 617 codon (V617F) is the dominant driver mutation in patients with myeloproliferative neoplasms (MPNs). JAK2V617F was proved to be sufficient for cell transformation; however, independent mutations might influence the following epigenomic modifications. To assess the JAK2V617F-induced downstream epigenomic changes without interferences, we profiled the epigenomic changes in ectopically expressed JAK2V617F in Ba/F3 cells. Antibodies against phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and enhancer of zeste homolog 2 (EZH2) were used for chromatin-immunoprecipitation sequencing (ChIP-seq) to detect the downstream epigenomic targets in the JAK2-STAT3 signaling pathway. To confirm the JAK2V617F-induced epigenetic changes in vivo, DNA methylation changes in the target loci in patients with MPNs were detected through methylation-specific polymerase chain reaction and were clustered against the changes within controls. We found that ectopically expressed JAK2V617F in Ba/F3 cells reduced the binding specificity; it was associated with cis-regulatory elements and recognized DNA motifs in both pSTAT3-downstream and EZH2-associated targets. Overlapping target loci between the control and JAK2V617F were <3% and 0.4%, respectively, as identified through pSTAT3 and EZH2 ChIP-seq. Furthermore, the methylation changes in the direct target loci (FOXH1, HOXC9, and SRF) were clustered independently from the control locus (L1TD1) and other mutation genes (HMGA2 and Lin28A) in the analyzed MPN samples. Therefore, JAK2V617F influences target binding in both pSTAT3 and EZH2. Without mutations in epigenetic regulators, JAK2V617F can induce downstream epigenomic modifications. Thus, epigenetic changes in JAK2 downstream targets might be trackable in vivo.

Methylation of the Tumor Suppressor Genes HIC1 and RassF1A Clusters Independently From the Methylation of Polycomb Target Genes in Colon Cancer.

BACKGROUND: Methylation changes within tumor suppressor (TS) genes or polycomb group target (PcG) genes alter cell fates. Chromatin associated with PcG targets is bivalent in stem cells, while TS genes are not normally bivalent. PcG target methylation changes have been identified in tumor stem cells, and abnormal methylation is found in TS genes in cancers. If the epigenetic states of genes influence DNA methylation, then methylation of PcG targets and TS genes may evolve differently during cancer development. More importantly, methylation changes may be part of a sequence in tumorigenesis. METHODS: Chromatin and methylation states of 4 PcG targets and 2 TS genes were determined in colon cancer cells. The methylation states were also detected in 100 pairs of colon cancer samples. Principle component analysis (PCA) was used to reveal whether TS methylation or PcG methylation was the main methylation change associated with colon cancers. RESULTS: Chromatin and methylation states differ in colon cancer cell lines. The methylation states within PcG targets clustered independently from the methylation states in TS genes, a finding we previously reported in liver cancers. PCA in colon cancers revealed the strongest association with methylation changes in 2 TS genes, HIC1 and RassF1A. Loss of HIC1 methylation correlated with decreased tumor migration. CONCLUSIONS: PcG and TS methylation states cluster independently from each other. The deduced principle component correlated better with TS methylation than PcG methylation in colon cancer. Abnormal methylation changes may represent a sequential biomarker profile to identify developing colon cancer.

Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms.

High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2 Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

Score of liver ultrasonography predicts treatment-related severe neutropenia and neutropenic fever in induction chemotherapy with docetaxel for locally advanced head and neck cancer patients with normal serum transamines.

Induction chemotherapy with docetaxel improved outcome in advanced head and neck squamous cell carcinoma (HNSCC) patients, but docetaxel was not recommended in liver dysfunction patients for treatment toxicities. Severe neutropenic events (SNE) including severe neutropenia (SN) and febrile neutropenia (FN) still developed in these patients with normal serum transaminases. Ultrasonography (US) fibrotic score represented degree of hepatic parenchymal damage and showed good correlation to fibrotic changes histologically. This study aims to evaluate the association of US fibrotic score with docetaxel treatment-related SNE in advanced HNSCC patients with normal serum transaminases. Between 1 January 2011 and 31 December 2013, a total of 47 advanced HNSCC patients treated with induction docetaxel were enrolled. The clinical features were collected to assess predictive factors for SNE. The patients were divided into two groups by the US fibrotic score with a cutoff value of 7. The Mann-Whitney U test and logistic regression method were used for the risk factor analysis. The background, treatment, and response were similar in both groups except for lower lymphocyte and platelet count in patients with higher US score. Twenty-seven patients (51 %) developed grade 3/4 neutropenia, and more SNE developed in patients with US score ≧7. In multivariate analysis, only US score ≥7 was independent predictive factor for developing SN (hazard ratio 7.71, p = 0.043) and FN (hazard ratio 20.95, p = 0.008). US score ≥7 is an independent risk factor for SNE in advanced HNSCC patients treated with induction docetaxel. US score could be used for risk prediction of docetaxel-related SNE.

Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis.

BACKGROUND: Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs). METHODS: A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis. RESULTS: TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21-0.35) and L858R (HR: 0.45, 95% CI: 0.35-0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60-0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47-0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69-1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95-1.39). CONCLUSIONS: In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.

Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells.

BACKGROUND AND PROPOSE: Changes in DNA methylation are associated with changes in somatic cell fate without the alteration of coding sequences. In addition to its use as a traceable biomarker, reversible DNA methylation could also serve as a therapeutic target. In particular, if the development of drug resistance is associated with changes in DNA methylation, then demethylation might reverse the resistance phenotype. The reversion of the drug-resistance might then be feasible if the association between abnormal DNA methylation and the development of drug-resistance could be identified. METHODS: Methylation differences between the drug-resistance cervical cancer cell, SiHa, and its derived oxaliplatin-resistant S3 cells were detected by methylation specific microarray. The drug-resistance cells were treated with demethylation agent to see if the resistance phenotype were reversed. Targeted methylation of one of the identified locus in normal cell is expected to recapitulate the development of resistance and a two-component reporter system is adopted to monitor the increase of DNA methylation in live cells. RESULTS: In this report, we identified methylation changes, both genome-wide and within individual loci, in the oxaliplatin-resistant cervical cancer cell S3 compared with its parental cell line SiHa. Treatment of S3 with a demethylation agent reversed increases in methylation and allowed the expression of methylation-silenced genes. Treatment with the demethylation agent also restored the sensitivity of S3 to cisplatin, taxol, and oxaliplatin to the same level as that of SiHa. Finally, we found that methylation of the target gene Casp8AP2 is sufficient to increase drug resistance in different cells. CONCLUSIONS: These results suggest that global methylation is associated with the development of drug resistance and could serve as a biomarker and therapeutic target for drug resistance in cervical cancer.

Increased risk of second primary malignancies following uterine cancer: a population-based study in Taiwan over a 30-year period.

BACKGROUND: Previous studies assessing second primary malignancies (SPMs) after uterine cancer have been conducted in Western populations with conflicting results. This study aimed to define the incidence and risk of SPMs in Taiwanese patients with an initial diagnosis of uterine cancer. METHODS: Using population-based data from the Taiwan Cancer Registry for the period 1979-2008, we quantified standardized incidence ratios (SIRs) among 11,571 women with an initial diagnosis of uterine cancer. RESULTS: Among the 11,571 women, 555 (4.80%) developed at least one SPM during 69,987 person-years of follow-up. There was a 71% increased risk of SPM following uterine cancer (SIR=1.71, 95% CI, 1.57-1.86), with higher risks in the vagina/vulva (SIR=9.06), small intestine (SIR=8.45), ovary (SIR=4.15), urinary bladder (SIR=2.31), kidney (SIR=2.24), colorectum (SIR=2.24), lung (SIR=1.96), and breast (SIR=1.43). The risk of SPM was found to be the highest within the first 5 years after diagnosis of uterine cancer, with surveillance bias possibly contributing to the extremely high risk observed in the first follow-up year. The overall risk and pattern of SPM development observed in this study differed from those previously reported in Western populations, possibly because of the methodology and shorter follow-up period employed in this study. The cumulative incidence of SPMs was significantly higher in older patients (≥50 years) than in younger patients (P<0.001). CONCLUSIONS: To our knowledge, this is the first study in an Asian population to report 71% increased risk in SPMs in women previously diagnosed with uterine cancer. A younger age at diagnosis of uterine cancer conferred an increased risk of second malignancies, and SPMs worsened survivorship in patients who survived uterine cancer.

Pegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study.

BACKGROUND: Anthracycline and taxane are classes of drugs that are frequently used in the adjuvant and palliative settings of metastatic breast cancer (MBC); however, treatment failure occurs in most cases. Limited data demonstrated favorable response in MBC after previous taxane-based treatment. The aim of this study was to evaluate the efficacy and safety of pegylated liposomal doxorubicin (Lipo-Dox®) used as part of a combination salvage therapy for patients with MBC whose tumors progressed during or after taxane-based treatment. METHODS: Patients with MBC who failed to respond to previous taxane-based treatments were recruited. Treatment with pegylated liposomal doxorubicin (40 mg/m(2)), cyclophosphamide (500 mg/m(2)), and 5-fluorouracil (500 mg/m(2)) was administered every 3 weeks. Tumor response to treatment was determined by using the Response Evaluation Criteria in Solid Tumor criteria version 1.0, and left ventricular ejection fraction was measured before and after treatment using echocardiography. Each patient was followed for 30 days after the last dose of study medication or until resolution/stabilization of any drug-related adverse event. RESULTS: Forty-five patients were recruited. As of December 2012, the median follow-up duration was 29.8 months, the overall response rate was 41.9 %, the median progression-free survival was 8.2 months, and the median overall survival was 36.6 months for all treated patients. Grade 3/4 neutropenia, leucopenia, and neutropenic fever were observed in 14 %, 9 %, and 1 % of the cycles, respectively. Other non-hematologic adverse effects were mild to moderate and were manageable. No decrease in left ventricular ejection function was noted. CONCLUSION: This regimen of combined of pegylated liposomal doxorubicin, cyclophosphamide, and 5-fluorouracil exhibited a promising overall response rate, progression-free survival rate, and overall survival rate, with a safe cardiac toxicity profile and manageable adverse effects. This regimen could be considered as a treatment option for patients with MBC whose tumors progressed during or after taxane-based treatment.

Gemcitabine plus cisplatin for patients with recurrent or metastatic nasopharyngeal carcinoma in Taiwan: a multicenter prospective Phase II trial.

OBJECTIVE: This multicenter Phase II trial evaluated the toxicity/efficacy of gemcitabine plus cisplatin as first-line chemotherapy in patients with recurrent/metastatic nasopharyngeal carcinoma. METHODS: Gemcitabine 1250 mg/m(2) on Days 1 and 8 and cisplatin 75 mg/m(2) on Day 1 were administered at a 3-week interval. The primary endpoint was the response rate. Secondary endpoints included progression-free survival, overall survival, response duration and safety. RESULTS: Fifty-two patients were recruited between 2004 and 2008. The response rate was 51.9% (complete remission rate, 9.6%) in the intent-to-treat group. The median progression-free and overall survivals were 9.8 and 14.6 months, respectively. The major Grade III/IV adverse event was leucopenia (61.6%). The mean number of cycles was 6.63 ± 0.40. The regimen was well-tolerated, although one treatment-related death occurred after severe sepsis from aspiration pneumonia. CONCLUSIONS: Gemcitabine plus cisplatin is an effective, well-tolerated regimen as a first-line treatment for recurrent/metastatic nasopharyngeal carcinoma.

Incidence and risk factors for central venous access port-related infection in Chinese cancer patients.

BACKGROUND/PURPOSE: Cytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy. METHODS: Between January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors. RESULTS: The overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both p < 0.001) and less infection-free catheter longevity (p < 0.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (p < 0.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida. CONCLUSION: Infection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line-associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings.

Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia.

Calreticulin (CALR) mutations were recently identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) devoid of JAK2 and MPL mutations. We evaluated the clinical, laboratory, and molecular features of a Taiwanese population of patients with ET. Among 147 ET patients, CALR mutations were detected in 33 (22.5 %), JAK2V617F in 94 (63.9 %), and MPL mutations in 4 (2.7 %). Sixteen (10.9 %) patients were negative for all three mutations (CALR, JAK2V617F, and MPL; triple negative). Interestingly, one patient with the type 2 CALR mutation also harbored a low allele burden (0.025 %) of JAK2V617F mutation. Furthermore, we found a novel CALR mutation, with the resultant protein sharing an identical amino acid sequence to the type 6 CALR mutant. Compared to those with JAK2 mutation, CALR-mutated ET patients were characterized by younger age, lower leukocyte count, higher platelet count, and decreased risk of thrombosis. CALR mutations had a favorable impact on thrombosis-free survival (TFS) for ET patients, whereas the respective TFS outcomes were similarly poorer in JAK2-mutated ET and PV patients. Multivariate analysis confirmed that younger age (<60 years), presence of CALR mutations, and a lower platelet count (<1,000 × 10(9)/L) were independently associated with a longer TFS in ET patients. The current study demonstrates that CALR mutations characterize a special group of ET patients with unique phenotypes that are not discrepant from those seen in Western countries.

Clinical characteristics and treatment outcome in a Taiwanese population of patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma.

OBJECTIVE: Epstein-Barr virus-positive diffuse large B-cell lymphoma is a provisional entity in the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Reports on the characteristics and clinical outcome of this disease in different geographic regions showed great disparities. METHODS: To define the clinical characteristics as well as the prognostic impact of Epstein-Barr virus infection on diffuse large B-cell lymphoma in Taiwan, we retrospectively investigated the Epstein-Barr virus status of 89 patients with newly diagnosed diffuse large B-cell lymphoma in our institute. RESULTS: Using a cutoff point of positive nuclear staining of Epstein-Barr virus-encoded RNA-1-in situ hybridization in ≥20% of the examined cells, we identified 15 cases (16.9%) of the entire study cohort as Epstein-Barr virus-positive diffuse large B-cell lymphoma. The clinical and laboratory features were not different between Epstein-Barr virus-positive and -negative diffuse large B-cell lymphoma patients. Univariate analysis showed patients with diffuse large B-cell lymphoma that were either Epstein-Barr virus-positive or had activated B-cell-like features had an inferior overall survival. Older age, advanced stage and lymphoma with activated B-cell-like features or Epstein-Barr virus-encoded RNA positivity were independent prognostic factors affecting overall survival on multivariate analysis. Patients with two or three of these adverse-risk factors were considered high risk and fared far worse than patients with no or only one adverse factor. CONCLUSIONS: Taken together, we demonstrated that a higher frequency of Epstein-Barr virus association was detected in a Taiwanese cohort of diffuse large B-cell lymphoma patients, and Epstein-Barr virus-encoded RNA positivity was shown to add important prognostic value in these patients.